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Indiana University School of Medicine researchers are studying how the reduction of a gene variant found in the brain’s immune cells could diminish the risk of late-onset Alzheimer’s disease.
The research team, led by Adrian Oblak, PhD, assistant professor of radiology and imaging sciences, and Peter Bor-Chian Lin, a PhD candidate in the Medical Neuroscience Graduate Program at Stark Neurosciences Research Institute, recently published their findings in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
They focused their investigation on INPP5D, a microglia-specific gene that has been shown to increase the risk for developing late-onset Alzheimer’s disease. Microglia are the brain’s immune cells and there are multiple microglial genes associated with neurodegeneration.
Oblak said the team’s previous data revealed that elevated levels of INPP5D in Alzheimer’s disease lab models resulted in increased plaque deposition. Knowing this, they aimed to understand how reducing expression of INPP5D might regulate disease pathogenesis.
Using models in the lab, the researchers reduced the expression of the gene by at least 50 percent — called haplodeficiency — rather than completely knocking out the expression of the gene to mimic the treatment of pharmacological inhibitors targeting INPP5D as therapeutic strategies.
“INPP5D deficiency increases amyloid uptake and plaque engagement in microglia,” Oblak said. “Furthermore, inhibiting the gene regulates microglial functions and mitigates amyloid pathology that are likely mediated by TREM2-SYK signaling pathway activation.”
The gene deficiency also led to the preservation of cognitive function in the lab models. By reducing the expression of the gene in the brain, it created a less neurotoxic environment and improved the movement of microglia — which act as the first line of defense against viruses, toxic materials and damaged neurons — to clear amyloid deposits and plaques.
“These findings suggest that mitigating the function of INPP5D can result in a protective response by diminishing disease risk and mitigating the effect of amyloid beta induced pathogenesis,” Lin said.
The research team is actively working with the IU School of Medicine-Purdue University TaRget Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT-AD) Drug Discovery Center to develop therapies to reduce INPP5D function in Alzheimer’s disease.
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Study findings out today in JAMA Network Open show an important step forward in treating the psychological injuries of war.
Researchers report that treatment for combat-related post-traumatic stress disorder (PTSD), which affects hundreds of thousands of U.S. military personnel and veterans, can be both fast and effective for a majority of patients. Their study showed clinically significant reductions in PTSD symptoms in more than 60 percent of patients and long-term remission of the diagnosis in more than 50 percent after three weeks of outpatient Prolonged Exposure therapy. Study participants similarly showed significant improvements in related disability and daily functioning.
Results were comparable whether patients received traditional Prolonged Exposure, also called PE, condensed into three weeks of daily treatment or an intensive outpatient format including several enhancements to address specific challenges of PTSD in war fighters.
The research team, led by Alan Peterson, PhD, of The University of Texas Health Science Center at San Antonio (UT Health San Antonio), conducted the randomized clinical trial with 234 military personnel and veterans recruited from four locations in South and Central Texas. The effort was part of the work of the Consortium to Alleviate PTSD (CAP), a national network jointly funded by the U.S. Departments of Defense and Veterans Affairs.
Dr. Peterson, professor of psychiatry and behavioral sciences at UT Health San Antonio and director of the CAP and the STRONG STAR Consortium, said the findings advance the group’s previous research and significantly improve upon earlier outcomes.
Improving outcomes for our war fighters
“We’re excited to see a more than 10-point increase in PTSD remission rates compared to a previous PE study we conducted, when we initiated the first ever clinical trials evaluating PTSD treatments in active-duty military populations,” said Dr. Peterson.

That first study tested the standard PE protocol, with 10 sessions of 90 minutes each over the course of eight weeks, as well as a massed format, with daily 90-minute sessions over two weeks. The two delivery formats proved equally effective in reducing symptoms and leading to a loss of diagnosis, with remission rates under 50 percent initially after treatment, and treatment gains maintained by about 40 percent of patients six months later. The massed format had much lower dropout rates.
“Those initial results were encouraging, indicating that PE is effective for combat-related PTSD,” said Dr. Peterson. “But with much lower success rates than in civilians treated with this therapy, we wanted to make and test treatment adaptations potentially to address unique aspects of combat-related PTSD and improve outcomes,” he said. That is what the current study did.
Design and rationale of the current study
Prolonged Exposure includes patients’ repeated retelling of their trauma stories along with homework assignments to engage in activities patients otherwise avoid because they trigger traumatic memories or anxious feelings. The goal is to help patients process thoughts about their trauma, calm the anxiety the memories provoke, and regain control of their lives.
It was thought that, in the original study — particularly with the massed format — patients may not have had adequate time to complete homework assignments and may also have faced a number of distractions. So, for both arms of the current study, patients took leave from work or other daily responsibilities to devote themselves full-time to treatment and recovery.

Also with the current study, treatment time in both arms was expanded from two weeks to three, with the consideration that combat-related PTSD is more difficult to treat, and patients may need additional time to process traumatic memories.
The comparison arm, called Massed-PE, had these treatment delivery changes only. The other arm, called Intensive Outpatient or IOP-PE, had several additional enhancements that researchers hypothesized would improve treatment outcomes with combat-related PTSD.
