Further evidence supports controversial claim that SARS-CoV-2 genes can integrate with human DNA

After being challenged, research team provides more data to back its controversial hypothesis but the relevance to human health is unclear

Science‘s COVID-19 reporting is supported by the Heising-Simons Foundation.

A team of prominent scientists has doubled down on its controversial hypothesis that genetic bits of the pandemic coronavirus can integrate into our chromosomes and stick around long after the infection is over. If they are right—skeptics have argued that their results are likely lab artifacts—the insertions could explain the rare finding that people can recover from COVID-19 but then test positive for SARS-CoV-2 again months later.

Stem cell biologist Rudolf Jaenisch and gene regulation specialist Richard Young of the Massachusetts Institute of Technology, who led the work, triggered a Twitter storm in December 2020, when their team first presented the idea in a preprint on bioRxiv. The researchers emphasized that viral integration did not mean people who recovered from COVID-19 remain infectious. But critics charged them with stoking unfounded fears that COVID-19 vaccines based on messenger RNA (mRNA) might somehow alter human DNA. (Janesich and Young stress that their results, both original and new, in no way imply that those vaccines integrate their sequences into our DNA.)

Researchers also presented a brace of scientific criticisms, some of which the team addresses in a paper released online today by the Proceedings of the National Academy of Sciences (PNAS). “We now have unambiguous evidence that coronavirus sequences can integrate into the genome,” Jaenisch says.

SARS-CoV-2, the virus that causes COVID-19, has genes composed of RNA, and Jaenisch, Young, and co-authors contend that on rare occasions an enzyme in human cells may copy the viral sequences into DNA and slip them into our chromosomes. The enzyme, reverse transcriptase, is encoded by LINE-1 elements, sequences that litter 17% of the human genome and represent artifacts of ancient infections by retroviruses. In their original preprint, the researchers presented test tube evidence that when human cells spiked with extra LINE-1 elements were infected with the coronavirus, DNA versions of SARS-CoV-2’s sequences nestled into the cells’ chromosomes.

Many researchers who specialize in LINE-1 elements and other “retrotransposons” thought the data were too thin to support the claim. “If I would have had this data, I would have not submitted to any publication at that point,” says Cornell University’s Cedric Feschotte, who studies endogenous retrovirus chunks in the human genome. He and others also said they expected higher quality work coming from scientists of the caliber of Jaenisch and Young. In two subsequent studies, both posted on bioRxiv, critics presented evidence that the supposed chimeras of human and viral DNA traces are routinely created by the very technique the group used to scan for them in chromosomes. As one report concluded, the human-virus sequences “are more likely to be a methodological product, [sic] than the result of genuine reverse transcription, integration and expression.”

In their new paper, Jaenisch, Young, and colleagues acknowledge that the technique they used accidentally creates human-viral chimeras. “I think it’s a valid point,” Jaenisch says. He adds that when they first submitted the paper to a journal, they knew it needed stronger data, which they hoped to add during the review process. But the journal, like many, requires authors to immediately post all COVID-19 results to a preprint server. “I probably should have said screw you, I won’t put it on bioRxiv. It was a misjudgment,” Jaenisch says.

In the new PNAS paper, the team provides evidence that artifacts alone can’t explain the detected levels of virus-human chimeric DNA. The scientists also show that portions of LINE-1 elements flank the integrated viral genetic sequence, further supporting their hypothesis. And they have collaborated with one of the original skeptics, Stephen Hughes of the National Cancer Institute, who suggested an experiment to clarify whether the integration was real or noise, based on the orientation of the integrated viral sequences relative to the human ones. The results support the original hypothesis, says Hughes, a co-author of the new paper. “That analysis has turned out to be important,” he says.

“The integration data in cell culture is much more convincing than what was presented in the preprint, but it’s still not totally clean,” says Feschotte, who now calls Jaenisch’s and Young’s hypothesis “plausible.” (SARS-CoV-2, he notes, can also persist in a person for months without integrating its genes.)

The real question is whether the cell culture data have any relevance to human health or diagnostics. “In the absence of evidence of integration in patients, the most I can take away from these data is that it is possible to detect SARS-CoV-2 RNA retroposition events in infected cell lines where L1 is overexpressed,” Feschotte says. “The clinical or biological significance of these observations, if any, is a matter of pure speculation at this point.”

Jaenisch’s and Young’s team do report hints of SARS-CoV-2 integration in tissue from living and autopsied COVID-19 patients. Specifically, the researchers found high levels of a type of RNA that is only produced by integrated viral DNA as the cell reads its sequence to make proteins. But, Young acknowledges, “We do not have direct evidence for that yet.”

Harmit Malik, a specialist in ancient viruses in the human genome at the Fred Hutchinson Cancer Research Center, says it’s a “legitimate question” to ask why people who should have cleared the virus sometimes have positive polymerase chain Reaction tests for its sequences. But he also remains unconvinced that the explanation is integrated virus. “Under normal circumstances, there is so little reverse transcription machinery available” in human cells, Malik says.

The controversy has grown decidedly more civil since December. Both Young and Jaenisch say they received more intense criticism for their preprint than any studies in their careers, in part because some researchers worried it played into the hands of vaccine skeptics spreading false claims about the newly authorized mRNA vaccines. “If there ever was a preprint that should be deleted, it is this one! It was irresponsible to even put it up as a preprint, considering the complete lack of relevant evidence. This is now being used by some to spread doubts about the new vaccines,” Marie-Louise Hammarskjöld, a microbiologist at the University of Virginia, posted in a comment on bioRxiv at the time.

And what of the original journal submission? “They rejected it,” Jaenisch says. source

The Rosenhan experiment was conducted by a psychologist named David Rosenhan, and it’s been considered to be one of the most striking studies in the field since then.

Rosenhan experiment

In 1973 a bombshell study appeared in the premier scientific journal Science. It was called “On Being Sane in Insane Places.” Its author, a Stanford psychology professor named David Rosenhan, claimed that by faking their way into psychiatric hospitals, he and eight other pseudo-patients had proven that psychiatrists were unable to diagnose mental illness accurately.

Psychiatrists panicked, and, as a result, re-wrote what’s known as “psychiatry’s bible”—the Diagnostic and Statistical Manual of Mental Disorders, or DSM. The study and the subsequent overhaul of the DSM changed the field forever. So it was a surprise when, decades later, a journalist reopened Rosenhan’s files and discovered that the study was full of inconsistencies and even blatant fraud. So should we throw out everything it revealed? Or can something based on a lie still contain any truths?

On being sane in insane places – Rosenhan, D.L. (1973)

Americans check their smartphones approximately an average of 205 times a day. It seems that almost everyone is dependent on their smartphone. According to one survey, 76% of U.S. adults get nervous if they can’t find theirs, and 44% say they couldn’t go one day without it.

Smartphone dependency and smartphone addiction are taking a toll on relationships everywhere, and some would even pick their device over the relationship if forced to choose between the two. A recent study found that one-third of individuals would rather give up sex than their smartphones.

This dependency is so widespread, partly because very few people have the choice to “opt out” of internet life and all the accompanying devices. Our work, social, and family lives depend upon email, texts, and internet access, and we are expected to be able to connect to these things at all times through our smartphones. This means we carry our addiction triggers with us everywhere we go—we have to.

In some ways, smartphones can enhance relationships. The ease of staying in touch with a partner through texts, calls, and FaceTime can strengthen relationship bonds by maintaining intimacy through busy days and long distances. On the other hand, people have difficulty truly connecting face to face when one or both partners are distracted by the constant urge to check their phone.

People today use their smartphones all the time, everywhere. The survey found they’re spending an average of five hours and 16 minutes per day staring into a screen.

Naturally, this degree of smartphone obsession gets in the way of intimacy.

Seven Ways That Smartphone Addiction is Getting in the Way of Your Relationship

1. Phubbing

This mashup term derived from “phone-snubbing,” refers to times when you become distracted by your phone, and your partner feels snubbed or rejected. It has become one of the major sources of relationship conflict in recent years.

2. Miscommunication

When you are constantly distracted by your phone, you’re more likely to miss what your partner is saying. This will not only show thoughtlessness towards your partner, it can lead to misunderstandings and miscommunications that can cause all kinds of problems—from failing to show up to an event your partner thought you’d agreed to come to, to failing to recognize when your partner is trying to tell you something important, and responding inappropriately or not at all.

3. Time and energy drain

Smartphone overuse can be a major drain on time and energy that you could be spending on your partner. It can result in a pattern of consistent neglect that drives a wedge between you.

4. Less sex, and/or worse sex

Many people report not wanting to stop what they’re doing on their smartphone to have sex with their partners, and one in five people actually checks their phone during sex.

5. More insecurity and less satisfaction

Individuals with smartphone-dependent or addicted partners could be less happy in their relationships. The higher the level of smartphone dependency within a couple, the higher the level of relationship uncertainty, and the lower the level of relationship satisfaction.

6. Self-centeredness

Spending a lot of time on social media can encourage self-absorption and narcissism. Getting caught up in displaying yourself in a certain way online, chasing acknowledgement from others, competing to get more followers, or to win online arguments, etc., can lead to an unhealthy level of self-centeredness.

7. Distance from your partner

Constant smartphone usage and distraction isolate people from their partners, making them feel like they have to compete with technology for attention, or that they can’t compete, so why even stay in the relationship?

It isn’t smartphone use itself that negatively impacts relationships, but rather the psychological reliance that people have on these devices. In other words, regularly using your smartphone won’t get in the way of your love life, but smartphone dependency and smartphone addiction will.

Signs of Smartphone Addiction

Just like alcohol or drugs, smartphones can stimulate the release of dopamine, a neurotransmitter associated with pleasure, emotions, motivation, and movement. Dopamine makes us feel good, and our brains reward us with it to reinforce life-sustaining activities such as eating food and taking care of ourselves.

Some activities release extra amounts of dopamine through over-stimulation (like the constantly changing forms of distraction accessible through a smartphone), causing the user to develop a tolerance that drives them to increase the amount of time spent on the activity just to experience the same degree of pleasure.

Tolerance is a sign of smartphone addiction, as is compulsively checking your phone, and experiencing withdrawal symptoms when you attempt to cut down or quit. These symptoms may also appear when you are simply without wi-fi, or in an area without cell service.

Withdrawal symptoms include: panic, anxiety, restlessness, hostility, irritability, anger, depression, difficulty concentrating, and intense cravings for device usage.

Other signs of smartphone addiction include:

• Using your phone in situations where you know you shouldn’t, such as while driving, attending an important event, or having sex
• Spending so much time on your phone that you neglect relationships, family responsibilities, work, school, or any other activity or hobby that is important to you
• Prioritizing online relationships and social media feedback over face-to-face interactions
• Hiding and lying about smartphone use
• Getting cranky when your smartphone time is interrupted
• Getting hostile when someone brings up how much time or energy you devote to your smartphone
• Feeling panicky at the idea of missing out on news, texts, social media happenings or anything else your phone can connect you to
• Getting up at night to check your phone
• Feeling phantom phone vibrations—imagining that you are getting a notification, text, email or call when you actually aren’t

The Cost of Smartphone Addiction

Many people use their phones to cope with or escape from deeper problems such as loneliness, depression, anxiety, or stress, but smartphone addiction can also exacerbate or even cause such emotional problems.

For example, you may tweet something funny, hoping to get enough responses, likes, and retweets to make you feel better about yourself, then wind up feeling worse if your tweet is ignored, or causes a negative backlash. You may also use your phone to hide during events due to social anxiety, but hiding behind your phone will only cut you off from others and cause you to miss out on opportunities to practice social skills, so that you feel even less capable and more anxious in future social situations.

