Publisher Health

Unintentional weight loss is associated with an increase in the risk of a cancer diagnosis within the coming year, according to a study from Dana-Farber Cancer Institute.
“If you are losing weight and you aren’t trying to lose weight by making changes in your exercise routine or diet, people should see their doctor to consider possible causes,” says lead investigator Brian Wolpin, MD, MPH, Director of the Gastrointestinal Cancer Center at Dana-Farber and Director of the Hale Family Center for Pancreatic Cancer Research. “There are many conditions that can result in unexpected weight loss. Your doctor can determine if there is something that needs evaluation.”
The findings were published in the Journal of the American Medical Association on January 23, 2024.
Compared with participants who did not lose weight, recent weight loss was associated with significantly increased risk for several types of cancer, including upper gastrointestinal tract (including esophageal, stomach, liver, biliary tract, and pancreatic cancer), hematological (including non-Hodgkin lymphoma, multiple myeloma, and leukemia), colorectal, and lung cancers. However, recent weight loss wasn’t found to be associated with increased risk for other cancer types, such as breast cancer, genitourinary cancer, brain cancer, or melanoma.
“Unexpected weight loss can come from cancer or many other conditions,” says Wolpin. “Sometimes weight loss is due to more exercise or a healthier diet, and this can be beneficial to people’s health. However, when a patient experiences unintentional weight loss not due to healthier behaviors, seeing your primary care doctor is appropriate, so they can determine whether additional evaluation is necessary for other causes of weight loss, including cancer.”
The study assessed 157,474 participants in two large longitudinal studies: the Nurses’ Health Study, which enrolled nurses aged 30 to 55 starting in 1976, and the Health Professionals Follow-Up Study, which enrolled male health professionals aged 40 to 75 years starting in 1986. Participants were followed until 2016.
Weight was reported by participants every other year in a biennial questionnaire that also included questions about physical activity. The questionnaire requested responses about dietary changes every four years. This information enabled Wolpin and colleagues to assess each participant’s level of weight loss promoting behaviors. Weight loss promoting behaviors were classified into “high” for those making both dietary improvements and increases to physical activity, “medium” if they made only one change, and “low” if they made no changes to diet and exercise.

“We wanted to differentiate healthy weight loss from unhealthy weight loss,” says Qiaoli Wang, MD, PhD, a research fellow at Dana-Farber and the manuscript’s first author. “Healthy weight loss can come from dietary changes or increased exercise. But unhealthy weight loss that occurs unexpectedly can be due to an underlying cancer.”
Patients with advanced cancer often lose weight, but weight loss is often not thought to occur with early-stage disease. This study found that similar levels of weight loss occurred before diagnosis of both early and late-stage disease. This is important because unintentional weight loss could be a sign of a developing cancer that could help diagnose the cancer earlier when there’s a chance for more effective treatment.
The mechanisms by which cancer results in weight loss varies depending on the type of cancer. This study strengthens findings from past research that connected unexpected weight loss with an increased cancer risk. In previous research, weight data was collected by doctors from patients potentially seeking out care for an illness. In this study, weight data was collected prospectively and regularly for decades and was not dependent on doctor visits to identify weight changes. This study also considered all types of cancers. However, the two studies analyzed were focused on health professionals, which is not a group that is fully representative of the U.S. population.
Funding: The National Institutes of Health, the Swedish Research Council, the Project P Fund, the Broman Family Fund for Pancreatic Cancer, the Hale Family Center for Pancreatic Cancer Research, the Lustgarten Foundation Dedicated Laboratory Program, Stand Up To Cancer, the Pancreatic Cancer Action Network, the Noble Effort Fund, the Wexler Family Fund, the Promises for Purple, and the Bob Parsons Fund.