Dr. Peterson explained one example. “Oftentimes, a civilian trauma involves a one-time traumatic event, such as an accident, or a repeated trauma of a certain type, such as abuse,” he said. “In the course of one or more combat deployments, service members may experience hundreds of traumatic events involving different types of traumas. They also may have experienced other types of trauma outside the combat environment. And so we wanted to adapt the traditional PE protocol, in which a patient focuses only on one primary trauma during treatment, and allow patients in this study to work with therapists on their three top traumas.”
He said the treatment involved starting with the least distressing of those three traumas to gain confidence in the therapy, then working up to the most distressing trauma. Some of the other modifications included team-based treatment, with more than one clinician supporting a patient’s care; clinic-based completion of homework assignments to decrease avoidance; brief therapist feedback sessions during the day for added support and increased opportunities for processing; involvement of a family member or friend during educational sessions to help improve social support; and post-treatment booster sessions to help maintain treatment gains.
Findings, implications and next steps
Outcomes differed from researchers’ expectations in that both arms showed similar levels of reductions in PTSD symptoms and related disability, as well as similar increases in PTSD remission rates and improved psychosocial functioning over time. With some measures, Massed-PE led to greater improvements initially that decreased by the six-month follow-up. IOP-PE patients were more likely to maintain their improvements six months after treatment.
Since long-term outcomes did not differ significantly, researchers say the additional investment of resources needed for the IOP-PE format may not be warranted, but the overall study findings are highly positive.
“With about two thirds of participants reporting clinically meaningful symptom improvement and more than half losing their PTSD diagnosis, this study provides important new evidence that combat-related PTSD can be effectively treated — in as little as three weeks,” said Dr. Peterson.
He and his colleagues stated that, while condensed treatments may not be feasible for everyone, “results show that compressed formats adapted to the military context resulted in significant, meaningful and lasting improvements in PTSD, disability and functional impairments for most participants.”
They say this makes condensed treatments an important option for U.S. service members and veterans after two decades of military operations in Iraq and Afghanistan. These treatments also could gain attention now as the war in Ukraine has raised international concerns about the risk of PTSD in military personnel and civilians.
Moving forward, the study team notes that their findings show room for continued improvement in treating combat-related PTSD. They add that the compressed treatment formats evaluated in this study are well suited for the evaluation of new, alternative modes of therapy combining cognitive-behavioral treatments with medications and medical devices. “We have those types of studies already underway,” said Dr. Peterson.
Collaboration on this important study was extensive, involving study team members from The University of Texas Health Science Center at San Antonio, South Texas Veterans Health Care System, Central Texas Veterans Health Care System, Brooke Army Medical Center at JBSA-Fort Sam Houston, C.R. Darnall Army Medical Center at Fort Hood, University of Pennsylvania, Stanford University, Duke University, Boston University, the VA’s National Center for PTSD, and VA Health Care Systems in Boston, Mass.; Durham, N.C.; and Menlo Park, Calif.

Scientists at St. Jude Children’s Research Hospital are reporting the most comprehensive study to date describing the variations in drug response across different genetic subtypes of acute lymphoblastic leukemia (ALL). The findings provide a blueprint for precision medicine to further individualize therapy. The study was published today in Nature Medicine.
ALL, a cancer of lymphocytes (a type of white blood cells), is the most common childhood cancer. About 98% of children with ALL go into remission within weeks after starting treatment, and about 90% of those children will eventually be cured. Modern treatment for ALL is risk-adapted, meaning chemotherapy is tailored based on clinical features, leukemia genomics and the degree of minimal residual disease (MRD), which is the presence of microscopic levels of cancer cells that remain after initial treatment.
Pharmacogenomics is the study of how genetic attributes affect drug response. St. Jude scientists have now comprehensively studied the pharmacogenomics of ALL by examining how the cancer cells respond to different therapeutics in the context of their cancer genomics. The results, from more than 800 patients, revealed wide variability across ALL, as well as distinct patterns of drug sensitivity by subtype.
“Compared to traditional cancer genomics research, our pharmacogenomics work starts with defining the drug response phenotype of each patient, after which we look into genomics to search for the biological basis for the inter-patient variability in leukemia drug sensitivity,” said corresponding author Jun J. Yang, Ph.D., St. Jude Department of Pharmacy and Pharmaceutical Sciences. “This approach sheds light on the therapeutic implications of specific genomic alterations, which may help clinicians alter care through a better understanding of how and why patients respond to treatment.”
“This work has yielded a wealth of new insights into the effectiveness of different medications used to treat childhood leukemia,” said William Evans, PharmD, an emeritus faculty member and former St. Jude president and CEO, who co-led the study with Yang. “This work is the product of decades of collaborative research at St. Jude and across the pediatric cancer community. St. Jude may be the only place that can deploy technologies to generate discoveries at this scale across such a large number of children with cancer.”
