Publisher Health

While we often think of diseases as caused by foreign bodies — bacteria or viruses — there are hundreds of diseases affecting humans that result from errors in cellular production of its proteins. A team of researchers led by the University of Massachusetts Amherst recently leveraged the power of cutting-edge technology, including an innovative technique called glycoproteomics, to unlock the carbohydrate-based code that governs how certain classes of proteins form themselves into the complex shapes necessary to keep us healthy.
The research, published in the journal Molecular Cell, explores members of a family of proteins called serpins, which are implicated in a number of diseases. The research is the first to investigate how the location and composition of carbohydrates attached to the serpins ensure that they fold correctly. Serious diseases — ranging from emphysema and cystic fibrosis to Alzheimer’s disease — can result when the cellular oversight of protein folding goes awry. Identifying the glyco-code responsible for high-fidelity folding and quality control could be a promising way for drug therapies to target many diseases.
Scientists once thought that the single code governing life was DNA, and that everything was governed by how DNA’s four building blocks — A, C, G and T — combined and recombined. But in recent decades, it has become clear that there are other codes at work, and especially in building the intricately folded, secreted proteins that are created in the human cell’s protein factory, the endoplasmic reticulum (ER), a membrane-enclosed compartment where protein folding begins. Approximately 7,000 different proteins — one third of all the proteins in the human body — mature in the ER. The secreted proteins — collectively known as the “secretome” — are responsible for everything from our body’s enzymes to its immune and digestive systems and must be formed correctly for the human body to function normally.
Special molecules called “chaperones,” help fold the protein into its final shape. They also help to identify proteins that haven’t folded quite correctly, lending them additional help in refolding, or, if they’re hopelessly misfolded, targeting them for destruction before they cause damage. However, the chaperone system itself, which comprises a part of the cell’s quality control department, sometimes fails, and when it does, the results can be catastrophic for our health.
The discovery of the carbohydrate-based chaperone system in the ER was due to the pioneering work that Daniel Hebert, professor of biochemistry and molecular biology at UMass Amherst and one of the paper’s senior authors, initiated as a postdoctoral fellow in the 1990s. “The tools we have now, including glycoproteomics and mass spectrometry at UMass Amherst’s Institute for Applied Life Sciences, are allowing us to answer questions that have remained open for over 25 years,” says Hebert. “The lead author of this new paper, Kevin Guay, is doing things I could only dream of when I first started.”
Among the most pressing of these unanswered questions is: how do chaperones know when 7,000 different origami-like proteins are correctly folded?
We know now that the answer involves an “ER gatekeeper” enzyme known as UGGT, and a host of carbohydrate tags, called N-glycans, which are linked to specific sites in the protein’s amino acid sequence.

Guay, who is completing his Ph.D. in the molecular cellular biology program at UMass Amherst, focused on two specific mammalian proteins, known as alpha-1 antitrypsin and antithrombin. Using CRISPR-edited cells, he and his co-authors modified the ER chaperone network to determine how the presence and location of N-glycans affected protein folding. They watched as the disease variants were recognized by the ER gatekeeper UGGT and, in order to peer more closely, developed a number of innovative glycoproteomics techniques using mass spectrometry to understand what happens to the glycans that stud the surface of the proteins.
What they discovered is that the enzyme UGGT “tags” misfolded proteins with sugars placed in specific positions. It’s a sort of code that the chaperones can then read to determine exactly where the folding process went wrong and how to fix it.
“This is the first time that we’ve been able to see where UGGT puts sugars on proteins made in human cells for quality control,” says Guay. “We now have a platform for extending our understanding of how sugar tags can send proteins for further quality control steps and our work suggests that UGGT is a promising avenue for targeted drug therapy research.”
“What’s so exciting about this research,” says Lila Gierasch, distinguished professor of biochemistry and molecular biology at UMass Amherst and one of the paper’s co-authors, “is the discovery that glycans act as a code for protein folding in the ER. The discovery of the role that UGGT plays opens the door to future advancement in understanding and eventually treating the hundreds of diseases that result from misfolded proteins.”