A team of international researchers, led by UC San Francisco, has completed the first large-scale study of posterior cortical atrophy, a baffling constellation of visuospatial symptoms that present as the first symptoms of Alzheimer’s disease. These symptoms occur in up to 10% of cases of Alzheimer’s disease.
The study includes data from more than 1,000 patients at 36 sites in 16 countries. It publishes in the Lancet Neurology on Jan. 22, 2024.
Posterior cortical atrophy (PCA) overwhelmingly predicts Alzheimer’s, the researchers found. Some 94% of the PCA patients had Alzheimer’s pathology and the remaining 6% had conditions like Lewy body disease and frontotemporal lobar degeneration. In contrast, other studies show that 70% of patients with memory loss have Alzheimer’s pathology.
Unlike memory issues, patients with PCA struggle with judging distances, distinguishing between moving and stationary objects and completing tasks like writing and retrieving a dropped item despite a normal eye exam, said co-first author Marianne Chapleau, Ph.D., of the UCSF Department of Neurology, the Memory and Aging Center and the Weill Institute for Neurosciences.
Most patients with PCA have normal cognition early on, but by the time of their first diagnostic visit, an average 3.8 years after symptom onset, mild or moderate dementia was apparent with deficits identified in memory, executive function, behavior, and speech and language, according to the researchers’ findings.
At the time of diagnosis, 61% demonstrated “constructional dyspraxia,” an inability to copy or construct basic diagrams or figures; 49% had “space perception deficit,” difficulties identifying the location of something they saw; and 48% had “simultanagnosia,” an inability to visually perceive more than one object at a time. Additionally, 47% faced new challenges with basic math calculations and 43% with reading.
We need better tools and training to identify patients
“We need more awareness of PCA so that it can be flagged by clinicians,” said Chapleau. “Most patients see their optometrist when they start experiencing visual symptoms and may be referred to an ophthalmologist who may also fail to recognize PCA,” she said. “We need better tools in clinical settings to identify these patients early on and get them treatment.”

The average age of symptom onset of PCA is 59, several years younger than that of typical Alzheimer’s. This is another reason why patients with PCA are less likely to be diagnosed, Chapleau added.
Early identification of PCA may have important implications for Alzheimer’s treatment, said co-first author Renaud La Joie, Ph.D., also of the UCSF Department of Neurology and the Memory and Aging Center. In the study, levels of amyloid and tau, identified in cerebrospinal fluid and imaging, as well as autopsy data, matched those found in typical Alzheimer’s cases. As a result, patients with PCA may be candidates for anti-amyloid therapies, like lecanemab (Leqembi), approved by the U.S Food and Drug Administration in January 2023, and anti-tau therapies, currently in clinical trials, both of which are believed to be more effective in the earliest phases of the disease, he said.
“Patients with PCA have more tau pathology in the posterior parts of the brain, involved in the processing of visuospatial information, compared to those with other presentations of Alzheimer’s. This might make them better suited to anti-tau therapies,” he said.
Patients have mostly been excluded from trials, since they are “usually aimed at patients with amnestic Alzheimer’s with low scores on memory tests,” La Joie added. “However, at UCSF we are considering treatments for patients with PCA and other non-amnestic variants.”
Better understanding of PCA is “crucial for advancing both patient care and for understanding the processes that drive Alzheimer’s disease,” said senior author Gil Rabinovici, M.D., director of the UCSF Alzheimer’s Disease Research Center. “It’s critical that doctors learn to recognize the syndrome so patients can receive the correct diagnosis, counseling and care.
“From a scientific point of view, we really need to understand why Alzheimer’s is specifically targeting visual rather than memory areas of the brain. Our study found that 60% of patients with PCA were women — better understanding of why they appear to be more susceptible is one important area of future research.”

A UC San Francisco-led study has for the first time identified genetic variants that predict whether patients will respond to treatment for preterm birth, a condition that affects one in 10 infants born in the United States.
The findings are critical because no medication is available in the U.S. to treat preterm birth. Last year, the Food and Drug Administration (FDA) pulled the only approved therapy to help prevent this condition, a synthetic form of progesterone sold under the brand name Makena, from the market, citing ineffectiveness.
The new research found that pregnant individuals with high levels of mutations in certain genes — specifically those associated with involuntary muscle contraction — were less likely to respond to the treatment. Screening for the mutations could allow doctors to target the medication to those most likely to benefit, the authors suggest.
“This study calls for a precision framework for future drug development,” said the study’s senior author, Jingjing Li, PhD, associate professor in UCSF’s Department of Neurology and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. “In addition to understanding drug effects based on population averages, we also need to take into account the drug response of each individual patient and ask why some respond and some don’t.”
The study, which was done in collaboration with Stanford University, appears Jan. 19, 2024, in the journal Science Advances.
New genes associated with preterm birth
Preterm birth, or babies born alive prior to 37 weeks of gestation, is the leading cause of infant mortality and affects some 15 million pregnancies worldwide each year. Preterm birth also leads to a range of long-term health consequences including breathing problems, neurological impairments such as cerebral palsy, developmental disabilities, visual and hearing impairments, heart disease and other chronic illnesses.