The researchers found that ALL subtypes with the most favorable prognosis are closely tied to sensitivity to the chemotherapeutic drugs asparaginase and glucocorticoids. Surprisingly, some subtypes are similar in their genomics but have different patterns of drug sensitivities. The team also found that patients could be divided into distinct groups based on their drug sensitivity profiles which was associated with prognosis even after accounting for known risk factors. This highlights the importance of understanding these groups, ALL pharmacotypes, for survival outcomes.

ALL from a functional perspective
The researchers studied children with newly-diagnosed ALL, spanning different St. Jude flagship Total Therapy ALL clinical trials. The trials cover a period of over 20 years, generating a large and unique cohort of patient data. The scientists determined the sensitivity of leukemia cells to 18 different chemotherapy drugs in patients representing 23 molecular subtypes defined by leukemia genomics.
The findings add a functional understanding to previous studies that identified high-risk or favorable subtypes. For example, ETV6-RUNX1 ALL has a favorable prognosis while BCR-ABL1-like ALL has a poor prognosis. These pharmacogenomics findings provided insight into why individuals with those subtypes had certain types of prognoses. Another potential application of these data is to discover biological pathways underlying drug sensitivity, which could pave the way for novel therapeutic development. For example, pharmacogenomics work by the Yang lab previously revealed that LCK activation underlies sensitivity to the drug dasatinib in T-ALL, making it an important target in some leukemias and spurring the development of several ongoing clinical trials to test the concept.
For this study, the researchers analyzed hundreds of thousands of individual data-points. The work thus provides an important resource for the scientific community.
“We hope our data will lead to more discoveries and new targets to drive a new generation of ALL trials in the near future,” said first-author Shawn Lee, M.B.B.S., formerly of St. Jude and now of Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital Singapore.

Results that matter for patients everywhere
“ALL is actually a very heterogenous disease — there are a lot of differences between genomic subtypes, such as presenting features and prognosis,” Lee said. “Now, we have shown how drug sensitivity also varies between subtypes.”
The researchers would like to expand the findings with added population diversity. Such efforts to capture a more comprehensive picture of pediatric ALL pharmacogenomics around the globe would bring a biologically informed approach to future treatments.
“This work is a big step in the right direction to individualize ALL therapy to spare children the side effects of drugs that will not work against their cancer, as well as to steer them to the novel therapies against which their cancer will likely respond,” Yang said. “It is functional precision medicine, it’s not just about the genetics and the targets but also about using the right drugs for the right patients.”
Authors and funding
The study’s other authors are Gary Rosner, Sidney Kimmel Comprehensive Cancer Center; and Wenjian Yang, Yoshihiro Gocho, August John, Lauren Rowland, Brandon Smart, Hannah Williams, Dylan Maxwell, Jeremy Hunt, Wentao Yang, Kristine Crews, Kathryn Roberts, Sima Jeha, Cheng Cheng, Seth Karol, Mary Relling, Hiroto Inaba, Charles Mullighan and Ching-Hon Pui of St. Jude.
The study was supported by grants from the National Institutes of Health (GM115279, GM141947, CA26487, CA264610, CA021765), a Singapore NMRC Research Training Fellowship and ALSAC, the fundraising and awareness organization of St. Jude.

National Institutes of Health researchers have published an assessment of 13 studies that took a genotype-first approach to patient care. This approach contrasts with the typical phenotype-first approach to clinical research, which starts with clinical findings. A genotype-first approach to patient care involves selecting patients with specific genomic variants and then studying their traits and symptoms; this finding uncovered new relationships between genes and clinical conditions, broadened the traits and symptoms associated with known disorders, and offered insights into newly described disorders. The study was published in the American Journal of Human Genetics.
“We demonstrated that genotype-first research can work, especially for identifying people with rare disorders who otherwise might not have been brought to clinical attention,” says Caralynn Wilczewski, Ph.D., a genetic counselor at the National Human Genome Research Institute’s (NHGRI) Reverse Phenotyping Core and first author of the paper.
Typically, to treat genetic conditions, researchers first identify patients who are experiencing symptoms, then they look for variants in the patients’ genomes that might explain those findings. However, this can lead to bias because the researchers are studying clinical findings based on their understanding of the disorder. The phenotype-first approach limits researchers from understanding the full spectrum of symptoms of the disorders and the associated genomic variants.
“Genomics has the potential to change reactive medicine into preventative medicine,” said Leslie Biesecker, M.D., NIH distinguished investigator, director of NHGRI’s Center for Precision Health Research and a senior author of the article. “Studying how taking a genotype-first approach to research can help us learn how to model predictive and precision medicine in the future.”
The study documents three types of discoveries from a genotype-first approach.
First, the researchers found that this approach helped discover new relationships between genomic variants and specific clinical traits. For example, one NIH study found that having more than two copies of the TPSAB1 gene was associated with symptoms related to the gastrointestinal tract, connective tissues, and the nervous system.

Second, this approach helped researchers find novel symptoms related to a disorder that clinicians previously missed because the patient did not have the typical symptoms. NHGRI researchers identified a person with a genomic variant associated with a known metabolic disorder. Further testing found that the individual had high levels of certain chemicals in their body associated with the disorder, despite having only minor symptoms.