Ketamine — an anesthetic also known for its illicit use as a recreational drug — has undergone a thorough reputational rehabilitation in recent years as the medical establishment has begun to recognize its wide-ranging therapeutic effects. The drug is increasingly used for a range of medical purposes, including as a painkiller alternative to opioids, and as a therapy for treatment-resistant depression.
In a new study published in the journal Cell Reports, Columbia biologists and biomedical engineers mapped ketamine’s effects on the brains of mice, and found that repeated use over extended periods of time leads to widespread structural changes in the brain’s dopamine system. The findings bolster the case for developing ketamine therapies that target specific areas of the brain, rather than administering doses that wash the entire brain in ketamine.
“Instead of bathing the entire brain in ketamine, as most therapies now do, our whole-brain mapping data indicates that a safer approach would be to target specific parts of the brain with it, so as to minimize unintended effects on other dopamine regions of the brain,” Raju Tomer, the senior author of the paper said.
The study found that repeated ketamine exposure leads to a decrease in dopamine neurons in regions of the midbrain that are linked to regulating mood, as well as an increase in dopamine neurons in the hypothalamus, which regulates the body’s basic functions like metabolism and homeostasis. The former finding, that ketamine decreases dopamine in the midbrain, may indicate why long-term abuse of ketamine could cause users to exhibit similar symptoms to people with schizophrenia, a mood disorder. The latter finding, that ketamine increases dopamine in the parts of the brain that regulate metabolism, on the other hand, may help explain why it shows promise in treating eating disorders.
The researchers’ highly-detailed data also enabled them to track how ketamine affects dopamine networks across the brain. They found that ketamine reduced the density of dopamine axons, or nerve fibers, in the areas of the brain responsible for our hearing and vision, while increasing dopamine axons in the brain’s cognitive centers. These intriguing findings may help explain the dissociative behavioral effects observed in individuals exposed to ketamine.
“The restructuring of the brain’s dopamine system that we see after repeated ketamine use may be linked to cognitive behavioral changes over time,” Malika Datta, a co-author of the paper said.
Most studies of ketamine’s effects on the brain to-date have looked at the effects of acute exposure — how one dose affects the brain in the immediate term. For this study, researchers examined repeated daily exposure over the course of up to ten days. Statistically significant alterations to the brain’s dopamine makeup were only measurably detectable after ten days of daily ketamine use. The researchers assessed the effects of repeated exposure to the drug at two doses, one dose analogous to the dose used to model depression treatment in mice, and another closer to the dose that induces anesthesia. The drug’s effects on dopamine system were visible at both doses.

“The study is charting a new technological frontier in how to conduct high-resolution studies of the entire brain,” said Yannan Chen, a co-author of the paper. It is the first successful attempt to map changes induced by chronic ketamine exposure at what is known as “sub-cellular resolution,” in other words, down to the level of seeing ketamine’s effects on parts of individual cells.
Most sub-cellular studies of ketamine’s effects conducted to-date have been hypothesis-driven investigations of one area of the brain that researchers have targeted because they believed that it might play an important role in how the brain metabolizes the drug. This study is the first sub-cellular study to examine the entire brain without first forming such a hypothesis.
Bradley Miller, a Columbia psychiatrist and neuroscientist who focuses on depression, said: “Ketamine rapidly resolves depression in many patients with treatment resistant depression, and it is being investigated for longer term use to prevent the relapse of depression. This study reveals how ketamine rewires the brain with repeated use. This is an essential step for developing targeted treatments that effectively treat depression without some of the unwanted side effects of ketamine.”
The research was supported by the National Institutes of Health (NIH) and the National Institute of Mental Health (NIMH). The paper’s lead authors are Malika Datta and Yannan Chen, who completed their research in Raju Tomer’s lab at Columbia. Datta is now a postdoctoral fellow at Yale.
“This study gives us a deeper brain-wide perspective of how ketamine functions that we hope will contribute to improved uses of this highly promising drug in various clinical settings as well as help minimize its recreational abuse. More broadly, the study demonstrates that the same type of neurons located in different brain regions can be affected differently by the same drug,” said Tomer.

Two new studies led by researchers from the UCLA Jonsson Comprehensive Cancer Center give insight into how cells use energy to influence the way prostate tumors survive and grow — advancements that can help explain why some prostate cancers become resistant to hormone therapy, the most commonly used treatment for men with advanced stages of the disease.
Hormone therapy, also known as antiandrogen therapy, plays a crucial role in temporarily halting the growth of prostate cancer cells. Over time, however, the majority of patients eventually see their cancer return and progress, underscoring the pressing need for continued advancements to enhance clinical outcomes.
“Identifying metabolic alterations and understanding patterns in cancer cells could be a critical component to developing new cancer treatments,” said Andrew Goldstein, associate professor of molecular, cell and developmental biology and urology at the David Geffen School of Medicine at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center. “New technological advances are giving us insight into actually how these tumors are breaking down their nutrients — known as cancer metabolism — to help them grow. And we might be able to harness or exploit that biology to make tumors more treatable.”
Metabolic insights reveal treatment sensitivity and resistance pathways
In the first study, published today in Nature Cell Biology, the team of investigators identified a specific process in prostate cells that helps determine how they evolve from one type of cell to another, which plays a crucial role in determining a response to treatment.
There are two types of cells in the prostate: basal and luminal cells. Whether cancer initially starts in a basal cell or a luminal cell, it almost always takes on the properties of luminal cells as the cancer grows. But over time, and in response to treatment, some tumors become less luminal. When a tumor is very luminal, it is more treatable using hormone therapy. And when it’s less luminal, it’s less treatable and more resistant, noted Goldstein, who is the senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.
While studying this process, researchers saw that when basal cells transform into luminal cells, the way they process a molecule called pyruvate changes. These changes in metabolism can influence the “genetic instructions” within the cells that determine how they develop and respond to treatment.