To conduct the study, researchers developed a machine-learning framework to analyze genomes of 43,568 patients that had spontaneous preterm births. The approach uncovered genes that had not previously been known to be associated with preterm birth.
They then examined mutations in the genes among those who had received the progesterone treatment Makena. The FDA had approved the drug in 2011 after a single clinical trial but took it off the market last spring after concluding the drug didn’t work.
The decision left doctors without an approved medication for preterm birth and frustrated those who had found it effective for a subset of their patients. This posed the question: Could there be a genetic reason why progesterone therapy worked for some, but not for others?
The researchers discovered that the patients in the group with low levels of mutations in the genes associated with muscle contractions were more likely to respond to Makena, but those with higher levels tended not to respond.
The finding indicates a personalized medicine approach that involves genetic screening could lead to successful results in patients without a high burden of those mutations.
“Progesterone therapy was the only treatment for recurrent preterm birth over the past decade, and its recent withdrawal by the FDA has left a void in the medication options available for preterm birth patients,” said the study’s first author, Cheng Wang, PhD, a postdoctoral scholar at UCSF.

“In previous clinical practice, we did see that many patients benefited from progesterone therapy,” Wang said. “We probably should reevaluate its efficacy, if we can identify those who respond positively to the treatment.”
The researchers included a cohort of African American patients in the study to determine whether the findings applied broadly across different races. Black women in the U.S. are almost twice as likely to give birth prematurely than white women.
They found the genetic burden did not vary by race. This suggests the high rate of preterm birth among Black mothers may be due primarily to environmental factors such as elevated stress hormones, health care biases and lack of prenatal care.
A new type of precision medicine
The researchers then went beyond that finding to identify new targets and potential therapies to treat preterm birth. They screened more than 4,000 compounds and homed in on 10 that were predicted to interact with the genes associated with preterm birth.
Many of these therapeutic compounds are already being used to treat cancer and other diseases, which means that these drugs could possibly be repurposed to help prevent preterm labor.
A top candidate is the small molecule RKI-1447, a drug that is currently being used to treat cancer, glaucoma and fatty liver disease. Additional study of the potential of these molecules in treating preterm birth is needed.

Previous research has established that childhood experience with abuse, neglect, and substance use in the home can worsen a person’s heart health throughout their life. New research, however, now shows that receiving warmth from a caregiver during childhood protects cardiovascular health later in life, according to a study led by NYU Grossman School of Medicine and The Ohio State University Wexler Medical Center.
The findings, published online January 23, 2024 in the journal Circulation: Cardiovascular Quality and Outcomes, are the first to frame adversity and protective factors across a large group when it comes to cardiovascular health over time, the researchers say. Given that cardiovascular disease (CVD) remains the leading cause of death in the United States, with Black adults more than twice as likely to die from CVD than White adults, the study cohort included individuals identifying as Black and White.
“We know that mitigating risk factors for cardiovascular disease must begin in childhood,” said Robin Ortiz, M.D., professor in the Departments of Pediatrics and Population Health at NYU Langone, and the study’s lead author and core faculty member at the Institute for Excellence in Health Equity. “At the same time, our findings show that adversity in early childhood does not equal destiny. While adverse childhood family environments were associated with lower odds of cardiovascular health in adulthood, our findings suggest that supportive and, importantly, stable caregiving may have a stronger influence on later heart health than early adversity.”
How the Study Was Conducted
The team of researchers analyzed a sample of more than 2000 enrollees in the CARDIA study, a long-term study of cardiovascular disease risk beginning in young adulthood which has been following more than 5,000 Black and White adults for over 35 years to help researchers understand which early life factors raise the risk of CVD later in life.
The investigators analyzed data from this group at baseline, at which time the cohort averaged 25 years of age, and data that followed up at seven and 20 year intervals. Using scales measuring adversity in childhood including child abuse and caregiver warmth, they found that each additional unit score of overall family environment adversity and then child abuse specifically, was associated with a 3.6 and 12.8 percent lower odds of ideal cardiovascular health (CVH), respectively, while each additional unit score of caregiver warmth, specifically, was associated with 11.7 percent higher odds of cardiovascular health. CVH score was rated according to a scale of seven health metrics defined by the American Heart Association, including diet, smoking, physical activity, weight, lipids, blood pressure and fasting glucose.
In what appeared perhaps counterintuitive to the research team, exposure to the greatest amount of caregiver warmth and greatest amount of child abuse, taken together, was associated with the lowest CVH scores. Meanwhile, exposure to the greatest amount of caregiver warmth and lowest amount of child abuse, taken together, was associated with the highest CVH scores. All findings remained consistent over 20 years of follow-up.