Third, this approach allowed researchers to determine the function of specific genomic variants, which has the potential to help clinicians understand newly described disorders. For example, in one study, NHGRI researchers and their collaborators found that a genomic variant was associated with immune dysfunction at the molecular level in blood cells.
The 13 studies that implemented a genotype-first approach used genomic data from NHGRI’s Reverse Phenotyping Core in the Center for Precision Health Research. The core aggregates genomic data from programs such as ClinSeq(R) and the National Institute of Allergy and Infectious Disease (NIAID) Centralized Sequencing Protocol, which together allowed analyses to be performed on more than 16,000 research participants who have undergone genome or exome sequencing.
Exome and genome sequencing data from participants who consented to broad genomic data sharing and recontact for future research studies are currently available to NIH intramural researchers through the Reverse Phenotyping Core Genomic Data Browser to identify genomic variants of interest for their own research.
“Importantly, we provide a framework for other institutions to build research programs that allow for genotype-first studies. With more programs taking this approach, we can better study the predictive potential of genomic medicine,” said Clesson Turner, M.D., director of NHGRI’s Reverse Phenotyping Core and a senior author of the article.
The framework includes broad genomic data sharing with the ability to recontact participants explicitly stated during the informed consent process. NHGRI researchers recommend institutions aiming to establish genotype-first centers create strategic plans, especially for deciding what genomic findings will be returned, which may involve genetic counseling services. Importantly, according to the study, researchers must actively communicate with study participants to build informed and trusting long-term relationships.
“In the future, as more researchers adopt this approach, we hope to identify more people who may be helped by the availability of their genome sequence, especially as more diverse populations join genome-sequencing studies,” says Dr. Wilczewski.

A new method of donor-lung distribution is projected to decrease the number of candidate deaths who are on the waitlist for lung transplant, according to a study by Cleveland Clinic and the U.S. Scientific Registry of Transplant Recipients (SRTR) published in The American Journal of Transplantation.
Under the current system, donor lungs are distributed to candidates waiting for lung transplant using the Lung Allocation Score. However, in early 2023, the LAS will be replaced by a new distribution system called the Composite Allocation Score.
Maryam Valapour, M.D., Director of Lung Transplant Outcomes at Cleveland Clinic, is the primary author of the study. Dr. Valapour also serves as the Senior Investigator for Lung Transplantation for the Scientific Registry of Transplant Recipients, the organization responsible for analyzing U.S. transplant data.
The Lung Allocation Score system measures donor and recipient compatibility, geographical restrictions and prioritizes calculated survival benefit from transplant. It first aligns compatibility for candidates within a 250-mile radius, sometimes resulting in an inefficient distribution of organs based on geographical restriction. Under this current system, sicker patients who live just outside the 250-mile radius may lose out on a life-saving transplant because of where they live.
The new Composite Allocation Score system was developed to improve equity in organ allocation by eliminating geographical boundaries and prioritizing the candidate’s medical needs. This system is expected to set a precedent for the Organ Procurement and Transplantation Network and United Network for Organ Sharing (UNOS) for all organs, with lungs being the first organ allocation system to undergo this change.
“The importance of removing the geographical barrier can’t be overstated here,” said Dr. Valapour. “The Composite Allocation Score system’s goal of making access to lung transplant more equitable for all candidates in the United States will help reduce waitlist mortality and we hope will even improve post-transplant survival over time.”
To understand the potential effects on lung transplant candidates waiting for organs, the research team tested six alternative scenarios over 10 simulations using data from individuals on the lung transplant waiting list from Jan. 1, 2018, through Dec. 31, 2019. Depending on the scenario tested, waitlist deaths decreased by 36% to 47% in the Composite Allocation Score system as compared to the current system.
Across all simulated Composite Allocation Score scenarios, the system led to improved overall measures of equity compared with the current Lung Allocation Score system, including reduced waitlist deaths, and resulted in similar post-transplant survival.
“With more candidates added to the waitlist every day, access to available lungs is incredibly important,” says study co-author, Carli Lehr, M.D., a pulmonary and critical care physician at Cleveland Clinic. “The Composite Allocation Score system will help those on the waitlist overcome challenges associated with their proximity to potential donors.”
In 2022, there were over 3,000 candidates added to the lung transplant waitlist with over 2,600 lung transplants performed, according to UNOS. While the numbers of donors and transplants are improving, there is still a shortage of available organs in the United States. For more information on how to become an organ donor, visit UNOS.
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A Ludwig Cancer Research study has discovered that the immune system’s surveillance of cancer can itself induce metabolic adaptations in the cells of early-stage tumors that simultaneously promote their growth and equip them to suppress lethal immune responses.
Led by Ludwig Lausanne Associate Member Ping-Chih Ho and published in Cell Metabolism, the study details the precise mechanism by which this “immunometabolic editing” of emergent tumors occurs in mouse models of the skin cancer melanoma and identifies a novel biochemical signaling cascade and proteins that orchestrate its effects. Aside from illuminating a previously unknown dimension of tumor evolution, the findings hold significant promise for improving the efficacy of cancer immunotherapy.