Studies have also shown that just having smartphones around can increase anxiety. Your phone can keep you from concentrating at work. At home, it can cause work pressures to bleed into your personal life.

Smartphones can also interfere with your ability to concentrate. The ever-changing types of stimulation that phones provide can prevent deep thoughts or creative ideas, and get you acclimated to shifting to something new every few minutes. It can also diminish your problem-solving ability by never allowing you a quiet moment to really work through an issue.

Nine Strategies to Reduce Smartphone Dependency and Smartphone Addiction

Whether you are fully addicted to your smartphone or merely dependent upon it, your quality of life will improve if you find ways to cut down on the time you spend glued to your device.

1. Minimize unnecessary smartphone usage

Try to figure out how much of your smartphone use is necessary—for work, for communicating with loved ones, for keeping up with caregiving duties, or for using apps to help with driving or checking movie times—and how much of it is unnecessary habit, like checking Facebook or reposting on Tumblr. Remember that in the early days of your recovery from smartphone addiction, all smartphone habits will FEEL necessary to you emotionally. This attachment will improve over time.

2. Allocate data-free time during the day

Designate a certain amount of data-free time every day. Silence your phone (no fair using vibrate), or turn it all the way off, between certain hours of the day at work or school, or whenever you’re working out or on a date. Putting it somewhere out of sight will help put it out of your mind—or at least cut down on how distracted you’ll be from the activity at hand.

3. Silence your phone when driving

Smartphone addicts should especially silence their phones while driving. The distraction of hearing a notification or the temptation to check email could have dangerous, even deadly consequences.

4. Find other interests for your free time

Develop new interests or hobbies to fill up the time you used to spend on your device.

5. Use an old-fashioned alarm clock

Avoid using your phone as an alarm—it’s too easy to shift from turning it off to checking email and browsing Instagram.

6. Remove excess apps

You’re much better off deleting apps that connect you to Twitter, Facebook, Tumblr, and other social media distractions from your phone. Having to set aside time to go to your computer to participate instead of being constantly connected to it 24/7 will free up your time, and prove that you aren’t missing out on as much as you fear you are.

7. Minimize app notifications

If you can’t bring yourself to ditch the apps yet, at least turn off the notifications, and if you can’t bring yourself to turn them all off, at least limit notifications to the most important apps, like the one connected to your child’s school. Today, you can also find apps specifically designed to block your access to other, more distracting apps during peak times of productivity, so you can focus better.

You also might want to consider setting special ringtones or vibrations for the most important people in your life, so you can know if it’s your best friend calling about your dinner plans without having to check, which may tempt you into other activities on your phone.

8. Stop checking your email before work

If there is an emergency, you will get a phone call. Otherwise, any message sent by email can safely wait for another hour or two. Also, consider shutting off your email entirely over the weekend. People might send you work emails on Saturday or Sunday, but you are not obligated to respond to them. In most cases, the sender doesn’t even expect you to—they were simply checking something off their to-do list when they had the time to do it.

9. Leave your phone out of the bedroom

This last strategy will not only help you sleep better by reducing distractions and eliminating the screen light that can contribute to insomnia, but it will also improve intimacy with your partner, even on nights when you don’t have sex.

Smartphone addiction doesn’t have to get in the way of a healthy, fulfilling relationship. By following the tips above, you can reclaim your connection with your partner and discover new and exciting ways to bond that don’t involve a screen. If you or someone you love is struggling with smartphone addiction and needs professional treatment to overcome it, rehab programs are avaiable. source

Eagles, as birds of prey, will sometimes kill crows as part of their natural diet. Crows, however, are known to harass and even attack eagles, particularly when defending their territory or nests. In these encounters, the eagle often responds by flying higher, taking advantage of the crow’s inability to breathe at higher altitudes, causing the crow to fall to its death. 

The crow falls to its own death, hurt by nothing more than its own actions turning inward.

Why Would A Crow Ride an Eagle?

It’s a bird, it’s a plane, it’s a….crow on the back of a Bald Eagle? The strange aerial encounter, caught on camera by bird photographer Phoo Chan about a year ago, is making the rounds online today, to the delight of many.

So what exactly is going on here? Was the crow just tired of flying, or was it intentionally trying to annoy its adversary?

It’s hard to tell, says Audubon field editor Kenn Kaufman. While it is not uncommon for smaller birds to harass larger birds that threaten their nesting territories, physically riding on their backs is an unusual tactic—and definitely an unusual sight.

Crows, along with other kinds of smaller birds such as Red-winged Blackbirds, Common Grackles and kingbirds, will not hesitate to defend their nests against eagles, hawks, vultures and Great Blue Herons if duty calls, especially during the nesting season, says Kaufman.

Typically when something like this happens “the eagle or other large bird being harassed will react in an aggressive way,” Kaufman says. Or, the larger bird will ignore its tormentor, “just as we might ignore a small dog yipping at our heels,” adds Kaufman—which very well may be what was happening in this photomontage.

Whether an innocent play-date or a moment of vindication, it is hard to deny Chan’s luck in capturing the remarkable occurrence on camera. The California-based photographer has plenty of experience capturing flying birds, so he must have been well-prepared.

The only bird that dares to peck an eagle is the crow. It sits on its back and bites the eagle’s neck. However, the eagle does not respond nor fight with the crow, it spends no time on the crow
instead the eagle opens its wing and soar higher to the heavens. The higher the flight the tougher it is for the crow to breathe then the crow fails down from the lack of energy. It simply means that once a person moves towards his/her goals, He/she is faced with obstacles and challenges but when they keep pushing yourself forward every other unnecessary thing will fall off by itself. So, keep soaring higher and overcome every obstacle with ease and not be distracted from your purpose. It simply means that once a person moves towards his/her goals, He/she is faced with obstacles and challenges but when they keep pushing yourself forward every other unnecessary thing will fall off by itself. So, keep soaring higher and overcome every obstacle with ease and not be distracted from your purpose.

“The only bird that dares to peck the eagle is the crow. It sits on its back and bites its neck. However, the eagle doesn’t respond, nor does it fight with the crow; it doesn’t waste any time or effort on it, it just opens its wings and begins to climb up the highest place in the sky. The higher the flight, the harder it is for the crow to breathe, and then the crow falls due to lack of oxygen.

Stop wasting time with crows, with dangerous people who only approach your life to try to destabilize you, to project their own storm on you. Just take them to your heights, and they will disappear on their own”.

He cannot breath anymore so he passes out

Now the crow will be the victim of circumstance

The crow has been defeated

source

and always remmeber

The only bird that will peck at an Eagle is the crow. He sits on his back and bites his neck. The eagle does not respond or fight with the crow, it doesn’t waste time or energy on the crow. It simply opens its wings and begins to rise higher in the sky. The higher the flight the harder it is for the crow to breathe and then the crow falls due to lack of oxygen. Stop wasting your time with the crows. Just take them to your heights and they’ll fade.

I know of a man named Paul that is the crow.

How Alcoholism Ruins Up Your Brain

Alcohol Consumption Leads to Brain Shrinkage

Brain Shrinkage from Alcohol

excessive alcohol consumption leads to brain shrinkage. Studies have shown that heavy drinking is associated with reduced brain volume, and even moderate drinking may have some negative effects on brain structure and cognitive function.

IF YOU SUFFER FROM ALCOHOLISM GET HELP. THERE IS GOD, DISCIPLINE AND PROGRAMS TO HELP YOU! YOU DESERVE A BETTER LIFE! MANY SUFFER LIKE YOU! YOU CAN CHANGE YOU WITH THE HELP OF GOD AND DISCIPLINE AND PROGRAMS THAT OFFER HELP

How Alcoholism Ruins Up Your Brain

A brief overview

I usually focus these posts on the spirituality of the 12 Steps as a path  of recovery from alcoholism and codependency, but today I’ve decided to look at a little medical research on this disease. You already know that chronic alcohol abuse causes brain damage – some of it permanent. Whether your brain can rebuild itself with prolonged abstinence depends upon the severity of the damage as well as correlated factors such as genetics, nutrition, and your life habits in sobriety.

Alcoholism Shrinks Your Brain
This is an indisputable fact. Prolonged abuse of alcohol shrinks all areas of the brain, causing the condition known as “wet brain.” All wet brain really means is that, as the brain tissue shrinks, the vacated areas, known as ventricles, fill with fluid to compensate. It doesn’t mean you become a drooling idiot. (My father developed it late in life and remained quite sharp.) Rather, the condition simply indicates that all functions of your brain have been compromised, so that you’re less aware, less physically able, less emotionally engaged, and less intelligent overall than you would be with a healthy, non-alcoholic brain.

But, hey, no big! The buzz is worth it, right?
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Why Does Alcoholism Shrink Your Brain?
Here we encounter competing theories. To quote an article from the National Institute on Alcohol Abuse and Alcoholism (what a bunch of party-poopers!):

According to one hypothesis, shrinkage (i.e., atrophy) of the cerebral cortex and white matter, as well as possible atrophy of basal forebrain regions, may result from the neurotoxic effects of alcohol… Alcoholics who are susceptible to alcohol toxicity may develop permanent or transient cognitive deficits associated with brain shrinkage.[i]

What is “neurotoxicity”? It’s medi-speak for toasts your brain cells. They don’t necessarily die, but the dendrites connecting them are damaged or lost, so the cells occupy less area.   But hey – at least they’re still kind of there, right?

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As you can see, when it comes to brains, plump is better. The graph on the right may seem a little confusing if you’ve gotten bombed enough times – or, heck, even if you haven’t. The straight line represents a normal brain. The blue line shows shrinkage of regions in a young alcoholic brain, and the yellow line shrinkage in an older alcoholic brain. (By the way, who the hell drinks only 20 gallons of alcohol in their whole life? Seriously? Even 625 gallons wouldn’t be nearly enough for my addict!)

Parts of the Brain Most Vulnerable
Everybody knows that when you’re fucked up, you temporarily lose coordination, short-term memory, and sound judgment. But who cares? Not much of a price to pay for not hating yourself for a bit, right? Of course, getting hammered also fries your behavioral inhibitions, emotional intelligence, and the ability to accurately read social cues – none of which can even compare, obviously, with the tremendous relief of no longer feeling terrified to converse with other human beings because you’re suddenly irresistibly hot and charming.

That said, it only makes sense that prolonged exposure to alcohol would eventually damage the parts of the brain responsible for those very functions.

Neuroimaging studies of living brains point to increased susceptibility of frontal brain systems to alcoholism-related damage… The frontal lobes, connected with all other lobes of the brain, receive and send fibers to numerous subcortical structures. The prefrontal cortex is considered the brain’s executive—that is, it is necessary for planning and regulating behavior, inhibiting the occurrence of unnecessary or unwanted behaviors, and supporting adaptive “executive control” skills such as goal-directed behaviors, good judgment, and problem-solving abilities.

In other words, the motherboard of your brain starts to malfunction.   As alcoholism progresses, this can lead to the chain of bad choices that screw up an alcoholic’s entire life. Because it only makes sense that as self-restraint abates and good judgment declines, egotism and selfishness jump in to take up the slack.

 Disruptions of the normal inhibitory functions of prefrontal networks often have the interesting effect of releasing previously inhibited behaviors. As a result, a person may behave impulsively and inappropriately – which may contribute to excessive drinking.

In other words, the more you injure your brain by drinking, the more likely you are to say, “aw… fuck it!” and drink more. Other excellent ideas include hooking up with other sick people, engaging in unethical/destructive behaviors, and royally screwing over the people you love.