Exposure to caregiver warmth in childhood was associated with greatest CVH (highest scores) in adults. However, what was most unique about the findings, according to Ortiz, was that of all adults with high levels of child abuse exposure, those who also reported high levels of caregiver warmth exposure had lower CVH scores than those with high child abuse but low levels of caregiver warmth exposure. This, Ortiz interprets, suggests that while having a supportive caregiver is crucial to a life course of health, the stability and consistency of that support and warmth in childhood is just as important of a predictor of later life CVH.
According to Ortiz, individuals who have experienced both abuse and warmth in childhood might face the inability to predict the presence of support overall in their childhood environment. Individuals who are exposed to only or mostly caregiver warmth (and no, or limited abuse) are able to predict and ultimately depend on a sense of support, safety, and perhaps, physiological balance. The findings further suggest that an unpredictable or unstable relational environment might be associated with poor health later in life, while stable or predictable support in childhood may optimize physiology and behavior to result in greater CVH later in life.
When stratifying the results by income in adulthood, the findings were more nuanced. The investigators found that the relationship between childhood adversity and CVH only stood out among those who had higher socioeconomic levels in adulthood (greater than $35,000 annually). Adverse family environments were associated with lower CVH across income levels between $35,000 to $74,000 annually, as well as with income greater than $75,000 annually, but no significant relationship between CVH and annual income less than $25,000 or between $25,00 to $34,000.
Prior studies in the field have shown that once in adulthood, explained Ortiz, it may be more difficult for people facing economic challenges to attain high levels of CVH for those with and without childhood adversity as measured in this study. “However, for individuals in adulthood right now with higher incomes, we are able to see this relationship emerge showing how important those early environmental risk factors really are,” she said.
The hope, says Ortiz, is that this study offers insight into how supporting healthy, both supportive and stable, caregiving relationships in childhood can offer greater attainment of CVH at a population level. Future research will also focus more heavily on the complex relationship between CVH and economic hardship at different points of the life course.
“We have to address healthy caregiver relationships as well as address socioeconomic hardship,” said Ortiz. “We need policies and programs that support both caregivers and children in order to achieve greater health equity.”
Funding for the study was provided by the National Heart, Lung, and Blood Institute in collaboration with numerous institutions supporting The CARDIA Study, as well as funding in support of authors’ time including the Endocrine Society, the National Institute of Diabetes and Digestive and Kidney Diseases, the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program, and the National Institute on Aging.
In addition to Ortiz, another NYU Langone investigator involved in the study is Gbenga Ogedegbe, MD, MPH. Other researchers include senior author Joshua J. Joseph, MD, MPH, Songzhu Zhao, MS, and David Brock, PHD, Ohio University State College of Medicine; Kiarri N. Kershaw, PhD, MPH, Northwestern University; David Kline, PhD, Wake Forest University School of Medicine; Sara Jaffee, PhD, University of Pennsylvania; Sherita H. Golden, MD, MHS, Johns Hopkins University School of Medicine; Judith Carroll, PhD, and Teresa E. Seeman, PhD, David Geffen School of Medicine, University of California, Los Angeles.