The team discovered that blocking a specific part of cell metabolism, called the mitochondrial pyruvate carrier, and adding a substance called lactate can change the cell behavior. These changes could potentially affect the success of treatments for prostate cancer, especially those targeting the androgen receptor, a key player in prostate cancer growth.
Additionally, altering how cells use a substance called lactate can cause significant changes in how the DNA is organized in the cells, affecting which genes are turned on or off.
“The study highlights the importance of considering how altering cell metabolism could impact prostate cancer and its response to treatment,” said first author of the study Jenna Giafaglione, a graduate student in UCLA’s Molecular Biology Interdepartmental Program and member of the Goldstein lab as well as the lab of Paul Boutros, director of cancer data science at the UCLA Jonsson Comprehensive Cancer Center. “If we know that certain aspects of metabolism are promoting a resistant phenotype, then we can go after new targets in those resistant tumors.”
MYC protein identified as key regulator
The second study, published in the journal Cell Reports, sheds new light into how prostate cancer cells react when the androgen receptor pathway is blocked, which is a common approach in treating advanced prostate cancer.
To understand what happens to the cell’s energy production and usage in response to this blocking, Goldstein and his team looked at how the cancer cells change the way they produce energy. They found that cells start out depending on a type of energy inside the mitochondria, pinpointing certain molecules and processes within the cell that control these changes.

One important protein in this process, called MYC, was found to be the critical regulator of the behavior. Specifically, they saw that if MYC activity decreases as a consequence of the therapy, then these cells seem to become very reliant on their mitochondria to survive. If MYC does not go down, then the cells are much more resilient and resistant to therapy, and not reliant on their mitochondria. Boosting MYC activity reversed the changes in energy production, making the cancer cells less sensitive to certain inhibitors.
“This study teaches us about treatment response and also suggests that if we could find the right combination of therapies, for example, to use hormone therapy initially, and then to use some kind of secondary therapy that influences the mitochondrial behavior, we might be able to reduce disease progression and recurrence,” Goldstein said.
Taken together, the new studies demonstrate a need to further study the link between metabolism and treatment resistance or treatment response. Understanding and controlling these changes could potentially help develop better treatments for prostate cancer.
Funding: The study appearing in Nature Cell Biology is supported in part by grants from National Institutes of Health, the UCLA Prostate Cancer Specialized Programs of Research Excellence (SPORE), The American Cancer Society, the U.S. Department of Defense and the Hutton Family Foundation.
Other UCLA authors include: Preston Crowell, Amelie Delcourt, Takao Hashimoto, Sung Min Ha, Aishwarya Atmakuri, Nicholas Nunley, Rachel Dang, Mao Tian, Johnny Diaz, Marie Payne, Neil Lin and Paul Boutros.
Funding: The study appearing in Cell Reports is supported in part by grants from National Institutes of Health, the UCLA Prostate Cancer Specialized Programs of Research Excellence (SPORE) and the Doris Duke Charitable Foundation.
Other UCLA authors include: Preston Crowell, Jenna Giafaglione, Anthony Jones, Nicholas Nunley, Takao Hashimoto, Amelie Delcourt, Anton Petcherski, Raag Agrawal, Matthew Bernard, Johnny Diaz, Kylie Heering, Rong Rong Huang, Nedas Matulionis, Huihui Ye, Heather Christofk, Matthew Rettig, Robert Reiter, Paul Boutros, Orian Shirihai and Ajit Divakaruni.