Because actually, you only kind of love them. To be honest, loving them is only a vague memory. Why is that?

Alcoholics may seem emotionally “flat” – i.e., they are less reactive to emotionally charged situations… Impairments in emotional functioning that affect alcoholics may reflect abnormalities in [the right hemisphere or] other brain regions which… influence emotional processing, such as the limbic system and the frontal lobes.

How many alcoholics know that feeling of not being able to feel?  When my grandmother died, when my husband walked away, when my partner shut the door on my begging – I knew I ought to feel something, but I didn’t. Not much more than, “Hmm… that sure sucks!” Who knew my limbic system was screwed up? Really, by the end I could feel only one thing: when I was pouring the drink, when I was chopping the lines, when it seemed I was winning the conquest, I felt, “YES!”

Alcohol directly stimulates release of the neurotransmitter serotonin, which is important in emotional expression, and of the endorphins, natural substances related to opioids, which may contribute to the “high” of intoxication and the craving to drink. Alcohol also leads to increases in the release of dopamine (DA), a neurotransmitter that plays a role in motivation and in the rewarding effects of alcohol.

The trouble is, the brain recognizes this overload of pleasure transmitters and tapers its production of each as a result. In other words, you feel like shit without a drink; in fact, severe neurotransmitter imbalances my cause you to develop “seizures, sedation, depression, agitation, and other mood and behavior disorders.”

The brain, of course, isn’t the only organ on the team to get fucked by alcohol. Every organ in the body suffers, but hardest hit is your liver. We all know the liver’s ability to remove toxins from the bloodstream gets compromised as alcohol overtaxes it. But did you know this?

These damaged liver cells no longer function as well as they should and allow too much of these toxic substances, ammonia and manganese in particular, to travel to the brain. These substances proceed to damage brain cells, causing a serious and potentially fatal brain disorder known as hepatic encephalopathy, which can result in mood and personality changes, anxiety, depression, shortened attention span, and coordination problems, including… hand shaking…

I think I might’ve had a spot of that…

Well, that’s about the end of my rollicking review of alcoholic brain damage. Missing from this account, of course, is the self-destructive spiritual illness that makes us not give a shit whether we’re killing ourselves, because life’s worthless anyway.

The good news is that studies also show all these physical processes can be reversed by long-term abstinence, while the spiritual malady – thank god! – can be cured via the 12 steps.  A healthy body is really just the means to an end – usefulness and the joy of living, which we’ve been granted in sobriety. source

IF YOU SUFFER FROM ALCOHOLISM GET HELP. THERE IS GOD, DISCIPLINE AND PROGRAMS TO HELP YOU! YOU DESERVE A BETTER LIFE! MANY SUFFER LIKE YOU! YOU CAN CHANGE YOU WITH THE HELP OF GOD AND DISCIPLINE AND PROGRAMS THAT OFFER HELP

Association between abnormal plasma metabolism and brain atrophy in alcohol-dependent patients

Introduction

Excessive and chronic alcohol consumption, caused by addictive behaviors in alcoholic patients, is closely related to the reduced viability of neuronal cells (neurons and glial cells) and axonal degradation, thus resulting in brain atrophy (Sutherland et al., 2014; Angebrandt et al., 2022). It has been reported that the degree of brain atrophy correlates with the rate and amount of alcohol consumed over a lifetime (de la Monte and Kril, 2014). Moreover, the latest research has detected negative relationships between alcohol consumption and gray and white matter volumes across the brain (Daviet et al., 2022). Abnormal patterns of macroscopic and microstructural changes in the brain, especially brain atrophy, are closely related to the cognitive dysfunction of alcoholics in the clinical setting (Zahr et al., 2011). Cognitive impairment, including deficits in memory, executive abilities, visuospatial processing, speed of processing and, to a lesser extent, attention and general intelligence, may dramatically influence a patient’s social function and quality-of-life (Godin et al., 2019). In view of the high prevalence of alcohol-related brain atrophy (ARBA) and its associated cognitive dysfunction, a comprehensive analysis of the mechanisms underlying ARBA and the identification of potential biomarkers for this disease are urgently needed.

Metabolomics, a systematic method for the qualitative and quantitative analysis of all low-molecular-weight metabolites, is suitable for identifying metabolic indicators and can provide a basis for individualized diagnosis and treatment (Ribbenstedt et al., 2018). Moreover, the discovery of new markers can provide new ideas for the diagnosis and treatment of difficult diseases and can provide a useful guide for clinical diagnosis and treatment (Vuckovic, 2018). Metabolomic research based on untargeted/targeted mass spectrometry (MS) and proton nuclear magnetic resonance (1H-NMR) spectroscopy approaches may represent a valuable research tool to identify the underlying pathogenesis of alcohol-related disorders. Mittal and Dabur previously studied the influence of an aqueous extract of Tinospora cordifolia on the urinary metabolic signature of chronic alcohol using liquid chromatography–tandem mass spectrometry (LC–MS/MS; Mittal and Dabur, 2015). In another study, Zhu et al. identified discriminatory metabolic profiles between healthy and alcohol dependent individuals by using metabolomics technology (Zhu et al., 2021). To our knowledge, no previous study has identified alterations in the metabolic and protein profiles of plasma samples taken from alcohol-dependent patients with brain atrophy.

Machine learning, as a field of artificial intelligence (AI), provides intelligent data processing while facilitating reasoning and the initial settings to determine functional relationships (Deo, 2015). Due to the diversification of algorithms, machine learning is gradually emerging in the field of multi-omics, including artificial neural networks (ANNs), and random forest (RF) algorithms (Liebal et al., 2020). The main applications of machine learning in disease-related multi-omics data analysis include (1) the stratification of patients to discover various subtypes of human diseases and to discover different treatment/prognostic outcomes, and (2) the investigation of various diseases by identifying biomarkers of omics features under various state (Nicora et al., 2020). Traditional methods for processing metabolomics data tend to only focus on bridging sample differences within groups. However, in applied pharmaceutical research (such as candidate target discovery and drug sensitivity), we also need to consider data perturbation and sensitivity to sample size (Schrimpe-Rutledge et al., 2016). Based on their specific characteristics, a combination of traditional single evaluation and machine learning algorithms could provide an efficient means of evaluating the performance of metabolomics data processing from multiple perspectives (Mirza et al., 2019; Picard et al., 2021). Specifically, this strategy can achieve effective data processing from five relatively independent directions: reducing within-group sample differences, differential metabolic analysis, the stability of marker identification, classification accuracy, and the consistency of biological gold standards.

In this study, we used a LC–MS/MS-based metabonomics approach to provide a robust technical platform to investigate the profiles of plasma metabolites in ARBA patients and identify characteristic metabolites that can be used to discriminate ARBA from non-ARBA. MetaboAnalyst version 5.0 was then used to identify metabolites and metabolic pathways showing significant enrichment in ARBA. Then, machine learning algorithms were used to identify the most important distinctive metabolites that might be associated with patients with ARBA. The findings of the present study may help to identify the molecular mechanisms that underlie ARBA.

Materials and methods

Study design and participants

This study was approved by the Ethics Committee of the Hunan Brain Hospital (Reference: 2016121). Signed and informed consent was obtained from each patient.

A total of 126 patients with alcohol addiction were enrolled from Hunan Brain Hospital between March 2019 and January 2020. Brain MRI were performed in all patients to evaluate the extent of brain atrophy.

The inclusion and exclusion criteria were described in our previous publication (Liu et al., 2020). Briefly, the inclusion criteria were as follows: (1) age 18–60 years, Han Chinese; (2) no contraindications for MRI. The exclusion criteria were as follows: (1) patients had any general medical conditions or neurological disorders, including infectious, hepatic, or endocrine disease; (2) patients with a history of severe head injury with skull fracture or loss of consciousness of more than 10 min; (3) patients had any current or previous psychiatric disorder; (4) patients had a family history of psychiatric disorder. The diagnosis of alcohol dependence was made according to the Structured Clinical Interview (SCID) based on the Diagnostic and Statistical Manual of Mental Disorders DSM-IV criteria (Battle, 2013). Alcohol-dependent patients were divided into two subgroups based on whether they have brain atrophy (the experimental group) or not (the control group).

Evaluation of brain atrophy

Brain MRI were performed in all patients after blood samples collection. The extent of brain atrophy was evaluated by at least two independent neuroradiologists using the global cortical atrophy scale (Pasquier et al., 1996). Both cortical regions (frontal, temporal, parietal and occipital) and subcortical regions (peri-insular, basal, and vault) were assessed. The severity of atrophy (low, moderate, or severe) was detected by the widening of sulci and narrow of gyri, as well as the reduction in amplitude of the respective regions. Figure 1 shows examples of different severity of brain atrophy.

FIGURE 1

Figure 1. Axial T1 weight (up) and T2 weight (down) magnetic resonance images showing different extent of brain atrophy in Alcohol-dependent patients. From left to right, columns represent absent, low, moderate and sever brain atrophy. In low brain atrophy, sulcal opening peripherally (yellow arrows) is observed. In moderate brain atrophy, widening along the length of the sulcus (green arrows) are observed. In severe brain atrophy, gyral thining (red arrows) is observed.

Sample collection and preparation

Blood samples were taken from all inpatients after hospital admission but prior to starting treatment. Blood samples were taken from the experimental and control patients between 6:00 and 6:30 am and placed into plasma collecting tubes. Samples were then centrifuged at 3,000 rpm for 10 min at 4°C and the plasma was aliquoted into 1.5 ml microcentrifuge tubes and immediately stored at −80°C.

For LC–MS, we removed 100 μl of each plasma sample and added 0.4 ml of pre-cooled 0.2% methanol-acetonitrile mixture (1:1, v/v); this was followed by vortex-mixing and ultrasonic extraction on iced water. Next, the solution was centrifuged at 13,000 × g for 15 min at 4°C; 400 μl of the supernatant was taken and dried with nitrogen. Finally, 100 μl of acetonitrile water (1:1, v/v) was added and the re-dissolved solution was injected into a sample bottle for detection. Quality control samples (a mixture of equal quantities of all sample extractions) were injected after every 10 analytical samples to monitor the stability of the LC–MS system.

LC–MS data acquisition and processing

Data acquisition was performed by UPLC-Q-TOF-MS/MS with the following parameter settings: an ethylene bridged hybrid C18 column (2.1 mm × 100 mm id, 1.7 μm; Waters), mobile phase A (water with 0.1% formic acid), and mobile phase B (acetonitrile with 0.1% formic acid). The gradient of the mobile phase was consistent with our previous metabolomic studies (Zhang et al., 2020). The MS signal was acquired in positive-ion and negative-ion modes.

Raw files for the acquired LC–MS/MS data were imported into the metabolomics-processing software Progenesis QI (Waters) to obtain matched and aligned peak data. Subsequently, peak data containing retention time (RT), molecular formula, along with accurate relative molecular mass and peak area information, were imported into Microsoft Excel so that we could normalize the peak area for further analysis.

Analyses of metabolomics data and pathways

Following normalization of the peak area, data were subjected to principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA). The variables showing the most significant differences were identified by selecting those with a VIP > 1 from an S-plot and p < 0.05 from an independent samples t-test. Based on the Human Metabolome Database (HMDB) and secondary fragment ions, we were then able to identify differential variables. Then, we performed metabolic pathway analysis for differentially expressed metabolites with MetaboAnalyst version 5.0 to gain insight into the pathogenesis of ARBA, as described previously (Zhang et al., 2020).