People living with HIV need to take antiretroviral treatment for life to prevent the virus from multiplying in their body. But some people, known as “post-treatment controllers,” have been able to discontinue their treatment while maintaining an undetectable viral load for several years. Starting treatment early could promote long-term control of the virus if treatment is discontinued. Scientists from the Institut Pasteur, the CEA, Inserm, Université Paris Cité and Université Paris-Saclay, in collaboration with Institut Cochin[1] and with the support of MSD Avenir and ANRS Emerging Infectious Diseases, used an animal model to identify a window of opportunity for the introduction of treatment that promotes remission of HIV infection: it appears that starting treatment four weeks after infection promotes long-term control of the virus following the interruption of treatment after two years of antiretroviral therapy.
These results highlight how important it is for people with HIV to be diagnosed and begin treatment as early as possible.
The findings were published in the journal Nature Communications on January 11, 2024.
Research on the VISCONTI cohort, composed of 30 post-treatment controllers, has provided proof of concept of possible long-term remission for people living with HIV. These individuals received early treatment that was maintained for several years. When they subsequently interrupted their antiretroviral treatment, they were capable of controlling viremia for a period lasting more than 20 years in some cases. At the time (in 2013), the team leading the VISCONTI study suggested that starting treatment early could promote control of the virus, but this remained to be proven.
In this new study, the scientists used a primate model of SIV2 infection which allowed them to control all the parameters (sex, age, genetics, viral strain, etc.) that may have an impact on the development of immune responses and progression to disease. They compared groups that had received two years of treatment, starting either shortly after infection (in the acute phase) or several months after infection (in the chronic phase), or no treatment.
The reproducible results show that starting treatment within four weeks of infection (as was the case for most of the participants in the VISCONTI study) strongly promotes viral control after discontinuation of treatment. This protective effect is lost if treatment is started just five months later. “We show the link between early treatment and control of infection after treatment interruption, and our study indicates that there is a window of opportunity to promote remission of HIV infection,” comments Asier Sáez-Cirión, Head of the Institut Pasteur’s Viral Reservoirs and Immune Control Unit and co-last author of the study.
The scientists also demonstrated that early treatment promotes the development of an effective immune response against the virus. Although the antiviral CD8+ T immune cells developed in the first weeks after infection have very limited antiviral potential, the early introduction of long-term treatment promotes the development of memory CD8+ T cells, which have a stronger antiviral potential and are therefore capable of effectively controlling the viral rebound that occurs after treatment interruption. “We observed that early treatment maintained for two years optimizes the development of immune cells. They acquire an effective memory against the virus and can eliminate it naturally when viral rebound occurs after discontinuation of treatment,” explains Asier Sáez-Cirión.

These results confirm how important it is for people with HIV to be diagnosed and begin treatment as early as possible. “Starting treatment six months after infection, a delay that our study shows results in a loss of effectiveness, is already considered as a very short time frame compared with current clinical practice, with many people with HIV starting treatment years after infection because they are diagnosed too late,” notes Roger Le Grand, Director of IDMIT (Infectious Disease Models for Innovative Therapies) and co-last author of the study. “Early treatment has a twofold effect: individually, as early treatment prevents diversification of the virus in the body and preserves and optimizes immune responses against the virus; and collectively, as it prevents the possibility of the virus spreading to other people,” adds Asier Sáez-Cirión.
Finally, these results should guide the development of novel immunotherapies targeting the immune cells involved in the remission of HIV infection.
These are the initial results of the p-VISCONTI study, which began in 2015 in collaboration with the institutions cited above and received funding from MSD Avenir and the support of ANRS Emerging Infectious Diseases as part of the RHIVIERA consortium.
[1] Institut Cochin is a biomedical research center affiliated with Inserm, the CNRS and Université Paris Cité.
2 SIV: simian immunodeficiency virus only affects non-human primates. SIV infection of animals recapitulates the key features of human HIV infection.

Whileexposure to a single substance like DDT has been shown to create inherited disease susceptibility, a recent study in animals found exposure to multiple different toxicants across generations can amplify those health problems.
In the study, published in the journal Environmental Epigenetics, an initial generation of pregnant rats was exposed to a common fungicide, then their progeny to jet fuel and the following generation to DDT. When those rats were then bred out to a fifth unexposed generation, the incidence of obesity as well as kidney and prostate diseases in those animals were compounded, rising by as much as 70%.
Researchers also found that their epigenetics, molecular processes independent of DNA that influence gene expression, were also greatly altered.
“We looked at multiple-generation exposures because these types of things are going on routinely, and previous research has only looked at single exposures,” said Michael Skinner, a WSU biology professor and the study’s corresponding author. “We found that if multiple generations get different exposures, then eventually there’s an amplification or compounded effect on some diseases.”
The study did show that for other diseases, those associated with the ovaries and the testes, the incidence rose in the first generation of progeny but appeared to plateau with the additional generational exposures.
Skinner and his colleagues also conducted epigenetic analysis of each generation of the animals, finding that the toxicant exposures shifted their entire epigenetics dramatically. Along with changes to genes themselves, inherited epigenetics which influence gene expression, are considered to have a significant impact on evolution.
“When we made the comparisons with different generations, we did not find a lot of overlap in epigenetics. In other words, every time each generation had a new exposure, it appeared to reprogram the whole epigenome,” Skinner said.