A study supported by the National Institutes of Health suggests that the response of immune system cells inside the protective covering surrounding the brain may contribute to the cognitive decline that can occur in a person with chronic high blood pressure. This finding, published in Nature Neuroscience, may shed light on new ways to counteract the effects of high blood pressure on cognition. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), a part of NIH.
“The role of immune signaling in cognitive decline is critically important to understand,” said Roderick Corriveau, Ph.D., program director, NINDS. “These findings offer insight into how signaling from the immune system could contribute to symptoms of cognitive decline that ultimately result in dementia diagnoses.”
Hypertension affects more than 1 billion people worldwide and can lead to a decline in cognitive function including when a stroke occurs, but also even when a person with high blood pressure does not have a stroke. However, efforts to control cognitive loss in people who do not experience a stroke with treatments that lower blood pressure have shown mixed results. The findings of this mouse study suggest that immune cells around and within the brain become abnormally activated under conditions that mimic a common form of hypertension, and this activation leads to impaired brain function.
Using a mouse model of high blood pressure, the researchers led by Costantino Iadecola, M.D., director and chair of the Feil Family Brain and Mind Research Institute, New York City, found abnormally increased levels of interleukin-17 (IL-17), a chemical normally released in the body to activate the immune system, in the cerebral spinal fluid and the brain. Previously, Dr. Iadecola’s team showed that a high salt diet increased IL-17 in the gut, which was followed by cognitive impairment. These new findings add to that story by showing that IL-17 is acting within the brain itself. It’s also notable that these experiments use a different mouse model, called the DOCA salt model, that more closely mimics a common form of hypertension in people.
“This is currently the most realistic model of hypertension that we have,” said Dr. Iadecola. “The DOCA mouse simulates low-renin hypertension, which is a common type of hypertension in people, particularly among Black Americans.”
Further work showed that, once in the brain, IL-17 turned on immune cells responsible for activating inflammation and fighting off infections, known as macrophages. A series of experiments confirmed that these macrophages are important for the observed decline in cognition, as both mice in which the receptor for IL-17 was deleted in brain macrophages and those that had their brain macrophages depleted showed no effects of high blood pressure on cognitive function despite having other symptoms of hypertension.
Researchers still sought the source of the IL-17 acting on the brain macrophages. Based on their previous work, the researchers’ initial hypothesis was that the gut releases IL-17, which then travels to the brain through the blood stream. Once there, it sets off a reaction that damages the ability of brain blood vessels to respond appropriately to increased brain activity. However, blocking the brain blood vessels’ ability to respond to IL-17 only partially rescued cognitive impairment, suggesting that there was another source of IL-17 acting on the brain.

One clue came from other recent studies suggesting that one layer of the protective covering of the brain, known as dura mater, contains immune T cells that can both secrete IL-17 and can affect the behavior of mice. Using special mice where cells light up fluorescent green when they make IL-17, the researchers confirmed that hypertension increases IL-17 in the dura mater which is then released into the tissue. Normally, barriers exist within the protective covering of the brain, called the meninges, to prevent unwanted spillage into the brain. However, this barrier appeared to be disrupted in the mice with experimentally induced hypertension, and this disruption allowed IL-17 to enter the cerebral spinal fluid.
Two additional experiments helped to confirm this hypothesis. First, a drug was used to prevent T cell movement from the lymph nodes into the meninges. Second, an antibody was used to block the activity of T cells in the meninges. In both cases, cognitive function was restored in the mice with hypertension, suggesting that targeting overactive T cells could be a new treatment approach worth exploring.
“Together, our data suggest two different effects are caused by hypertension,” said Dr. Iadecola. “One is IL-17 acting on blood vessels, but this appears to be relatively minor. A more prominent, central effect is caused by cells in the meninges releasing IL-17 that directly affects immune cells in the brain. It is these immune cells, activated by signaling from the meninges, that ultimately affect the brain in a way that causes cognitive impairment.”
Dr. Iadecola and his team are now looking to connect the dots between the activation of immune cells in the meninges and decreased cognitive function. Previous work by the group suggested a connection between a high salt diet which suppressed the production of the chemical nitric oxide in brain vessels that in turn led to buildup of tau, a toxic protein that forms clumps in neurons affected by Alzheimer’s disease. The present findings also show suppression of nitric oxide production within brain vessels, and whether this also leads to an increase in tau production is currently under investigation.

Researchers from the group of Jop Kind developed a new technique called MAbID. This allows them to simultaneously study different mechanisms of gene regulation, which plays a major role in development and disease. MAbID offers new insights into how these mechanisms work together or against each other. The results were published in Nature Methods on the 4th of December.
DNA is the most important carrier of genetic information. Each cell contains approximately two meters of DNA. To ensure that all this genetic material fits into the small cell nucleus, it must be tightly packed. The DNA is therefore wrapped around a special type of protein, a histone. The packages of DNA and histones are called chromatin.
Reading DNA
Chromatin not only ensures that all the DNA fits into the cell, it also determines which parts of the genetic material can be read by the cell. For example, a piece of DNA that is tightly wrapped around the histone is more difficult to read than a piece of DNA that is packed more loosely. Ultimately, the way in which chromatin is folded determines which parts of the genetic material are expressed and which parts are not. This pattern of gene expression differs per cell type. Different genes are active in a skin cell than in a liver cell, for example.
Changes in chromatin
The activity of genes is not always the same: a different pattern of genes may be active in one moment compared to another. That is because the structure of chromatin can change. For instance, changes can occur in the histones, which are called histone modifications. Certain proteins can also bind to the chromatin. Both processes influence the readability of the DNA and therefore the gene expression.
New technique
In recent years, various technologies have been developed to investigate the mechanisms of gene regulation. However, there was still a technique missing to allow researchers to simultaneously look at multiple mechanisms in one cell. The group of Jop Kind therefore designed a new technique: MAbID. With MAbID, researchers can simultaneously study multiple types of histone modifications and the proteins that bind to chromatin.