“We have uncovered dozens of metabolic enzymes that contribute to immune evasion in melanoma tumors,” said Ho. “These enzymes, as well as some of the individual components of the signaling pathway we’ve identified, represent a rich trove of potential drug targets to undermine the defenses erected by immunometabolic editing. Such drugs could make tumors vulnerable to immune clearance and could also be used in combination with checkpoint blockade and other immunotherapies to overcome the resistance most cancers have to such treatments.”
The immune system’s surveillance of cancers is thought to contribute to malignancy by driving the evolution of cancer cells that can undermine the machinery of immune detection and attack. This theory of “immunoediting” — developed most notably by the former Scientific Director and CEO of the Ludwig Institute for Cancer Research, the late Lloyd Old, and Ludwig’s current Scientific Advisory Committee member Robert Schreiber — is now a fundamental principle of tumor immunology.
Researchers have also long known that the metabolic adaptations common to cancer cells — such as their avid consumption of the sugar glucose — undermine anti-tumor immune responses. What was unclear, however, was whether immune surveillance can also induce metabolic adaptations in cancer cells and whether those adaptations can additionally help them resist immune responses. This is what the current study has established, exposing a facet of tumor evolution that has been hypothesized, but has so far remained unproven.
Ho and his colleagues identify three key proteins that orchestrate this effect: IFNγ, STAT3 and c-Myc. An instrument of anti-cancer surveillance, IFNγ is secreted by T cells and other immune cells and known to block the growth of cancer cells. But the signaling it triggers, mediated by a protein named STAT1, also induces adaptations in cancer cells that help them evade T cell attack — the process known as immunoediting.
The researchers show in the current study that IFNγ additionally activates a distinct and little-explored signaling pathway mediated by a related protein named STAT3. This pathway alters the expression patterns of the cancer cell’s genome by inducing “epigenetic” changes that determine which genes are active. It also hyperactivates a master regulator of cellular metabolism known as c-Myc, which is overexpressed in many cancers.
The researchers show that genes activated by c-Myc don’t just shape cancer metabolism, they also compromise the infiltration of T cells into tumors and disable their attack on cancer cells. The signaling pathways mediated by STAT1 and STAT3, in fact, appear to synergize to confer on emergent tumors the critical ability to avoid immune clearance, driving the immunometabolic editing that helps power their evolution into full-blown malignancy.
“Previous studies have shown that the loss of STAT3 activity in cancer cells promotes immune infiltration and induces tumor regression,” said Ho. “Our findings here explain why and suggest that targeting STAT3 with a drug could restore sensitivity to IFNγ in cancer cells that have evolved beyond its inhibitory reach.”
The researchers also used CRISPR genome editing to screen 2,078 metabolic enzymes in the tumors of mice and identified 40 metabolic genes controlled by c-Myc that play an important role in helping cancer cells evade immune surveillance and attack. These enzymes too are prime candidates for drug targeting.
“Aside from its pharmacologic implications,” says Ho, “this study exposes a previously unappreciated dimension of immunoediting that will influence our understanding of the metabolic crosstalk between cancer cells and immune cells in the tumor microenvironment.”
In addition to his Ludwig position, Ping-Chih Ho is an associate professor at the University of Lausanne.

Life depends on the precise functioning of several proteins synthesized in cells by ribosomes. This diverse set of proteins, known as a proteome, is maintained by the robust translation elongation of amino acid sequences taking place in the ribosomes. The translation mechanisms which ensure that nascent chains of polypeptides — long chains of amino acids — are elongated without getting detached are conserved in all living organisms. However, the rates of elongation are not constant. Elongation is often interrupted by interactions between positively charged nascent polypeptides and negatively charged ribosomal RNA.
Studies have found that in prokaryotic Escherichia coli cells, the nascent peptide chains not only disrupt the elongation process but destabilize the ribosomes themselves. This type of premature termination of translation is called intrinsic ribosome destabilization (IRD). Evidence shows that IRD was mainly triggered by nascent peptides with N-terminals rich in aspartic and glutamic acid sequences. Since translation mechanisms are conserved, researchers began to wonder if a similar phenomenon could be seen in the cells of eukaryotic organisms, such as plants, fungi, and animals.
Recently, a team of researchers from Japan, led by Prof Hideki Taguchi from Tokyo Institute of Technology (Tokyo Tech), were successful in providing some answers to this question. In their recent study published in Nature Communications, the team using budding yeast cells and a reconstituted cell-free translation system to investigate the IRD phenomenon in eukaryotes. “Previous studies have explored the impact of aspartic acid and glutamic acid sequences on bacterial ribosomal translation. However, not much is about eukaryotic cells. So, we chose a eukaryotic organism like yeast to investigate the premature termination of translation and if there were any mechanisms present to counter IRD,” explains Prof. Taguchi, one of the corresponding authors of the study.