Machine learning methods for biomarker screening

Three machine learning methods (Extreme Gradient Boosting (XGBoost), random forest (RF), and AdaBoost Classifier) were used to identify potential biomarkers from differential metabolites or proteins. The five most important metabolites were identified by XGBoost, RF and AdaBoost, and then combined for subsequent analysis. Machine learning was then performed using the Extreme Smart Analysis Platform.¹

The sensitivity and specificity of the combined biomarkers were further analyzed using logistic regression analysis and receiver operating characteristic (ROC) curves. In ROC analysis, the area enclosed by the curve and the x-axis (x = 1 line) was defined as the area under the curve (AUC). Logistic regression analysis was performed using OmicStudio.²

Results

Baseline characteristics of the study population

A total of 226 participants were recruited for the present study: 62 were assigned to the NBA-ADP group, 64 were assigned to the BA-ADP group, and 100 were assigned to the Healthy Control (HC) group. Clinical and demographic characteristics were summarized in Table 1. The sex, age, and duration of alcohol dependence between NBA-ADP and BA-ADP group were equivalent. There was no statistical difference in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores between two groups. However, the RBANS scores (including attention, delay memory, immediate memory, language, visuospatial) in BA-ADP group were all slightly higher than these in NBA-ADP group.

TABLE 1

Table 1. Demographic and baseline patient characteristics.

Global metabolomic profiling

A total of 13,601 peaks were obtained, including 6,189 positive-mode features and 8,432 negative-mode features. A total of 178 positive-mode and 253 negative-mode metabolites were annotated and mapped to public databases. Corresponding to the two modes, 52 and 84 metabolites were, respectively, annotated and mapped to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. These metabolites belonged to 15 different KEGG compound classifications. Figure 2A shows that these metabolites were mainly classified as phospholipids. According to the KEGG database, these metabolites belonged to 25 different KEGG pathways (Figure 2B). Of these, the lipid metabolism pathway was the pathway that contained the most metabolites.

FIGURE 2

Figure 2. The KEGG classification of metabolites identified in all plasma samples. The classification criteria were: (A) KEGG Compound Classification; (B) KEGG Pathway.

According to the HMDB version 4.0 database, 431 selected metabolites belonged to 9 predominant super-classes (Figure 3A) and 21 subclasses (Figure 3B). The former included lipids and lipid-like molecules (63.03%), organic acids and derivatives (11.61%), organoheterocyclic compounds (7.21%), and organic oxygen compounds (6.98%). The latter includes glycerophosphocholines (10.00%), amino acids, peptides, and analo (9.07%), fatty acids and conjugat (8.14%), bile acids, alcohols and deves (6.98%), and glycerophosphoethanolamines (5%).

FIGURE 3

Figure 3. The HMDB classification of metabolites identified in all plasma samples. Pie chart illustrating the abundance ratio of different classes of plasma metabolites detected with untargeted metabolic profiling. The classification level was: (A) Superclass; (B) Subclass.

Identification of dysregulated metabolites

A total of 172 significant differential metabolites (FDR < 0.05) among the three groups were detected by analysis of variance (ANOVA). To further identify group differences in the metabolic profiles between groups, we performed OPLS-DA score plots; these identified notable separations between both the BA-ADP and HC group and between the NBA-ADP and HC group (Figure 4).

FIGURE 4

Figure 4. OPLS-DA score plots of alcohol-dependent patients (ADP) versus healthy controls. (A) OPLS-DA score plots of NBA-ADP vs. HC; (B) OPLS-DA score plots of BA-ADP vs. HC.

Differentially expressed metabolites were identified using multivariate and univariate statistical significance criteria (VIP > 1 and FDR < 0.05). In total, 139 metabolites were identified to be significantly different between the NBA-ADP and HC group and 26 metabolites between the BA-ADP and NBA-ADP group (Figure 5; Table 2).

FIGURE 5

Figure 5. Differential plasma metabolic profiles of alcohol-dependent patients vs. healthy controls. The hierarchical clustering and heat map in the left panel shows the top 30 metabolites that were significantly differentially abundant between NBA-ADP and HC (A), and 26 metabolites that were significantly differentially abundant between BA-ADP and NBA-ADP (B). The histogram in the right panel represents variable importance in projection (VIP) scores derived from the OPLS-DA model for each metabolite. ∗∗∗ indicates P < 0.001.

TABLE 2

Table 2. Differentially expressed endogenous metabolites detected by UHPLC-QTOF/MS.

Functional analysis of differentially expressed plasma metabolites from alcohol-dependent patients

To gain a further understanding of the metabolic disturbances between the NBA-ADP and HC group and between the BA-ADP and NBA-ADP group, we performed KEGG pathway enrichment analysis; we also used MetaboAnalyst version 5.0 to perform a functional analysis of plasma metabolites.

As shown in Figure 6A, primary bile acid biosynthesis (map00120), taurine and hypotaurine metabolism (map00430) were the most important metabolic pathways that showed alterations in the alcohol-dependent patients (both the NBA-ADP group and the BA-ADP group) when compared with the HC group. In contrast, pentose and glucuronate interconversions (map00040) and glycerophospholipid metabolism (map00564) were detected in the BA-ADP group when compared with the NBA-ADP group (Figure 6B).

FIGURE 6

Figure 6. Metabolite pathway changes identified using MetaboAnalyst 5.0. Pathway analysis of the differential plasma metabolites between NBA-ADP vs. HC (A), and BA-ADP vs. NBA-ADP (B). The y axis shows the p-values and the x axis, representing pathway impact values; node color is based on its p-value and node size reflects the pathway impact values.

Screening of potential metabolic biomarkers for alcohol-dependent patients with brain atrophy

The five most important metabolites selected by AdBooST were Sulfolithocholylglycine PC (16:0/18:2(9Z,12Z)), Allolithocholic acid, MG(0:0/22:1(13Z)/0:0), and Cyclopassifloic acid E (Figure 7A). The five most important metabolites selected by Random forest were PC (16:0/18:2(9Z,12Z)), N-[(3a,5b,7a)-3-hydroxy-24-oxo-7-(sulfooxy)cholan-24-yl]-Glycine, Cyclopassifloic acid E, 2,4-Dihydroxyacetophenone 5-sulfate, and Allolithocholic acid (Figure 7B). The five most important metabolites selected by Naive Bayes were Deoxycholic acid 3-glucuronide, Sulfolithocholylglycine, Cholic Acid, N-[(3a,5b,7a)-3-hydroxy-24-oxo-7-(sulfooxy)cholan-24-yl]-Glycine, and 2,4-Dihydroxyacetophenone 5-sulfate (Figure 7C). Nine metabolites (Cholic Acid, PC (16:0/18:2(9Z,12Z)), allolithocholic acid, sulfolithocholylglycine, N-[(3a,5b,7a)-3-hydroxy-24-oxo-7-(sulfooxy)cholan-24-yl]-Glycine, cyclopassifloic acid E, MG(0:0/22:1(13Z)/0:0), deoxycholic acid 3-glucuronide, 2,4-Dihydroxyacetophenone 5-sulfate) were identified as potential metabolic biomarkers for alcohol-dependent patients with brain atrophy. As shown in Figure 7D, the AUC of the ROC curve reached was 0.7719 for distinguishing between BA-ADP and NBA-ADP patients.

FIGURE 7

Figure 7. Screening of potential plasma metabolite biomarkers of alcohol-dependent patients with brain atrophy. The nine most important metabolites selected by Naive Bayes (A), AdaBoost (B), and Random Forest (C). The AUC value of the ROC curve of potential plasma metabolite biomarkers for distinguishing BA-ADP patients from NBA-ADP (D).

Discussion

It is well-known that alcohol can causes serious health problems, long-term abuse, and irreversible alterations in the structure and function of the brain (Rehm et al., 2017; Kranzler and Soyka, 2018). However, to the best of our knowledge, this is the first study that sought to identify potential plasma biomarkers of alcohol-dependent patients who have brain atrophy by applying non-targeted metabolomics and machine learning.

In this study, a total of 26 metabolites were found to show significant changes between the BA-ADP and NBA-ADP group. Each of the identified metabolites were searched against synonyms in HMDB. These metabolites covered a range of chemical classes; lipids and lipid-like molecules were ranked highest and featured 22 of the metabolites. The obtained metabolites were classified based on the KEGG compound annotation database.³ Phospholipids and phospholipid metabolism were ranked first in the secondary classification category of KEGG compounds. As the main substance of the brain, lipids not only act as the building blocks of all membrane structures but also act as the repository for chemical energy and play a significant role in cellular signaling pathways (Holthuis and Menon, 2014; Van Deijk et al., 2017). Characteristic alterations in lipid—including structure, composition, or distribution—are thought account for alterations in neuronal function, synaptic signaling, and neurotransmitter transmission. A previous lipidomics study investigating the links between chronic alcohol infusion and whole brain lipid profile, demonstrated that specific lipid categories, mainly PS, PC and PE, appeared to be related to neuro-pathology (Wang et al., 2019). To further identify the potential metabolic biomarkers of BA-ADP, machine learning was used and nine metabolites ((Cholic Acid, PC (16:0/18:2(9Z,12Z)), Allolithocholic acid, Sulfolithocholylglycine, N-[(3a,5b,7a)-3-hydroxy-24-oxo-7-(sulfooxy) cholan-24-yl]-Glycine, Cyclopassifloic acid E, MG(0:0/22:1(13Z)/0:0), Deoxycholic acid 3-glucuronide, 2,4-Dihydroxyacetophenone 5-sulfate) were identified. The AUC of these metabolite biomarkers was 0.7719, thus indicating an acceptable correlation using metabolite biomarkers and an outstanding correlation using protein biomarkers.

Of the nine differential metabolites identified in this study, there were several different species of bile acids, including cholic acid, allolithocholic acid, and deoxycholic acid 3-glucuronide. Bile acids readily cross the blood–brain barrier and their receptors are expressed in central tissues, suggesting that they may have important functional roles (Romanazzi et al., 2021). The bile acid signaling pathway plays an extremely important role in diseases and is a target for drug intervention. Drugs related to bile acids include chenodeoxycholic acid and its derivatives, ursodeoxycholic acid and its derivatives, bile acid sequestrants (such as cholestyramine), and apical sodium-dependent bile acid transporter (ASBT) inhibitors. In the nervous system, ASBT-mediated bile acid reabsorption significantly increases the level of bile acid in the serum and brain tissue, reduces the acidity of the intestinal cavity, increases the pH of the intestine, and promotes the conversion of intestinal ammonium into ammonia, thus resulting in abnormally increased levels of neurotoxic ammonia and cytotoxic bile acid in the blood and brain. Previous studies have confirmed that changes in bile acid occur in patients who progress from cognitive impairment to Alzheimer’s disease, and the relationship between this change and cognitive decline is well documented. In addition, our study identified two metabolites related to bile acids. The expression of these two-acyl glycine and bile acid-glycine conjugates varied significantly between the BA-ADP and NBA-ADP group. Therefore, we assumed that bile acids may strongly associated with alcohol-related brain atrophy. And additional targeted absolute quantitative analyze of the bile acid spectrum in future studies may be helpful.