Working together
“With our new technique, we can see how the different mechanisms of gene expression are connected, for example how they work together or against each other. And the great thing is that we no longer need separate experiments for this, we can study everything at once in each individual cell. That makes the research much more efficient,” Silke Lochs, one of the researchers on the project, explains.
Applications
The technology can be widely applied. Robin van der Weide, another researcher on the project, says: “MAbID can help us answer fundamental scientific questions, for example about how gene regulation works during the development of humans or animals. But we can also use it for research into the development of diseases that can be caused by abnormalities in gene regulation, such as cancer.” The versatile new technology can therefore in the future provide important insights into both health and disease.

An international team of researchers has elucidated the process by which the major flavonoids naringenin, apigenin, and genistein are metabolized in the body. These findings are fundamental in elucidating the correlation between the metabolism of flavonoids in the body and their potential health benefits.
In a world where plant-based lifestyles are on the rise, the power of foods such as broccoli, celery, and tofu, which are rich in flavonoids, is becoming clearer. Flavonoids are phenolic compounds produced by plants that are essential for plant development and defense and have long been said to have therapeutic and preventive effects against cancer and heart disease. However, the exact process of how our bodies metabolize flavonoids remains unclear.
An international team of researchers led by visiting researcher Tsutomu Shimada and Professor Shigeo Takenaka of the Graduate School of Human Life and Ecology at Osaka Metropolitan University, has shed light on the mechanism of three major flavonoids — naringenin, apigenin and genistein — and the processes by which the body metabolizes them. Molecular docking analyses revealed that human enzymes modify flavonoids in a similar way to how plants modify flavonoids.
“The results of this research are fundamental in elucidating the correlation between the metabolism of flavonoids in the body and their potential health benefits,” explained Professor Takenaka.

People with chronic problems after falls and car crashes scored better on cognition tests after getting a brain implant, a new study found.Traumatic brain injuries have left more than five million Americans permanently disabled. They have trouble focusing on even simple tasks and often have to quit jobs or drop out of school.A study published on Monday has offered them a glimpse of hope. Five people with moderate to severe brain injuries had electrodes implanted in their heads. As the electrodes stimulated their brains, their performance on cognitive tests improved.If the results hold up in larger clinical trials, the implants could become the first effective therapy for chronic brain injuries, the researchers said.“This is the first evidence that you can move the dial for this problem,” said Dr. Nicholas Schiff, a neurologist at Weill Cornell Medicine in New York who led the study.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? 

Published1 day agoShareclose panelShare pageCopy linkAbout sharingImage source, Julia’s House By Sophie ParkerBBC News, WiltshireParents of a seven-year-old with a rare disease have said they are aware that this Christmas is “probably going to be the last one” with her.Hayley and Dave Clarke’s daughter Addy has a rare type of Batten Disease, also known as childhood dementia.The family, from Swindon, are being supported by children’s hospice Julia’s House in Devizes.Mrs Clarke said the illness – which affects only about 30 in the UK – “felt worse than the worst-case scenario”.She said the family “don’t know what’s around the corner”.”We don’t know what next month will hold, what next year will hold,” she said.”So we are just trying to live and make the most of what’s in our lap at this point.”Image source, Julia’s HouseThey have been telling their story as part of the Christmas appeal for the hospice charity, which Mrs Clarke said had been there for the family “since almost the beginning”.She said: “They have walked through a journey with us where we have been losing things with Addy. They’ve been there as Addy has stopped walking by herself, stopped eating.”‘It steals her skills’Mr Clarke said he can still remember “the initial shock” of hearing his daughter’s diagnosis in the hospital.”I remember going back home and I couldn’t look at her, because within those words everything changed,” he said.They found out that Addy had Batten disease when she was four years old, after she began to have seizures.  Mrs Clarke added: “The disease steals every skill the children have ever learned.”In effect, her brain is shrinking from the body’s ineffectiveness of being able to get rid of cell waste.”I remember my husband dissolving into tears and saying, ‘We’re going to have to bury our daughter.'” Image source, Julia’s HouseThe hospice allows Addy’s parents to have some respite, and also helps her older brother Samuel.”When you feel so worn thin from caring round-the-clock for your seriously-ill child, just to have a few hours to sleep or have time as a couple is such a blessing,” Mrs Clarke said. Explaining that Addy “loves” Christmas, Mrs Clarke added: “I think looking back, we know we will have done all that we can to make her happy and enjoy what she can when she can.” Follow BBC West on Facebook, X and Instagram. Send your story ideas to: bristol@bbc.co.ukMore on this story’This disease is one of the worst in the world’Published18 July 2022Girl with rare disease trials new eye treatmentPublished13 January 2022Balloon dog auction raises over £165k for charityPublished20 SeptemberChildren’s hospice appeals for donationsPublished16 November 2022Related Internet LinksJulia’s HouseBatten Disease Family AssociationThe BBC is not responsible for the content of external sites.