While the study does not exactly mimic what may have happened to human generations, people in the US have potentially been exposed to these particular toxicants at different times. The authors note a likely sequential exposure over human generations might involve an exposure to DDT which was widely used in the 1950s, then plastics in the 1970s, followed by many modern herbicides still in use today.
The study provides evidence that multiple toxicant exposures of past human generations likely had a compounded impact on grandchildren and great-grandchildren. Knowing about these possible impacts can help people and doctors address potential diseases before they develop, Skinner said.
Researchers including Skinner’s lab at WSU have been working to identify epigenetic biomarkers for inherited health conditions in humans including for obesity, autism and pre-term birth.
“We need to know to what degree our past generations activities that have affected us,” Skinner said. “We cannot necessarily fix this problem, but it’s important to know that it happened so that we can try to better treat potential health problems through preventative medicine.”
This research received support from the John Templeton Foundation and the National Institutes of Health.

One of the things that makes developing effective treatments for Parkinson’s disease so challenging is its complexity. While some forms are caused by genetics, others have environmental factors, and patients can show a wide range of symptoms of varying severity. Diagnosis of Parkinson’s is also currently made very late, after the disease may have been in the brain for a decade or more.
In a paper published in The Lancet Neurology, a group of scientists argue that this complexity demands a new way of classifying the disease for research purposes, one based not on clinical diagnosis but biology. The authors have called their biological model “SynNeurGe.”
The “Syn” stands for alpha-synuclein, a protein that in most Parkinson’s patients causes abnormal deposits called Lewy bodies. Abnormalities in synuclein identify and probably cause degenerative changes in the brain that can impact movement, thinking, behaviour and mood.
“Neur” stands for neurodegeneration. This is the breakdown of the function of neurons in the brain. In doctor’s offices, specific neurons in the dopamine system are the way that Parkinson’s is diagnosed. In the SynNeurGe model, however, neurodegeneration in all areas of the brain are included in the classification.
The “Ge” stands for genetics. The role of genetics in Parkinson’s is complex. Mutations in many different genes have been found to predispose someone to the disease. The likelihood of developing Parkinson’s disease depends on the gene involved, the specific mutation within the gene and environmental exposures.
The authors argue that for research purposes, patients should be classified by the presence or absence of these three factors. This would allow the identification of Parkinson’s patients before symptoms appear, and aid the development of treatments tailored to patients’ unique biology. Right now, patients are diagnosed based on symptoms and signs, even though the disease may have been present in their brain for many years . By shifting classification criteria, researchers can identify disease earlier (even before people may experience symptoms), and target specific patient groups that have more in common with each other biologically, giving drug development a higher chance of success.
“Although this is still for research purposes, this is a major shift in thinking,” says Dr. Ron Postuma, a clinician-scientist at The Neuro (Montreal Neurological Institute-Hospital) of McGill University and one of the study’s authors. “If you think of it, it’s quite unusual that we’ve had to wait until Parkinson’s patients have important symptoms before we could make a diagnosis. We don’t wait for someone to feel pain from cancer before we diagnose it.Instead, we detect and diagnose it, hopefully before someone is aware of any symptoms. This research classification is a critical step towards bringing our thinking about Parkinson’s into the 21st century.”

Over the last 20 years, researchers in biology and medicine have created Boolean network models to simulate complex systems and find solutions, including new treatments for colorectal cancer.
“Boolean network models operate under the assumption that each gene in a regulatory network can have one of two states: on or off,” says Claus Kadelka, a systems biologist and associate professor of mathematics at Iowa State University.
Kadelka and undergraduate student researchers recently published a study that disentangles the common design principles in these mathematical models for gene regulatory networks. He says showing what features have evolved over millions of years can “guide the process of accurate model building” for mathematicians, computer scientists and synthetic biologists.
“Evolution has shaped the networks that control the decision-making of our cells in very specific, optimized ways. Synthetic biologists who try to engineer circuits that perform a particular function can learn from this evolution-inspired design,” says Kadelka.
Gene regulatory networks determine what happens and where it happens in an organism. For example, they prompt cells in your stomach lining — but not in your eyes — to produce hydrochloric acid, even though all the cells in your body contain the same DNA.
On a piece of paper, Kadelka draws a simple, hypothetical gene regulatory network. Gene A produces a protein that turns on gene B, which turns on gene C, which turns off gene A. This negative feedback loop is the same concept as an air conditioner that shuts off once a room reaches a certain temperature.
But gene regulatory networks can be large and complex. One of the Boolean models in the researchers’ dataset involves more than 300 genes. And along with negative feedback loops, gene regulatory networks may contain positive feedback loops and feed-forward loops, which reinforce or delay responses. Redundant genes that perform the same function are also common.