Interestingly, another class of potential metabolic biomarkers here we identified are lipid metabolites. It is widely documented that the homeostasis of lipid metabolism plays a significant role in the central nervous system. Many lipidomic-based studies have reported the relationship between the dysregulation of specific lipids and pathological conditions, including diabetes, Alzheimer’s disease, hypertension, and cancer. It has been reported that long-term alcohol exposure significantly modifies the serum lipid profile, especially the metabolic pathways involving glycerophospholipid, sphingolipid and glycerolipids. Alcohol exposure can dramatically influence the lipidome of both the prefrontal cortex and striatum, thus leading to alcohol-related neurotoxicity and neuroplasticity. In the present study, by applying metabolomics analysis, we found that some glycerophospholipid (GP) metabolites, such as PC(P-16:0/18:2(9Z,12Z)), were significantly altered in alcohol-dependent patients with brain atrophy. GPs are the main components of the membrane structure. Different cell types, organelles, and inner/outer membranes in mammalian mitochondria, are known to have distinct glycerophospholipid compositions; these differences relate to the specific biological functions of these structures (Klaming et al., 2019). As GPs provide neural membranes with stability, fluidity and permeability, they are necessary for the normal biological function of integral membrane proteins, receptors, and ion-channels. Our present results suggest that chronic alcohol exposure may lead to brain atrophy and affect brain functionality by altering the composition of GPs. Alterations of the GP composition in neural membranes could therefore be related to neurological disorders. In addition, we found that some glycerolipids, such as MG(0:0/22:1(13Z)/0:0), were significantly altered in alcohol-dependent patients with brain atrophy. Further research now needs to investigate the key metabolic enzymes that mediate alcohol-induced dysfunction of lipidome profiling in the brain.

Based on the identified metabolites, we further identified two significantly altered metabolic pathways (primary bile acid biosynthesis, and taurine and hypotaurine metabolism) that were most closely related to alcohol dependence irrespective of whether brain atrophy was involved or not. As endogenous signaling molecules, bile acids are synthesized in the liver and secreted into the gastrointestinal tract for postprandial nutrient absorption and to control the overgrowth of microbial growth. In addition, gut microbes metabolize bile acids and in doing so, determine the composition of the circulating bile acids, thus regulating host metabolism (Chiang and Ferrell, 2019). Patients with acute alcohol intake exhibit increased serum levels of bile acids and cholestatic liver injury; alcohol intake also increases bile acid pool size and reduces bile acid flow and fecal excretion (Donepudi et al., 2018). Wang et al. found that the abundance of firmicutes and clostridium was notably increased in alcohol-addicted mice, and the levels of secondary bile acids produced by firmicutes had increased (Wang et al., 2018). In conclusion, compared with healthy individuals, there are certain changes in the expression levels of bile acid metabolites (including tauroursodeoxycholic acid, cholic acid and allocholic acid) in alcohol-addicted patients. The analysis showed that regulation of bile acid biosynthesis is likely to contribute to the occurrence and development of alcohol-related diseases.

As for taurine and hypotaurine metabolism, taurine has already been shown to protect mice with alcoholic liver injury by reducing hepatic oxidative stress and interrupting the alcohol-induced renal inflammatory cycle (Tang et al., 2019). It is well known that taurine can also prevent and repair liver damage and balance liver lipid metabolism indicators in a mouse model of alcoholic liver disease. The mechanism involved in this protection may be related to the regulation of related enzymes and transcriptional regulators involved in lipid metabolism (Latchoumycandane et al., 2014). In another study, Xia et al. suggested that the metabolic pathways of ascorbic acid, taurine, and hypotaurine, may play an active role in the protection against Antrodin A secreted by Antrodia camphorata and thus protect against alcoholic liver injury (Yi et al., 2021). Our present study also found that the BA-ADP group showed an elevation in taurine, compared with the NBA-ADP group. Thus, those imply that the metabolic pathways of taurine and hypotaurine may be also associated with alcohol-related brain atrophy.

To further identify the potential pathways that may be associated with alcohol-related brain atrophy, the KEGG pathway analysis using difference metabolites between BA-ADP and NBA-ADP was performed. We found that glycerophospholipid metabolism, along with pentose and glucuronate interconversions, were significantly associated with alcohol-related brain atrophy. This finding is in line with previous studies that demonstrated the impact of glycerophospholipid metabolism on neurodegenerative changes (Frisardi et al., 2011). Previous studies have shown that the degradation products of glycerophospholipids have pro-inflammatory effects and that their production is often accompanied by the activation of astrocytes and microglia and the release of inflammatory cytokines; these changes lead to oxidative stress and neuroinflammation (Bonelli et al., 2020). Changes in glycerophospholipid metabolism have also been shown to lead to changes in cell membrane permeability and ion homeostasis, thus leading to oxidative stress and neurodegenerative changes (Fuller and Futerman, 2018). Increased small vascular disease load was linked to changes in glycerophospholipid metabolism, as seen by increased white matter hyperintensity volume, decreased mean diffusivity normalized peak height, increased brain atrophy, and decreased cognition (Harshfield et al., 2022). Previous report has found that pentose and glucuronate interconversions is associated with the cognitive impairment in Alzheimer disease (He et al., 2020). In the present study, we report, for the first time, that pentose and glucuronate interconversions are also associated with alcohol-related brain atrophy. However, the precise role of these two regulatory metabolic pathways in the pathophysiological mechanism of alcohol dependence-related brain atrophy requires further investigation.

Limitations

This study has several limitations that need to be considered. First, the metabolomic analysis performed in the present study did not provide absolute quantification. If this model is to be applied clinically, more rigorous quantification and extensive validation of metabolites would be needed. Targeted metabolomics could be used to validate these specific plasma metabolomic biomarkers. Second, the sample size of this study was rather small, particularly in proteomic analysis; thus, additional patients are required for future analysis. Third, only XGBoost, RF, and AdaBoost Classifier were used to screen for potential biomarkers. Other machine learning methods, such as Support Vector Machine and Boruta could be used in future analyses. Fourth, due to the complex genetic and microenvironmental backgrounds of our patients, other biofluids, such as urine, serum, and cerebrospinal fluid, could also be used to identify additional novel biomarkers. This will provide a more to comprehensive understanding of the pathogenesis of brain atrophy in alcohol-dependent patients. Last, we failed to reveal any differences in cognitive tests between control patients and those identified as having brain atrophy in this study, more detailed cognitive tests may be help in future research.

Conclusion

This was the first attempt to conduct a metabolomic analysis of plasma samples from healthy control groups and alcohol-dependent patients. Our data showed that patients with alcohol-dependent brain atrophy had distinct metabolic profiles compared with healthy controls and alcohol-dependent patients who do not have brain atrophy. Furthermore, bioinformatic analysis suggested that alterations in the metabolome may be involved in disease pathogenesis. Although further research is needed, our results offer useful diagnostic and therapeutic clues for the management of alcohol-dependent patients with brain atrophy. source

Gratitude, far from being a sentimental notion, has emerged as a scientifically supported force capable of transforming the human brain and improving overall mental health.

Neuroscientific studies have shown that regularly practicing gratitude activates brain regions associated with moral cognition, emotional regulation, and reward, particularly the medial prefrontal cortex and anterior cingulate cortex (Zahn et al., 2009).

Notably, Dr. Alex Korb, in his book The Upward Spiral, describes how gratitude stimulates the release of dopamine and serotonin—two neurotransmitters vital for mood stabilization and happiness —making it a powerful natural antidepressant.

A growing body of evidence confirms that this effect is not fleeting: a study by the University of California, Berkeley, led by Joel Wong and Joshua Brown (2017), found that individuals who wrote gratitude letters showed significantly better mental health outcomes even 12 weeks after the exercise, regardless of whether the letters were sent.

In parallel, Emmons and McCullough (2003) demonstrated that individuals who kept a gratitude journal for just 10 weeks reported increased optimism, better sleep, and more physical activity.

Furthermore, gratitude has been shown to enhance the neural modulation of the prefrontal cortex, which reduces symptoms of depression and anxiety by strengthening pathways that suppress negative emotions.

According to McCraty & Childre (2004), gratitude also reduces cortisol levels—the primary stress hormone—improving cardiovascular health and emotional resilience. At the structural level, researchers like Zahn et al. (2014) have found that individuals who frequently feel gratitude show increased gray matter volume in the right inferior temporal gyrus, which plays a key role in interpreting social signals and emotional meaning.

As UCLA’s Mindfulness Awareness Research Center puts it, “Gratitude changes the neural structures of the brain,” reshaping how we perceive and engage with the world. ”

Ultimately, gratitude doesn’t just feel good—it rewires the brain toward greater emotional intelligence, social connection, and resilience, offering a neuropsychological foundation for a healthier and more fulfilling life.

NOT JUST SCIENCE, BIBLICAL AS WELL. ONE DAY SCIENCE WILL ALIGN ITSELF FULLY WITH CREATION!

Gratitude Transforms Anxiety into Peace Bible verses to help us through our daily life and life in General

Philippians 4:6-7
“Do not be anxious about anything, but in every situation, by prayer and petition, with thanksgiving, present your requests to God. And the peace of God, which transcends all understanding, will guard your hearts and your minds in Christ Jesus.”

Gratitude Shifts Perspective and Brings Joy

1 Thessalonians 5:16-18
“Rejoice always, pray continually, give thanks in all circumstances; for this is God’s will for you in Christ Jesus.”

Gratitude Leads to God’s Presence

Psalm 100:4
“Enter his gates with thanksgiving and his courts with praise; give thanks to him and praise his name.”

Gratitude Transforms Hardship into Growth

James 1:2-4
“Consider it pure joy, my brothers and sisters, whenever you face trials of many kinds, because you know that the testing of your faith produces perseverance. Let perseverance finish its work so that you may be mature and complete, not lacking anything.”

Gratitude Deepens Our Relationship with God

Colossians 3:16-17
“Let the message of Christ dwell among you richly as you teach and admonish one another with all wisdom through psalms, hymns, and songs from the Spirit, singing to God with gratitude in your hearts. And whatever you do, whether in word or deed, do it all in the name of the Lord Jesus, giving thanks to God the Father through him.”

Gratitude Opens Our Eyes to God’s Blessings

Ephesians 5:20
“Always giving thanks to God the Father for everything, in the name of our Lord Jesus Christ.”

Gratitude Is an Act of Worship

Hebrews 12:28
“Therefore, since we are receiving a kingdom that cannot be shaken, let us be thankful, and so worship God acceptably with reverence and awe.”

Gratitude Leads to Wholeness and Healing

Luke 17:15-19 (The healing of the ten lepers)
“One of them, when he saw he was healed, came back, praising God in a loud voice. He threw himself at Jesus’ feet and thanked him… Then he said to him, ‘Rise and go; your faith has made you well.'”

Gratitude in Scripture is often a catalyst for profound change. Below, the examples are organized by the type of transformation experienced – Emotional, Spiritual, Physical, and Social – with each verse or passage quoted and explained.

Emotional Transformation (Anxiety to Peace, Sadness to Joy)

• Philippians 4:6–7 – “Do not be anxious about anything, but in everything by prayer and supplication with thanksgiving let your requests be made known to Godbiblehub.com. And the peace of God, which surpasses all understanding, will guard your hearts and your minds in Christ Jesus”biblehub.com. Transformation: A thankful posture in prayer turns anxiety into peace. Paul teaches that when we present our worries to God with gratitude, God’s transcendent peace will calm our hearts and mindsgotquestions.org. The act of thanking God, even as we petition Him, shifts our focus from troubles to trust, resulting in inner peace replacing fear.

• Psalm 30:11–12 – “You have turned for me my mourning into dancing; you have loosed my sackcloth and clothed me with gladness… O Lord my God, I will give thanks to you forever”biblehub.combiblehub.com. Transformation: David expresses that God transformed his sadness into joy (“mourning into dancing”). In response, David’s heart overflows with thanksgiving. Gratitude here is both a reaction to God’s deliverance and a means of fully embracing joy. By vowing to thank God forever, David shows how thankfulness sustains the joy that replaced his sorrow. His praise-filled gratitude cements the emotional transformation from grief to rejoicing.