The team discovered that similar to bacteria, nascent peptide chains enriched in aspartic acid (D) or glutamic acid (E) in their N-terminal regions led to abortion of translation in the yeast cells by IRD. They also found that the accumulation of the peptidyl-tRNAs inhibited the cell growth in yeast lacking peptidyl-tRNA hydrolase, an essential cellular enzyme. “The peptidyl-tRNAs produced by IRD are cleaved by peptidyl-tRNA hydrolase, which recycles the peptidyl-tRNAs outside the ribosome complex. The accumulation of these abortive peptidyl-tRNAs is toxic, since yeast lacking the enzyme cannot grow when IRD-prone sequences are overexpressed,” Prof. Taguchi says.
The bioinformatics analysis carried out by the team, however, revealed a unique way yeast cells reduce the risk of IRD. They found that the proteomes had a biased amino acid distribution, where the translation elongation process disfavored the amino acid sequences with D/E runs in their N-terminal region.
This study provides novel insights into the elongation dynamics of eukaryotic cells and the counteracting mechanisms in place to reduce translation defects during protein synthesis. “Understanding the factors that affect overall amino acid usage in proteomes can help us improve the expression of recombinant proteins. This is essential for the production of useful proteins that can have clinical and industrial applications,” concludes Prof. Taguchi.
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Proven to protect against a wide array of diseases, exercise may be the most powerful anti-aging intervention known to science. However, while physical activity can improve health during aging, its beneficial effects inevitably decline. The cellular mechanisms underlying the relationship among exercise, fitness and aging remain poorly understood.
In a paper published in the Proceedings of the National Academy of Sciences, researchers at Joslin Diabetes Center investigated the role of one cellular mechanism in improving physical fitness by exercise training and identified one anti-aging intervention that delayed the declines that occur with aging in the model organism. Together, the scientists’ findings open the door to new strategies for promoting muscle function during aging.
“Exercise has been widely employed to improve quality of life and to protect against degenerative diseases, and in humans, a long-term exercise regimen reduces overall mortality,” said co-corresponding author T. Keith Blackwell, MD, PhD, a senior investigator and section head of Islet Cell and Regenerative Biology at Joslin. “Our data identify an essential mediator of exercise responsiveness and an entry point for interventions to maintain muscle function during aging.”
That essential mediator is the cycle of fragmentation and repair of the mitochondria, the specialized structures, or organelles, inside every cell responsible for producing energy. Mitochondrial function is critical to health, and disruption of mitochondrial dynamics the cycle of repairing dysfunctional mitochondria and restoring the connectivity among the energy-producing organelles — has been linked to the development and progression of chronic, age-related diseases, such as heart disease and type 2 diabetes.
“As we perceive that our muscles undergo a pattern of fatigue and restoration after an exercise session, they are undergoing this mitochondrial dynamic cycle,” said Blackwell, who is also acting section head of Immunobiology at Joslin. “In this process, muscles manage the aftermath of the metabolic demand of exercise and restore their functional capability.”
Blackwell and colleagues — including co-corresponding author Julio Cesar Batista Ferreira, PhD, Institute of Biomedical Sciences, University of Sao Paulo — investigated the role of mitochondrial dynamics during exercise in the model organism C. elegans, a simple, well-studied microscopic worm species frequently used in metabolic and aging research.

Recording wild type C. elegans worms as they swam or crawled, the investigators observed a typical age-related decline in physical fitness over the animals’ 15 days of adulthood. The scientists also showed a significant and progressive shift toward fragmented and/or disorganized mitochondria in the aging animals. For example, they observed in young worms on day 1 of adulthood, a single bout of exercise induced fatigue after one hour. The 60-minute session also caused an increase in mitochondrial fragmentation in the animals’ muscle cells, but a period of 24 hours was sufficient to restore both performance and mitochondrial function.
In older (day 5 and day 10) worms, the animals’ performance did not return to baseline within 24 hours. Likewise, the older animals’ mitochondria underwent a cycle of fragmentation and repair, but the network reorganization that occurred was reduced compared to that of the younger animals.
“We determined that a single exercise session induces a cycle of fatigue and physical fitness recovery that is paralleled by a cycle of the mitochondrial network rebuilding,” said first author Juliane Cruz Campos, a postdoctoral fellow at Joslin Diabetes Center. “Aging dampened the extent to which this occurred and induced a parallel decline in physical fitness. That suggested that mitochondrial dynamics might be important for maintaining physical fitness and possibly for physical fitness to be enhanced by a bout of exercise.”
In a second set of experiments, the scientists allowed wild type worms to swim for one hour per day for 10 consecutive days, starting at the onset of adulthood. The team found that — as in people — the long-term training program significantly improved the animals’ middle-aged fitness at day 10, and mitigated the impairment of mitochondrial dynamics typically seen during aging.
Finally, the researchers tested known, lifespan-extending interventions for their ability to improve exercise capacity during aging. Worms with increased AMPK — a molecule that is a key regulator of energy during exercise which also promotes remodeling of mitochondrial morphology and metabolism — exhibited improved physical fitness. They also demonstrated maintenance of, but not enhancement of, exercise performance during aging. Worms engineered to lack AMPK exhibited reduced physical fitness during aging as well as impairment of the recovery cycle. They also did not receive the age-delaying benefits of exercise over the course of the lifespan.