Jennifer Livovich started a nonprofit to give socks to the homeless population in Boulder, Colo. She lost it, and more, in a legal and policy dispute.On the last Thursday of August, Jennifer Livovich spent the morning simmering beans and cheese sauce in her Boulder, Colo., apartment, preparing nachos. Then friends helped her load a truck with the food, along with donations she had secured — socks, toothbrushes, cellphones — to distribute at a downtown park where dozens of chronically homeless people congregate.“Hopefully, no drama,” she said as the truck pulled away.Ms. Livovich has become a central figure in Boulder’s efforts to help the homeless. In 2020, she created a nonprofit, Feet Forward, to serve several hundred people whom the county estimates lack permanent shelter. And she regularly consults with, and is consulted by, policymakers, housing officials and the Boulder County district attorney. In late November she wrote an op-ed in a local paper on homelessness and substance use. To these conversations, she brings an intimate expertise: For five years, from 2012 to 2017, she lived on the streets of Boulder, often inebriated, until a brush with frostbite scared her into treatment.“She struck a chord in Boulder that I’ve not ever seen before,” said Benita Duran, a former Boulder assistant city manager.In 2021, the American Civil Liberties Union asked Ms. Livovich and Feet Forward to join as plaintiffs in a lawsuit that would force the city to reform its homeless policies. She was told that the lawsuit was “going to change homeless lives,” she recalled. “So of course I joined.”Lawsuits like this one are increasingly common around the country, as cities grapple with stubbornly chronic homeless populations and a vexing legal and moral question: Can a person be given a ticket for sleeping in a public area? Or, as the A.C.L.U. contends, does such a policy constitute “cruel and unusual punishment” when there are not enough shelter beds to accommodate everyone in need?The issue in Boulder became further fraught in May, when Ms. Livovich told the A.C.L.U. that she was withdrawing from the lawsuit. In an interview, she said that she had signed on as a plaintiff without fully understanding the case being made — and that she now feels that the A.C.L.U. and its supporters ultimately do not understand the people that they are trying to help.Ms. Livovich argued that many people who gather and often sleep around Boulder’s downtown park represent a particular subset of “the homeless.” For them, she said, the primary problem is substance abuse; cheap, potent drugs are so readily available that the “housing first” policy oversimplifies the issue. Treatment should be the first priority and, while Ms. Livovich does not favor ticketing people sleeping outside, she said that some people might need to be removed from the park for their safety, and that of the public.“I’m not anti-housing first,” she said. “I’m not anti-housing.” But in a world of constrained resources, she added, the spending priorities need to be shifted to put greater emphasis on treatment. “There is a growing subset struggling with addiction, and I have a hard time just giving them an apartment,” she said. “That’s not going to solve their problems.”“They need treatment,” Ms. Livovich said. “Every dollar not spent on treatment is a dollar wasted.”The A.C.L.U., she added, “is looking at this through the lens of what is constitutional and not what is happening on the street.”Volunteers packed supplies for a pop-up lunch for homeless people who congregate in Central Park in Boulder.Stephen Speranza for The New York TimesTim Macdonald, the legal director for the A.C.L.U. of Colorado, countered that the lawsuit sought to combat what he called the “criminalization” of sleeping in public spaces without an alternative. Treatment was important, too, he said, and housing and treatment were not mutually exclusive. He declined to comment on what the A.C.L.U. said to Ms. Livovich when she joined the lawsuit, citing attorney-client privilege.“Our focus is to protect the constitutional rights of the plaintiffs we still represent in this case, and continue our efforts to end the criminalization of people who are unhoused in Boulder,” Mr. Macdonald said.He added that Ms. Livovich was important initially at the outset but her decision to withdraw doesn’t end the claims of other plaintiffs. Among them is Feet Forward, the nonprofit that Ms. Livovich founded. After she announced her withdrawal from the suit, she asked her board of directors to do the same. But it declined and the nonprofit stayed on as a plaintiff, and Ms. Livovich resigned from her own organization.“They hijacked my nonprofit for this lawsuit,” she said of the A.C.L.U. and its allies on the Feet Forward board. “I was played.”‘This is my park’At the park, Ms. Livovich, 51, and her team set tables under a large tree and began distributing the tortilla chips, cheese, jalapeños and other fixings.Wearing a T-shirt bearing the words “Be Kind,” she jovially greeted friends she knew from her street days as she handed out supplies to the hundred or so people waiting in line. A 54-year-old woman who gave her name as Julie clutched new socks and a muffin as she described how she had just been released from the hospital after being treated for pneumonia. An argument among several men rose in volume from somewhere nearby.In its lawsuit, the A.C.L.U. contends that “homelessness in the region is generally the result of economic conditions,” and that Boulder must first provide sufficient housing before enacting “cover bans” and issuing citations for sleeping in public spaces under blankets and other forms of cover. It characterizes the ticketing as “cruel and unusual punishment.”Boulder has countered that its police department has discretion over people sleeping in public places. In several early judgments, a district judge agreed with the city that a tent ban does not violate the state constitution but said legal arguments could continue on the question of whether people could be cited for sleeping with a blanket or other covering. A trial date is set for August.“There is no sobriety in the park,” Ms. Livovich said, looking around. Many of the people who gather there are desperately addicted, trying to stave off withdrawal, and sometimes violent and psychotic. Ms. Livovich said that the A.C.L.U. misunderstood this subset of homeless people. In Boulder County, one-half of 1 percent of the population is homeless but accounts for 10 percent of felonies in 2018-2019, according to the county district attorney.Volunteers served food in Central Park. Stephen Speranza for The New York TimesMs. Livovich has argued for streamlined services, supervised treatment when necessary and even detaining people who present a risk to themselves or others. She said the lawsuit did not prioritize the well-being of people who were at risk of dying everyday. “Nobody has constitutional rights when they’re dead,” she said.Mr. Macdonald, of the A.C.L.U., noted that some of the plaintiffs in the lawsuit had been cited for sleeping outside and that their cases “had nothing to do with drug use or illegal behavior.”The city does not keep a daily total of its homeless population, with most data collected at the county level. In January, Boulder County reported 839 people who lacked permanent shelter; around one-half stayed in a shelter and one-quarter were in transitional housing, leaving 243 people outside. People avoid shelters for many reasons, including fear of violence or constrained freedom. Drugs play a role, too, according to a city analysis: “Either the person has self-medicated