Spiritual Transformation (Deeper Faith and Relationship with God)

• Luke 17:15–19 – One of the ten lepers, after being healed, “turned back, and with a loud voice glorified God, and fell down on his face at Jesus’ feet, giving Him thanks”biblehub.com. In response, “Jesus said to him, ‘Rise and go; your faith has made you well’”biblehub.com. Transformation: Gratitude was central to this man’s spiritual healing. All ten were cured physically, but only the thankful Samaritan received Jesus’ affirmation of saving faith. His thankful return to praise Jesus indicated a heart change and deeper faith. Jesus implied that this man gained something more – a spiritual wholeness: “There was an extra healing for this tenth leper… The other lepers had whole bodies, but sick hearts.”enduringword.com In other words, his grateful faith not only cleansed his body but also brought salvation and a restored relationship with God, whereas the others missed that deeper transformation.

• Colossians 2:6–7 – “So then, just as you received Christ Jesus as Lord, continue to live your lives in Him, rooted and built up in Him, strengthened in the faith as you were taught, and overflowing with thankfulness.”askaboutmyfaith.com Transformation: Thankfulness is portrayed as a byproduct of and catalyst for spiritual growth. As believers deepen their roots in Christ, their faith grows stronger and is marked by abundant gratitudeaskaboutmyfaith.com. This suggests that practicing thankfulness reinforces our faith. A grateful heart keeps us mindful of God’s goodness and sovereignty, drawing us into a closer walk with God. Thus, gratitude leads to a transformed spiritual life – one of deeper faith, steadiness in Christ, and continual awareness of God’s presence.

• Psalm 50:23 – “The one who offers thanksgiving as his sacrifice glorifies Me; to one who orders his way rightly I will show the salvation of God!”biblehub.com. Transformation: Here God promises that a thankful worshiper will see salvation. Offering thanks honors God and “prepares his way so that I will show God’s salvation”biblehub.com. This implies that gratitude opens the heart to God’s saving work. In a spiritual sense, a grateful attitude “orders” our life correctly before God, leading to a greater experience of His salvation and deliverance. In sum, thankfulness paves the way for a transformed heart that knows God’s saving power more intimately.

Physical Transformation (Healing, Provision, Protection)

• John 6:11 – “Jesus then took the loaves, and when He had given thanks, He distributed them to those who were seated… so also the fish, as much as they wanted.”biblehub.com Transformation: Jesus demonstrates gratitude before the miracle of feeding the 5,000. His giving of thanks to God preceded the multiplication of the loaves and fish, providing abundant provision for the hungry crowd. This shows thankfulness leading to a tangible transformation of circumstances – from lack to plenty. The simple act of thanking God for the little they had invited God’s power to supply the physical needs of thousandsflbchurch.org. Our example is that faithful thanks, even in scarcity, can unleash God’s provision.

• Jonah 2:9–10 – “But I, with the voice of thanksgiving, will sacrifice to You… Salvation comes from the Lord. And the Lord commanded the fish, and it vomited Jonah onto dry land.”biblehub.com Transformation: Inside the great fish, Jonah offered a prayer of grateful praise, even before his rescue: “With shouts of grateful praise, I will sacrifice to you… Salvation comes from the Lord”biblehub.com. Immediately after this thanksgiving proclamation, God delivered Jonah, commanding the fish to release him. Jonah’s gratitude in the darkest place preceded a dramatic physical deliverance from death. This illustrates how an attitude of thankfulness can invite God’s saving power into dire circumstances – turning near tragedy into rescue.

• Daniel 6:10, 22 – “[Daniel] got down on his knees three times a day and prayed and gave thanks before his God, as he had done previously.” (Daniel 6:10) Despite a royal ban on prayer, Daniel continued his habitual gratitude toward God. Later, after being thrown into the lions’ den, he emerged unharmed, declaring, “My God sent His angel and shut the lions’ mouths, and they have not harmed me” (Daniel 6:22). Transformation: Daniel’s unwavering thankfulness brought about divine protection. His grateful prayers demonstrated trust in God above all, and God miraculously saved him from deadly lions. Even the pagan king recognized God’s power: “He rescues and He saves”thewriteconversation.blogspot.com. Thus, in Daniel’s story, thankfulness under trial led to a powerful transformation of impending death into deliverance – a testimony to God’s protective intervention.

• Acts 16:25–26 – “About midnight Paul and Silas were praying and singing hymns to God… and suddenly there was a great earthquake, so that the foundations of the prison were shaken. And immediately all the doors were opened and everyone’s bonds were unfastened.”flbchurch.org Transformation: In this instance of praise (an expression of gratitude) amid suffering, God intervened with a physical miracle. Paul and Silas’s thankful worship turned a prison into a place of freedom – literally opening doors and breaking chains. Their gratitude to God despite wounds and confinement led to an earthquake that transformed their situation from captivity to liberty. This not only freed them physically but also set the stage for the jailer’s conversion (a spiritual change), showing how thankfulness can trigger God’s power to heal, protect, and save.

Social Transformation (Reconciliation, Favor, Influence)

• Acts 27:35–36 – Facing a storm at sea, “Paul took bread and gave thanks to God in the presence of all… then he broke it and began to eat. Then they all were encouraged and ate some food themselves.”biblehub.com Transformation: Paul’s public expression of gratitude during a crisis had a profound influence on those around him. His calm thankfulness to God for the meal (despite the impending shipwreck) lifted the others from despair to hope. All 276 passengers “took heart” and followed his example of eatingbiblehub.com. The social atmosphere on the ship shifted from panic to encouragement. Paul’s thankfulness instilled confidence that God would deliver them, demonstrating how one person’s grateful faith can positively transform a whole group’s outlook and unity.

• Acts 2:46–47 – In the early church, believers met together “with glad and sincere hearts, praising God,” and as a result they were “enjoying the favor of all the people. And the Lord added to their number daily those who were being saved.”biblehub.com Transformation: Corporate gratitude and praise produced a social impact in the community. The first Christians’ joyful, thankful worship fostered unity among themselves and earned them favor with outsiders. Their gratitude to God was contagious, drawing others to them. Scripture notes that this environment of praise and thankfulness led to continual growth of the church, as more people were being saved dailybiblehub.combiblehub.com. In other words, a culture of thankfulness in the community helped bring about reconciliation between individuals and God, and also gave the believers a positive reputation, transforming their social standing and influence in society.

• 2 Chronicles 20:21–22 – “Jehoshaphat appointed those who were to sing to the Lord and praise Him… As they began to sing and praise, the Lord set ambushes against the [enemy]… and they were defeated.” Transformation: Here praise and thanks became a “weapon” that led to a national victory and peace. Judah’s army marched into battle thanking God for His love, and God turned the enemies against each otherflbchurch.orgbiblehub.com. This brought deliverance without Judah fighting at all. The social/national transformation was twofold: fear gave way to faith among God’s people, and neighboring nations stood in awe. This example shows gratitude to God helping reconcile and unite a people, while also granting them favor and influence over surrounding nations who witnessed God’s power.

Each of these examples underscores a principle: thankfulness is often the key that unlocks God’s transformative work. Emotional turmoil gives way to joy and peace, faith is strengthened, physical needs are met or miracles occur, and even social situations are changed – all when people choose to “give thanks in all circumstances” as God’s will for us (1 Thessalonians 5:18). The Bible consistently demonstrates that a grateful heart isn’t just an appropriate response to God’s grace, but a powerful force that God uses to change lives and situations for the better.

• Releasing Negative Emotions: Holding onto anger, resentment, and bitterness creates a heavy burden that hinders inner peace. Forgiveness is an active process of consciously releasing these negative feelings.
• Breaking the Cycle of Pain: Forgiveness can interrupt the cycle of anger and hurt, leading to a state of peace.
• Personal Growth and Healing: By choosing to forgive, you make room for healing and personal growth, enabling you to move forward without being defined by past pain.
• Reducing Stress: Research shows a strong link between forgiveness and reduced stress levels. This, in turn, can improve mental health outcomes like anxiety and depression.
• Improving Relationships: Forgiveness can help rebuild trust and open communication, fostering stronger and more supportive relationships. 
• The benefits of forgiveness:Forgiveness can lead to reduced stress, improved mental and physical health, stronger relationships, and a greater sense of inner peace and happiness. 
• Forgiveness and letting go: Forgiveness often involves letting go of the past and its associated pain, allowing one to focus on the present and future. 
• Forgiveness and personal growth: It can be a powerful catalyst for personal growth and transformation, helping individuals to heal, evolve, and move forward with a more positive outlook.

• Forgiveness does not mean forgetting or condoning the offense. It’s about letting go of the negative emotional and psychological impact of the offense on yourself.
• Forgiveness is a process that may require time and reflection. 

Forgiveness is for us, not for them. For us to heal and move on but I really cant seem to do it. I get so angry every time I see my mom and I stay angry for a while. I hate the feelings it brings out of me.

Now my parents weren’t physically abusive but they were so unhappy in their marriage and their lives, they accidentally created shit childhoods for us.

I never felt loved or seen, there was only judgement and a sense of burdening them. Mom was angry at everything I did, she constantly complained about everything. She was a SAHM who did nothing to better herself or take care of her kids but she was judging the entire universe.

I see the impact of her choices on me and I see how much her own insecurities affected me and I cant help but think – why, why didn’t you better yourself? You had a lifetime and nothing else to do

If you have felt a similar way, what were the things that helped you forgive your parents?

Forgiveness Is the Key to Unlocking Your True Peace

Everyone experiences hurt – an inconsiderate friend, a betrayal, or worse – and the weight of grudges can be heavy. Increasingly, psychologists and even neuroscientists are finding truth in an age-old wisdom: forgiveness is the key to inner peace. Letting go of anger and resentment isn’t just a moral ideal celebrated by spiritual traditions; it’s a practical strategy for emotional freedom, better health, and resilience. “Forgive us our debts, as we forgive our debtors,” an ancient prayer intones, recognizing that forgiving others is crucial for our own well-being. Modern research agrees. Holding onto bitterness elevates stress, blood pressure, and anxiety, while choosing to forgive can lower stress hormones, improve mental clarity, and even rewire the brain for the better. This article explores forgiveness from a broad perspective – its psychological and physical benefits, its reflection in both secular and spiritual wisdom, and how real people have achieved personal peace by forgiving. By the end, you’ll see why turning the key of forgiveness unlocks true peace in your mind and life.

Why Letting Go is Good for You (Understanding Forgiveness)

Forgiveness is often misunderstood. It does not mean forgetting what happened, condoning the harm, or reconciling with an abuser. Rather, psychologists define forgiveness as a conscious choice to release feelings of anger, resentment, or vengeance toward someone who hurt you, whether they deserve it or not. It’s “replacing ill will toward an offender with goodwill,” as one Harvard expert puts ithealth.harvard.edu. In essence, you decide to cancel the “debt” of the offense so that it no longer controls your life. This act is fundamentally for your benefit – the other person may never even know you forgave them.

Why go through this difficult process? Because refusing to forgive keeps you stuck in a cycle of stress and pain. Ruminating over past wrongs triggers the body’s stress response each time: heart rate and blood pressure spike, muscles tense, and emotions churn with anger or sadness. Over time, this state of unforgiveness can take a serious toll on mental and physical health. In fact, remaining in a hostile, resentful state has been likened to a wound that never heals. “Feeling stuck in hostility can torment us mentally,” causing “intense rumination – a looping of negative thoughts”health.harvard.edu. We relive the hurt repeatedly, which impedes our ability to move forward. On the flip side, forgiveness allows us to finally exhale that toxic anger. It’s an emotional release – a way of saying “I’m not going to let this grievance dominate my life anymore.” As the Greater Good Science Center reports, forgiving someone engages brain regions that “empower you to step beyond painful experiences in an energized, motivated, and connected way.” It actually builds resilience and strengthgreatergood.berkeley.edu. In choosing to forgive, you free yourself from the grip of the past. The result is often a profound sense of peace and freedom, as countless individuals attest.