“An important goal of the aging field is to identify interventions that not only extend lifespan but also enhance health and quality of life,” said Blackwell, who is also a professor of genetics at Harvard Medical School. “In aging humans a decline in muscle function and exercise tolerance is a major concern that leads to substantial morbidity. Our data point towards potentially fruitful intervention points for forestalling this decline — most likely along with other aspects of aging. It will be of great interest to determine how mitochondrial network plasticity influences physical fitness along with longevity and aging-associated diseases in humans.”
Additional authors included Takafumi Ogawa of Joslin Diabetes Center; Luiz Henrique Marchesi Bozi (co-first author) and Edward Chouchani of Dana-Farber Cancer Institute; Barbara Krum, Luiz Roberto Grassmann Bechara, Nikolas Dresch Ferreira, Gabriel Santos Arini, Rudá Prestes Albuquerque of University of Sao Paulo; Annika Traa of McGill University; Alexander M. van der Bliek of David Geffen School of Medicine at University of California, Los Angeles; Afshin Beheshti of NASA Ames Research Center; and Jeremy M. Van Raamsdonk of Harvard Medical School.
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grants 2013/07937-8, 2015/22814-5, 2017/16694-2 and 2019/25049-9); Conselho Nacional de Pesquisa e Desenvolvimento — Brasil (CNPq) (grants 303281/2015-4 and 407306/2013-7); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior — Brasil (CAPES) Finance Code 001 and Instituto Nacional de Ciência e Tecnologia and Centro de Pesquisa e Desenvolvimento de Processos Redox em Biomedicina; National Institutes of Health (NIH) (grants R35 GM122610, R01 AG054215, DK123095, AG071966); the Joslin Diabetes Center (grants P30 DK036836, and R01 GM121756); FAPESP postdoctoral fellowships 2017/16540-5 and 2019/18444-9, and 2016/09611-0 and 2019/07221-9; the American Heart Association Career Development Award (2022/926512); the Claudia Adams Barr Program; the Lavine Family Fund; the Pew Charitable Trust. William B. Mair (Harvard T.H. Chan School of Public Health) and Malene Hansen (Sanford Burnham Prebys Medical Discovery Institute) provided some of the worm strains used in this study. Other strains were provided by the CGC, which is funded by the NIH (P40 OD010440).
Chouchani is a founder and equity holder in Matchpoint Therapeutics. The other authors declare no competing interests.

The two chains said they would begin the certification process under a new F.D.A. regulation that will allow retail pharmacies to dispense the prescription pills for the first time.Two major pharmacy chains will apply to sell abortion pills under a new Food and Drug Administration regulation that will allow the medication to be offered by retail pharmacies for the first time.The chains, CVS and Walgreens, said they planned to seek certification to sell the pill, mifepristone, the first pill used in the two-drug medication abortion regimen. Patients will still need a prescription from a certified health care provider, but the new federal action could significantly expand access to medication abortion because it allows any pharmacy that agrees to accept those prescriptions and abide by certain other criteria to dispense the pills in its stores and by mail order.The pharmacy chains did not provide details about when they expected to be able to offer the pills, in which states or whether they would offer them only in stores or via mail order, or both. They said they would comply with laws in states that ban or restrict abortion, currently about half of the states.“We plan to seek certification to dispense mifepristone where legally permissible,” Amy Thibaut, a spokeswoman for CVS, said.A spokesman for Walgreens, Fraser Engerman, said in statement: “We intend to become a certified pharmacy under the program. We are working through the registration, necessary training of our pharmacists, as well as evaluating our pharmacy network in terms of where we normally dispense products that have extra F.D.A. requirements and will dispense these consistent with federal and state laws.”Abortion pills, already used in more than half of pregnancy terminations in the United States, are becoming even more sought after in the aftermath of the Supreme Court decision last year overturning the federal right to abortion. With conservative states banning or sharply restricting abortion, the pills have increasingly become central to political and legal battles, and the decision to sell them could make the big chains another focus of the country’s divisive abortion debate.The steps for pharmacies to become certified to dispense mifepristone are not difficult, but they involve some administrative requirements that go beyond the process pharmacies use with most other medications, such as designating an employee to ensure compliance..css-1v2n82w{max-width:600px;width:calc(100% – 40px);margin-top:20px;margin-bottom:25px;height:auto;margin-left:auto;margin-right:auto;font-family:nyt-franklin;color:var(–color-content-secondary,#363636);}@media only screen and (max-width:480px){.css-1v2n82w{margin-left:20px;margin-right:20px;}}@media only screen and (min-width:1024px){.css-1v2n82w{width:600px;}}.css-161d8zr{width:40px;margin-bottom:18px;text-align:left;margin-left:0;color:var(–color-content-primary,#121212);border:1px solid var(–color-content-primary,#121212);}@media only screen and (max-width:480px){.css-161d8zr{width:30px;margin-bottom:15px;}}.css-tjtq43{line-height:25px;}@media only screen and (max-width:480px){.css-tjtq43{line-height:24px;}}.css-x1k33h{font-family:nyt-cheltenham;font-size:19px;font-weight:700;line-height:25px;}.css-1hvpcve{font-size:17px;font-weight:300;line-height:25px;}.css-1hvpcve em{font-style:italic;}.css-1hvpcve strong{font-weight:bold;}.css-1hvpcve a{font-weight:500;color:var(–color-content-secondary,#363636);}.css-1c013uz{margin-top:18px;margin-bottom:22px;}@media