into a state in which they cannot make a reasoned decision about sheltering, or they do not want to shelter because they cannot actively use the substance while staying at the shelter.”Kurt Firnhaber, head of Housing and Human Services for the city, said he endorsed “housing first” but that housing alone did not solve the problem for some people grappling with drug addiction. “Many individuals struggle to get through the night,” he said. And shelters were not always a refuge. One night this summer, Mr. Firnhaber said, a man at a local shelter “took a chair and started breaking all the glass in the building.”At the park, as Ms. Livovich’s team was cleaning up, an argument that had been escalating between two men suddenly exploded when the older of the two — who was tall, with a long white beard, and wielded a six-inch knife — began chasing the other.Ms. Livovich quickly learned the cause: There had been a fentanyl overdose in the park the night before, and the older man was chasing the dealer he thought was responsible. The police arrived and dispelled the tension. Later, Ms. Livovich said she was disappointed but not surprised by the older man’s attempt to defend the park from a perceived threat. “When I lived out here,” she said, “I used to say, ‘This is my park.’”‘Privilege’ and desperationMs. Livovitch’s organization, Feet Forward, offers services such as distributing harm reduction supplies or obtaining a shuttle bus to provide mobile outreach services.Stephen Speranza for The New York TimesMs. Livovich grew up in Hammond, Ind., her father a financial executive and mother an administrator in a law school. She described her childhood as “privileged.” She attended Indiana University briefly but dropped out.She married at 35, and the relationship was abusive. “Drinking was our common denominator,” Ms. Livovich said. She left the marriage at age 38, landing in South Bend, Ind., where “my drinking got crazy,” she said. In 2012, she came to Boulder.Her life centered on feeding her alcohol addiction. “It ruled my every move,” she said. She often woke behind King Soopers, a supermarket, and then pooled her cash with other habitual drinkers and designated someone to go inside and make the purchase. “All day, every day,” she said.People who knew her then described her as charismatic and sometimes ornery. “There are two sides of Jen — there’s sober Jen and drunk Jen,” said Brentt Van Wagner, 39, who was homeless for two dozen years until recently. When intoxicated, Ms. Livovich was “angry,” he said. “She puts her foot down a lot. Commanding — we’re going to do this, and we’re going to do it this way.” He added, “She’s a good person. She’s got a good heart.”From 2014 to 2016, Ms. Livovich received 51 citations, spent 266 nights in jail and was “hauled to detox 72 times,” she said. Some detentions “saved my life,” she said, because she stopped drinking for a few days.In December 2016, after a scare from frostbite, she entered sober transitional living, spent 18 months in recovery and enrolled at Colorado State University, where she earned a bachelor’s degree in human services. She was placed into housing in Boulder through a state voucher program. In October 2018, she started collecting socks to give to the homeless.In late 2020 that effort grew into Feet Forward, whose mission expanded to provide food and other staples. It coordinated with Boulder County to provide clean needles and other harm reduction supplies, soliciting items from donors and obtaining a shuttle bus to provide mobile outreach services.“She has a wealth of knowledge of working with people in trenches around the homeless,” said Michael Dougherty, the Boulder County district attorney, who said he has had multiple conversations with Ms. Livovich over the years.Her manner could be direct. “She’s good at calling everybody out in the room who thinks they know better,” said Molly East, executive director of Focused Reentry, a nonprofit that helps people transition from incarceration to society. “Her lived experience is fundamental to solving things.”A familiar storyMs. Livovich is working with a new nonprofit, Street Scape, that she hopes will give her a platform to continue helping Boulder’s homeless population.Stephen Speranza for The New York TimesLast spring, after Ms. Livovich withdrew from the lawsuit, she asked the board of Feet Forward to do the same. When they declined, she asked the board members to resign so that she could replace them. Only one — Ms. Duran, the former assistant city manager — did so.“Jen kept raising the issue and saying, ‘This isn’t right. I don’t want to be involved,’” Ms. Duran said. In the end, Ms. Livovich herself resigned, to follow her own “moral compass,” she said.Darren O’Connor, a board member, sent an email to Feet Forward volunteers. “The board was saddened to receive this resignation,” he wrote, adding, “It was important for Feet Forward to remain as a named plaintiff, as deciding to withdraw would require dismissal of the lawsuit.” Later, Mr. O’Connor said, the board learned that the lawsuit could have proceeded even if the nonprofit had dropped out.In August, when Ms. Livovich marshaled supplies to give to the homeless, she did so under the aegis of a new nonprofit, Street Scape, that she hoped would give her and her team a platform to continue helping.Ten days later, Ms. Livovich started drinking. Over the next week, her drinking was intermittent but consistent. She sat in a recliner in her apartment sipping 100-proof peppermint schnapps from the bottle or a tumbler, her laptop and cigarettes nearby.This was not her first relapse, she said, but she had been largely sober for four years until the troubles started over the lawsuit. “I was so devastated,” she said. After resigning from Feet Forward, she relapsed badly, went into rehab and got sober again, briefly.“The one thing that I had is gone,” she said, her voice slurring, eyes heavy. She had developed a mission and organization, and felt it had been taken from her. “I don’t have a place,” she said.Friends, including local officials, checked in to remind her that she played a vital role in the community. With their support, Ms. Livovich found her way into a detox program and then started intensive work through Alcoholics Anonymous, aiming to attend 30 meetings in 30 days. Soon she was sober and “fighting for my life,” she said in a text. “Root for me.”While she was in detox, she overheard soon-to-be-released substance users on a phone in the public area desperately calling around to find placement in long-term clinics but coming up empty. She worried for them. “The moments for recovery are fleeting,” she said. Some people may lose motivation. “And where are they going?” she said. “They’re going back to the park.”As the weeks went by, Ms. Livovich struggled to find a Medicaid-supported therapist and a clinician to prescribe drugs for depression and anxiety, and those that might help reduce her alcohol cravings. She said there were not enough treatment options and she couldn’t find help. She made it 64 days sober, and then she relapsed again just before Thanksgiving. A few days after the holiday, she fell in her apartment, hit her head and cut the inside of her mouth, leading to an emergency room visit. Friends got her back into detox. One of them, a physician, pulled some strings and got her an appointment with a therapist and a clinician during the first week of December.“Look at how difficult it has been for me to get treatment, and I’m relatively well connected,” Ms. Livovich said. “Imagine what it looks like for somebody who knows nobody but other guys that are getting high in the park.”