Psychological Benefits of Forgiveness (Healing the Mind)

Modern psychology has amassed substantial evidence that forgiveness benefits mental health. Whether through formal forgiveness training or personal practice, letting go of grudges has been shown to produce positive changes in mood and mindset. A 2023 multi-country study led by Harvard researchers found that when people actively learned how to forgive, they saw significant reductions in depression and anxiety symptoms compared to a control grouphealth.harvard.eduwashingtonpost.com. In fact, forgiving was so impactful that researchers suggested it as a public health intervention for improving mental well-beingwashingtonpost.com. Here are some key psychological benefits highlighted by recent studies and experts:

• Less anxiety and depression: Across five countries, those who practiced forgiveness reported feeling less anxious and less depressed than beforehealth.harvard.edu. By releasing resentment, they alleviated emotional burdens that fuel mental distress. Other research concurs that forgiveness therapy leads to fewer symptoms of depression and anxiety and greater feelings of hope for the futurepmc.ncbi.nlm.nih.gov.

• Reduced anger and stress: It’s no surprise that forgiving someone reduces anger – you’re letting go of the grudge, after all. But importantly, this also lowers chronic stress. Psychologists note that holding onto anger puts your body in a state of tension. When you forgive, you switch off that “fight or flight” response, often experiencing immediate relief and calm. Over time, this can break the cycle of rumination (repeatedly revisiting the hurt), which frees your mind to focus on more positive things.

• Improved self-esteem and mental clarity: Remarkably, studies have found that as people forgive, their self-esteem tends to risepmc.ncbi.nlm.nih.gov. Why? Forgiveness empowers you – you’re no longer a victim of the offense, but a victor over the negative emotions associated with it. This positive shift can boost confidence and clarity. Many report that after forgiving, they feel lighter, as if a mental fog has lifted. Decisions come easier, and they regain a sense of control over their emotions rather than feeling controlled by past pain.

• Greater resilience: Forgiveness doesn’t just help you heal from this hurt; it can build resilience to face future challenges. Brain imaging studies reveal that forgiving engages brain pathways associated with problem-solving, empathy, and emotional regulationgreatergood.berkeley.edu. Essentially, practicing forgiveness is like a workout for your brain’s “resilience muscles,” teaching you how to cope with adversity in a healthy way. Over time, people who cultivate forgiveness often bounce back faster from setbacks and exhibit more optimism in difficult situations.

In sum, forgiveness is therapeutic. As one researcher noted, “When we learn to forgive others, we simultaneously heal ourselves.”pmc.ncbi.nlm.nih.gov By cleaning the wound of old anger, we prevent further infection of our psyche. What’s left is a mind at peace, better equipped to experience joy and engage fully with life.

Physical Health Benefits of Forgiveness (Healing the Body)

The body responds dramatically to our emotional state. Harboring grudges has been linked to physical stress ailments, while forgiving can trigger physiological healing. Science is now catching up to this wisdom. According to a review of studies, forgiveness contributes to lower blood pressure, better sleep quality, and even a stronger immune systemwashingtonpost.com. Here are some notable physical health benefits:

• Heart health and blood pressure: The act of forgiveness has a calming effect on the cardiovascular system. In moments of anger or recalling a grudge, your blood pressure spikes and heart beats faster. Chronic unforgiveness keeps you in this state, which over time can damage arteries and strain the heart. Forgiving, however, can “lower blood pressure and heart rate,” effectively reducing cardiovascular strainhealth.harvard.edu. Some studies found that people who let go of grudges showed improvements in hypertension (high blood pressure) readings. Simply put, a peaceful heart tends to be a healthier heart.

• Stress reduction and immunity: Emotional stress from resentment can suppress your immune function, making you more vulnerable to illness. By releasing resentment, you dial down the body’s stress hormones (like cortisol). Lower stress can improve everything from digestion to immune response. Many individuals report that after forgiving, they feel fewer physical symptoms of stress – for example, tension headaches or muscle pain might diminish as the body relaxes. Over the long term, this means fewer stress-related ailments. In fact, researchers in one study noted that people stuck in unforgiveness showed higher physiological stress responses, whereas those practicing forgiveness had more normalized stress levelshealth.harvard.edu.

• Better sleep and energy: Ever lain awake stewing over how someone wronged you? Grudges are exhausting. Forgiveness, on the other hand, is associated with better sleep. A 2019 study in Psychology & Health found that those who scored higher on forgiveness measures tended to have better sleep quality and less fatigue than those who held grudges. By resolving inner conflicts, forgiveness quiets the mind at night, leading to more restful sleep. In turn, improved sleep boosts your daytime energy and concentration. It’s a virtuous cycle: peace of mind yields peaceful sleep, which yields a healthier, more energetic you.

• Longer lifespan and overall wellness: While research is ongoing, some evidence suggests that forgiving might even contribute to longevity. Chronic anger and hostility have been identified as risk factors for health conditions that shorten life (like heart disease). Conversely, people who forgive more readily often have lower inflammation levels and healthier lifestyles (since they may cope through positive means rather than substance abuse or overeating out of stress). All these factors can add up to a longer, healthier life. As one health publication put it, forgiveness is “not just good for the soul,” it’s good for the body toohealth.harvard.edu.

The takeaway is clear: your body listens to your heart. By purging bitterness from your heart, you also purge toxins from your body. Medical clinics, including the renowned Mayo Clinic, now advocate forgiveness as part of a holistic approach to wellness, citing benefits like lower blood pressure, less anxiety, and reduced chronic pain. In summary, forgiveness is a mind-body medicine – free to use, with only positive side effects!

The Spiritual Dimension of Forgiveness (Universal Wisdom)

Even in a secular discussion, it’s worth noting that forgiveness has deep spiritual and cultural roots. Virtually every major religion and moral philosophy extols the virtue of forgiving others. This isn’t a coincidence; across time and culture, people observed that forgiveness leads to inner freedom and social harmony. For example, Christian scripture teaches, “Do not judge… do not condemn… Forgive, and you will be forgiven.” (Luke 6:37biblehub.com). In Judaism and Islam, forgiving others is highly honored, and withholding forgiveness is seen as corrosive to the soul. Buddhism advocates compassion and letting go of anger as a path to enlightenment. Secular humanist thinkers, too, recognize the transformative power of forgiveness in conflict resolution and personal growth.

What all these traditions share is the understanding that holding hate only hurts the hater. Forgiveness, by contrast, is often described as liberation. It frees your spirit from the burden of past injuries. Many who forgive describe feeling lighter or as if “a weight was lifted” off them – imagery common to spiritual rebirth. In a broader sense, forgiveness can also mend the social fabric. When we forgive, we break cycles of retaliation and revenge that cause endless suffering. This is why leaders like Martin Luther King Jr. and Mahatma Gandhi, though leading secular movements, spoke frequently about forgiveness and love as powerful forces for change.

Importantly, you don’t have to follow a particular faith to appreciate the inner transformation forgiveness brings. However, for some, spiritual beliefs can provide strength in the forgiveness journey. They might find it helpful to reflect on their own imperfections and how they’d want to be forgiven (echoing the Golden Rule). Others draw on concepts like karma or divine grace to release their grudges. Even without religious context, one might frame forgiveness as aligning with your highest self – choosing empathy and peace over anger. Ultimately, whether one views it as a divine command or simply wise living, forgiving others is a profound act of self-care and virtue recognized worldwide. It connects us to something larger – be it community, humanity, or a sense of higher purpose – by dissolving the walls that resentment builds between us.

Real-Life Story: Finding Personal Peace Through Forgiveness

To see how forgiveness can unlock true peace, consider the remarkable story of Mary Johnson. Mary is a woman from Minneapolis whose only son was tragically murdered in 1993 by a teen named Oshea. Understandably, Mary was consumed by grief and bitterness after her son’s death. “I was angry and resentful,” she admitted – the thought of forgiving the killer seemed impossible at first. Oshea went to prison, but Mary remained a prisoner of her own rage for over a decade. Seventeen years later, still without peace, Mary felt led to meet Oshea face-to-face. She says her faith and desire to move forward pushed her to do this. The meeting, held in the prison visiting room, was life-changing. Oshea sincerely apologized for what he had done and, with tears, asked Mary for forgiveness. In that pivotal moment, Mary chose to let go of the hatred she’d harbored. As they cautiously embraced, she recalls, “I just hugged the man that murdered my son… and I instantly knew that all anger and animosity… was over.”prisonfellowship.org The burden she’d carried for years melted away in an instant of mercy.

Mary Johnson’s act of forgiveness not only brought her inner peace – it also sparked an unlikely friendship. After Oshea served his sentence, Mary welcomed him back to society. In fact, he eventually moved into the apartment next door to Mary, with her blessingprisonfellowship.org. She began referring to Oshea as her “spiritual son,” saying, “I forgave him and gained a son”. In 2010, when Mary remarried, Oshea was even the one who walked her down the aisleprisonfellowship.orgprisonfellowship.org. The two now frequently share their story together at community events, showing the world that reconciliation and healing are possible. Mary went on to found an organization called From Death to Life, which helps others impacted by violence to find healing through forgivenessprisonfellowship.org.

Mary’s journey illustrates that forgiveness is not about the offender deserving it – it’s about you deserving peace. By forgiving the young man who took her son’s life, she released herself from a prison of bitterness. The transformation was tangible: her blood pressure dropped, her depression lifted, and she smiled again. “Forgiveness freed both the one forgiven and the one forgiving from the bondage of the past,” as one article noted about Mary’s experienceprisonfellowship.org. Indeed, both she and Oshea were able to move forward and find purpose beyond the tragedy. Not every story of forgiveness will end in such a beautiful friendship, but Mary’s example shows that even the deepest wounds can be healed. The key was her willingness to let go for her own sake, to trade rage for serenity. In doing so, she unlocked a life of peace that had been sealed away by resentment.

Forgiveness is the key – whether viewed through the lens of science, psychology, or spirituality, this truth stands. Letting go of anger might be hard, but it is one of the most liberating choices we can make. It clears out the negativity occupying our hearts and minds, making room for peace, joy, and connection. As you consider your own life, ask: is there a past hurt that still locks up a part of you? By turning the key of forgiveness, you open the door to freedom. The path may not be easy, but on the other side lies the true peace we all deserve. Embrace forgiveness – for your health, your happiness, and your future. The sooner you do, the sooner you’ll step into the lightness and relief that comes from a heart unburdened, finally at peace. pureflix.comprisonfellowship.org

the unintended exclusivity that can arise when a symbol intended for inclusiveness instead alienates others.

true inclusivity must consider all perspectives, including those who may feel excluded by current cultural displays.

When “Inclusivity” Excludes: A Christian or Jewish Perspective at Hugo’s in West Hollywood

By Good Shepherd News Media Editorial

Walk into Hugo’s Restaurant in West Hollywood during Pride Month, and you’re immediately greeted with a sea of rainbow flags. The decor, the signage, even the uniforms in some cases—everywhere you look, there’s visual reinforcement of LGBTQ+ pride. The intended message is clear: You’re welcome here.