only screen and (max-width:480px){.css-1c013uz{font-size:14px;margin-top:15px;margin-bottom:20px;}}.css-1c013uz a{color:var(–color-signal-editorial,#326891);-webkit-text-decoration:underline;text-decoration:underline;font-weight:500;font-size:16px;}@media only screen and (max-width:480px){.css-1c013uz a{font-size:13px;}}.css-1c013uz a:hover{-webkit-text-decoration:none;text-decoration:none;}What we consider before using anonymous sources. Do the sources know the information? What’s their motivation for telling us? Have they proved reliable in the past? Can we corroborate the information? Even with these questions satisfied, The Times uses anonymous sources as a last resort. The reporter and at least one editor know the identity of the source.Learn more about our process.For chains like CVS and Walgreens, the most logistically intricate step might be the requirement that pharmacies keep confidential the names of the certified health providers who prescribe mifepristone to protect their privacy and safety.To fulfill that requirement, a chain like CVS would not be able to list a doctor’s name in a companywide database, for example, and would have to keep that information restricted to the store that fills that doctor’s prescriptions, according to an official with Danco Laboratories, one of the two makers of mifepristone, who spoke on the condition of anonymity because of the company’s concerns about threats from abortion opponents.Mifepristone, which blocks a hormone necessary for pregnancy development, is authorized by the F.D.A. to be taken in the first 10 weeks of pregnancy, although many clinics and telemedicine providers have begun offering it up to 12 or 13 weeks into pregnancy. This is a step they can legally take because most states allow physicians to use medical discretion to prescribe a drug for a particular “off label” use if there is scientific evidence that it is safe and effective for that use. The World Health Organization supports medication abortion through 12 weeks’ gestation, and studies suggest it is safe and effective during that time frame.The second drug in the regimen, misoprostol, has never been as tightly restricted as mifepristone and is used for many different medical conditions. It is easily obtained at pharmacies through a typical prescription process. Misoprostol, which causes contractions that expel pregnancy tissue, is taken 24 to 48 hours after mifepristone.Mifepristone is currently approved only for abortion. But it is also used in the treatment of some miscarriages, and there may be pressure for pharmacies to dispense it for that purpose as well. Recently, dozens of groups, including the American College of Obstetricians and Gynecologists and the American Medical Association, filed a citizen petition asking the F.D.A. to take action to make it easier for mifepristone to be used for miscarriages.

Collaborative research between University of Galway and Brunel University London has found that patients with severe and complicated obesity respond differently to a dietary weight loss programme based on their genes.
The GERONIMO project studied patients attending the obesity clinic at Galway University Hospital who were undergoing an intensive short-term programme of medically supervised dietary restriction in order to attempt to reverse some of the medical problems with severe obesity.
During the research scientists were able to analyse small variations in hundreds of genes that are known to be associated with obesity. By combining information from these measured gene variations together, a “genetic risk score” was calculated for six different obesity-related traits.
Professor Francis Finucane, senior lecturer in the School of Medicine at University of Galway and Consultant Endocrinologist at Galway University Hospitals who led the clinical study, said: “Mechanistic studies like these, which help us to understand why some people respond better than others to the same intervention, are really important in providing more personalised and effective treatments for people with obesity.
“We know that in general, heritability and ‘genetics’ play a huge role in influencing body weight and the risk of obesity-related complications like diabetes, but finding the genes that account for this risk has been a challenge.”
Professor Alex Blakemore, Professor in Human Genomics at Brunel University London, said: “No-one chooses their genes, so, as a society, we need to recognise that when it comes to maintaining a healthy weight, the challenge is greater for some people than for others. This study reveals just a small part of the picture of how our genes can help or hinder us in reaching our health goals.”
The GERONIMO project involved 93 patients who volunteered for the study. They were monitored while taking part in a meal replacement programme.
Their average body mass index at the start of the study was 52kgm-2, which means that they weighed more than twice their maximum ‘healthy weight’.
The participants lost an average of 16% of their body weight, or 21kg after 24 weeks.
The research found that that the “waist hip ratio” genetic risk score, which measures an individual’s genetic tendency to hold on to central or abdominal fat, was associated with less weight loss after the intervention.
Speaking about next stages in the research Professor Finucane said: “This work is exciting and important because it is the first Irish study to demonstrate a genetic effect on the response to a treatment for obesity.
“The genetic effects we found here were subtle, but we think it would be good to explore this further, in larger studies and with different obesity treatments, such as drug therapy or ‘metabolic surgery’.”
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Materials provided by National University of Ireland Galway. Note: Content may be edited for style and length.