University of Queensland-led research shows being overweight can impair the body’s antibody response to SARS-CoV-2 infection but not to the protection offered by vaccination.
Research lead, School of Chemistry and Molecular Biosciences PhD candidate Marcus Tong, said the finding built on the team’s existing research on how COVID-19 affects people who are overweight.
“We’ve previously shown that being overweight — not just being obese — increases the severity of SARS-CoV-2,” Mr Tong said.
“But this work shows that being overweight creates an impaired antibody response to SARS-CoV-2 infection but not to vaccination.”
The research team collected blood samples from people who had recovered from COVID-19 and not been reinfected during the study period, approximately 3 months and 13 months post-infection.
“At 3 months post-infection, an elevated BMI was associated with reduced antibody levels,” Mr Tong said.
“And at 13 months post-infection, an elevated BMI was associated with both reduced antibody activity and a reduced percentage of the relevant B cells, a type of cell that helps build these COVID-fighting antibodies.”
In contrast, an elevated BMI had no effect on the antibody response to COVID-19 vaccination at approximately 6 months after the second vaccine was administered.

Associate Professor Kirsty Short said the results should help shape health policy moving forward.
“If infection is associated with an increased risk of severe disease and an impaired immune response for the overweight, this group has a potentially increased risk of reinfection,” Dr Short said.
“It makes it more important than ever for this group to ensure they’re vaccinated.”
Dr Short said from a public health perspective, this data draws into question policies around boosters and lockdowns.
“We’d suggest that more personalised recommendations are needed for overweight people, both for ongoing COVID-19 management and future pandemics,” she said.
“Finally, the data provides an added impetus to improve SARS-CoV-2 vaccination in low-income countries, where there’s a high percentage of people who are overweight and are dependent on infection-induced immunity.”
The research is published in Clinical & Translational Immunology.