But what if you’re a Christian? Or a Jew? What if the very flags you’re surrounded by represent something deeply offensive—not just personally, but spiritually? What if what others call “inclusive” feels more like a moral provocation to you?

For observant Christians and Jews, both Scripture and tradition make clear that certain behaviors—particularly those celebrated during Pride Month—are not in alignment with God’s design. In fact, they are often considered sinful, even evil. This isn’t hate. It’s theology. It’s belief. It’s the moral compass that has guided millions for thousands of years. And yet, that belief is not just absent from this “inclusive” environment—it’s actively contradicted, mocked, and pushed aside.

A Christian man walks into Hugo’s for lunch. He simply wants to eat a meal. But now, everywhere he looks, he’s reminded—explicitly—that his convictions are not only unwelcome but are being visually trampled. This isn’t neutrality. This isn’t coexistence. This is a statement: Your religion is wrong. Your values are outdated. You’re in our space now.

Would Hugo’s ever consider filling its walls with crosses during Easter? Or putting the Ten Commandments on every table for Passover? Would a rainbow flag be joined by the Star of David or an image of the risen Christ? Of course not. Because the same culture that demands visibility and validation for one group insists on silence and subtlety from others.

HUGOS IN WESTHOLLYWOOD DECLARED FAMILY UNSAFE, DUE TO THE PRIDE FLAGS.

And that’s the paradox.

In the name of “welcoming everyone,” the restaurant has created an atmosphere where religious people—particularly Jews and Christians—are made to feel deeply uncomfortable. Their sacred beliefs are symbolically desecrated in the very place they’re expected to break bread.

This is not inclusion. This is coercion dressed up as compassion.

Inclusivity does not mean elevating one group’s identity at the expense of another’s beliefs. True inclusivity is neutral. It respects all by refraining from becoming a billboard for any ideology—especially in shared public or commercial spaces. It means creating an environment where no one feels pressured to endorse something they fundamentally disagree with, just to eat in peace.

And make no mistake—there’s a political element here too. The pride flag, while presented as harmless and loving, has become a loaded symbol. It carries not only messages of identity but of activism, politics, and often hostility toward traditional faiths. To many Christians and Jews, it’s not just a celebration—it’s an affront. Not because they hate, but because they have the right to hold convictions that differ without being shamed or shouted down.

When did public spaces become arenas for moral confrontation?

Isn’t the goal to coexist?

If Hugo’s truly wanted to be inclusive, it wouldn’t plaster its walls with any political or moral symbol—not rainbows, not crosses, not creeds. It would welcome everyone by refusing to force anyone’s beliefs onto its customers. That is how you respect diversity. That is how you practice true tolerance.

Until then, it’s fair to say: the loudest calls for inclusivity may be creating the most silent exclusions.

4. Romans 1:26–27

Paul describes what he calls the result of turning from God:

“For this reason God gave them up to dishonorable passions. For their women exchanged natural relations for those that are contrary to nature; and the men likewise gave up natural relations with women and were consumed with passion for one another…”
— Romans 1:26–27 (ESV)

5. 1 Corinthians 6:9–10

Paul lists sinful behaviors that exclude one from inheriting the kingdom of God:

“Do not be deceived: neither the sexually immoral, nor idolaters, nor adulterers, nor men who practice homosexuality… will inherit the kingdom of God.”
— 1 Corinthians 6:9–10 (ESV)

Some translations split the Greek words “malakoi” (effeminate) and “arsenokoitai” (men who lie with men).

6. 1 Timothy 1:9–10

Paul again includes homosexuality in a list of sins:

“…the law is not made for the righteous but for lawbreakers… for

HUGOS IN WESTHOLLYWOOD DECLARED FAMILY UNSAFE

8401 Santa Monica Blvd, West Hollywood, CA 90069
THIS IS PROGRAMMING FOR CHILDREN, ALL CHILDREN LOVE RAINBOWS, THE LGBTQ+ PEOPLE START EARLY ON THE PROGRAMMING

Bible Verses Addressing Homosexuality (Old and New Testaments)

Sources: Biblical texts are from the English Standard Version (ESV) unless otherwise noted. Traditional interpretations are summarized from Jewish Talmudic commentary and mainstream Christian exegesis and catechesisen.wikipedia.orgen.wikipedia.org, supported by historical writings and modern biblical scholarship.

When Inclusivity Becomes Exclusion: Rethinking the Ubiquity of the Pride Flag

When Inclusion Becomes Exclusion: A Christian and Jewish Reflection on the Pride Flag in Public Spaces

Edible vaccines produced in lettuce – Edible mRNA vaccine in lettuce chloroplasts

The concept of embedding vaccines, particularly mRNA-based vaccines, into everyday foods such as lettuce and tomatoes is a growing research area that, while innovative, poses profound concerns about consumer rights, health safety, and ecological balance.

Emerging Research on Edible Vaccines Recent studies have proposed incorporating mRNA vaccines into the chloroplasts of lettuce and other edible plants, with the aim of creating an easily distributable vaccination method. Researchers argue that this could potentially streamline vaccine distribution, reduce cold storage dependency, and simplify global vaccination efforts (MDPI, 2016; PMC8329267, 2021).

In Mexico, researchers have developed TOMAVAC, a tomato-based edible COVID-19 vaccine intended to produce antibodies against the virus (ResearchGate, 2024). Similarly, initiatives in Tennessee and other regions suggest modifying lettuce for drug delivery, sparking debates on public health ethics and regulatory oversight (Newsweek, 2024).

Potential Risks and Ethical Concerns Despite optimistic claims from proponents, critical analysis highlights alarming potential risks associated with edible mRNA vaccines. Firstly, the long-term health implications of consuming genetically altered foods containing mRNA vaccines remain insufficiently studied. Historically, rushed approvals, as observed with some COVID-19 mRNA vaccines, have raised public distrust due to emerging side effects and limited transparency regarding long-term safety profiles.

Moreover, edible vaccines could unintentionally expose consumers to pharmaceutical interventions without informed consent. Introducing mRNA vaccines into widespread food sources could result in involuntary medical treatments, infringing upon individual rights to bodily autonomy and informed medical consent.

Ecological and Agricultural Risks Embedding mRNA vaccines in plants risks unintended cross-contamination and gene flow into wild ecosystems. These genetically modified plants, if released into open agriculture, could potentially disrupt ecological balance, affecting pollinators, soil microbiology, and non-target plant species. This bioengineering initiative poses profound ecological risks, extending beyond controlled laboratory environments into broader ecosystems.

Transparency and Consumer Rights The move towards edible vaccines embedded in everyday foods raises significant transparency issues. Consumers must retain the unequivocal right to know precisely what they are consuming. If vaccines are embedded in common produce, clear labeling and stringent regulations would be essential, yet enforcing such oversight presents considerable practical challenges.

Regulatory Gaps and Precautionary Principle Currently, regulatory frameworks remain insufficiently equipped to address the rapid advancement and deployment of genetically modified organisms (GMOs) intended for medical consumption. The pace of biotech innovation is often far ahead of existing regulation, potentially placing consumers at risk. Advocates for cautious progression emphasize the precautionary principle: rigorous and comprehensive risk assessments must precede widespread adoption.

Conclusion While edible mRNA vaccines offer a superficially appealing solution to vaccine distribution challenges, the unresolved health, ethical, ecological, and regulatory concerns cannot be overlooked. Protecting consumer rights, ensuring transparent labeling, and thoroughly evaluating ecological and health impacts must be paramount. Without addressing these critical factors comprehensively, altering our fundamental food supply with edible vaccines is an endeavor fraught with significant and lasting risks.

Tennessee Moves to Classify ‘Vaccine Lettuce’ as a Drug

Abill that would classify as a drug certain foods with vaccine materials added to them was passed by the Tennessee Senate and now awaits Governor Bill Lee’s signature into law amid concerns about research on putting immunity boosters into lettuce.

The proposed law, HB 1894, was passed in a 23-6 Senate vote last Thursday after getting the House’s green light in a 73-22 vote in early March.

It would classify any food that “contains a vaccine or vaccine material” as a drug under Tennessee law, meaning the food would have to be labeled accordingly. The bill defines vaccine material as a substance intended to “stimulate the production of antibodies and provide immunity against disease.”

The legislation would not ban vaccine-imbued foods from being sold in the state but would require them to carry the same sort of medical labeling as injectable vaccines or medications.

While proponents of the measure cited ongoing research into this method of conveying vaccines and the need to give people the recommended dose of a vaccine, opponents questioned the bill’s necessity and whether such foodstuffs would ever be sold alongside their unvaccinated counterparts at grocery stores.

During a debate on the bill before Thursday’s vote, state Senator Heidi Campbell, a Democrat, asked for evidence of “any instances of there being food offered in the state of Tennessee that contains vaccines.”

Speaking of the research, she said that “the idea that this would somehow correlate to some kind of a retail offering of vegetables, especially when that vegetable would cost many thousands of dollars, just seems to me [to be] messy to be passing legislation for that reason.”

Senate advocates of the bill said that they did not know of any specific examples of vaccine-imbued foods being sold but that the bill was to ensure regulations are in place if such sales occur. They also noted the relative inexpensiveness of some vaccines and lettuce.

State Representative Scott Cepicky, a Republican who originally sponsored the bill, said in February that lettuces containing vaccines would require a prescription “to make sure that we know how much of the lettuce you have to eat based off of your body type so we don’t under-vaccinate you—which leads to the possibility of the efficacy of the drug being compromised—or we overdose you based off how much lettuce is [eaten],” according to Nashville’s WKRN-TV.

A research project, funded by a $500,000 federal grant, at the University of California is looking into whether pathogen-targeting mRNA, like that used in COVID-19 vaccines, could be implanted in the cells of edible plants to replicate and then be consumed.

“We are testing this approach with spinach and lettuce and have long-term goals of people growing it in their own gardens,” Juan Pablo Giraldo, an associate professor at the university’s Department of Botany and Plant Sciences, who is leading the research, said in 2021. “Farmers could also eventually grow entire fields of it.”

The idea of edible vaccines is not new. A 2013 scientific paper noted attempts to put vaccines against various diseases, such as measles, hepatitis B and cholera, into foodstuffs like potatoes, bananas, corn, soybeans and rice.

Researchers say that successfully placing vaccines in plants would mean they don’t have to be stored at low temperatures, which is the case for many injectable vaccines. source

While large companies and public sector consortiums in the United States, Canada, China and Europe are running at full speed to develop a vaccine grown in genetically modified (GM) tobacco plants, a research group at a Mexican university is working toward the same terrorzing objective, but with a different and innovative strategy. They are using bioinformatics and computational genetic engineering to identify candidate antigens for a vaccine that can be expressed in tomato plants. Eating the fruit from these plants would then confer immunity against COVID-19.

sources

https://pmc.ncbi.nlm.nih.gov/articles/PMC8329267/

https://pubmed.ncbi.nlm.nih.gov/38260078/

https://allianceforscience.org/blog/2020/05/gmo-tomato-as-edible-covid-vaccine-mexican-scientists-work-to-make-it-a-reality/

https://www.sciencedirect.com/science/article/pii/S2590262825000218

http://mdpi.com/1422-0067/17/10/1715

https://www.nature.com/articles/s44222-025-00299-1

https://www.uottawa.ca/faculty-science/please-pass-salad-edible-vaccines-produced-lettuce-protect-against-covid-19

LA Times Today: The dirty secret of California’s legal weed

Watch L.A. Times Today at 7 p.m. on Spectrum News 1 on Channel 1 or live stream on the Spectrum News App. Palos Verdes Peninsula and Orange County viewers can watch on Cox Systems on channel 99.