Among these and other design principles highlighted in the new paper, Kadelka says one of the most abundant is “canalization.” It refers to a hierarchy or importance ordering among genes in a network.
Accessible data, bolstered with undergraduate research
Kadelka emphasizes that the project would have been difficult to complete without the First-Year Mentor Program, which matches students in the Iowa State Honors Program with research opportunities across campus.
Undergraduate students helped Kadelka develop an algorithm to scan 30 million biomedical journal articles and filter those most likely to include Boolean biological network models. After reviewing 2,000 articles one by one, the researchers identified around 160 models with close to 7,000 regulated genes.
Addison Schmidt, now a senior in computer science, is one of the paper’s co-authors. When he worked on the project as a freshman in 2021, he created an online database for the project.
“A major benefit of the research is that it collects and standardizes Boolean gene regulatory networks from many sources and presents them, along with a set of analysis tools, through a centralized web interface. This expands the accessibility of the data, and the web interface makes the analysis tools useable without a programming background,” says Schmidt.

Kadelka says systems biologists have used the database for their research and expressed gratitude for the resource. He plans to maintain and update the website and investigate why evolution selects for certain design principles in gene regulatory networks.
As for Schmidt, he says working on the project as a freshman helped him expand his expertise with the Python programming language and become more comfortable applying his skills to research.
“This project also motivated me to pursue other research at Iowa State where I developed other tools and, coincidentally, another website to present them,” says Schmidt.
He adds that he appreciated Kadelka’s mentorship and hopes the First-Year Mentor Program will continue to foster opportunities for undergraduate research at Iowa State.

Published2 days agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Steve Duffy & Jenny ReesBBC NewsWhooping cough cases have risen rapidly in Wales in the first few weeks of 2024.There have already been 135 notified cases so far in January, compared with about 200 in the whole of 2023.Public Health Wales (PHW) expert Dr Chris Johnson said, from what GPs had been reporting, it appeared to show the start of a relatively large wave.He has urged all pregnant women and parents of babies and young children to ensure they are vaccinated. PHW said whooping cough has waves of increased infection every three to four years and notifications had grown sharply in the past few weeks. Dr Johnson, a consultant epidemiologist, said: “With rates suppressed during the lockdowns of the pandemic we are naturally seeing a resurgence this year.”How many cases are there?Of the 53 cases notified in the most recent week, 12 were in Pembrokeshire, eight in Flintshire and six in Rhondda Cynon Taf but there were cases also in 12 other council areas.Only Blaenau Gwent,, Merthyr Tydfil and Monmouthshire have not had any cases notified in the past six weeks.The last whooping cough peak was in the year before Covid – 2019 – and before that a big surge came in 2012, when notifications averaged 180 a week in the run-up to Christmas.Cases were four times higher in 2023, compared with the previous two years and this trend was echoed in England too.Dr Johnson, who heads PHW’s vaccine preventable disease programme, added: “Whooping cough is highly contagious and is spread by breathing in small droplets in the air from other people’s coughs and sneezes.”Q&A: Whooping coughWhy are measles cases rising and what is the MMR vaccine?Measles jab campaign targets unprotected millionsImage source, Getty ImagesWhat is whooping cough?Whooping cough is also known as pertussis and is a lung or breathing tube infection, which is contagious.It can present similarly to a cold initially but lead to coughing bouts, according to the NHS.The name comes from a “whoop” sound which some sufferers get, when they gasp for breath between coughs and coughing can last for several weeks. People are recommended to get rest and take plenty of fluids but may be prescribed antibiotics if in the infectious early stages.What has the vaccination take-up been like?This video can not be playedTo play this video you need to enable JavaScript in your browser.There has not been an infant death from whooping cough in Wales since vaccinations for pregnant women were introduced in 2013.The take-up for babies has reached 95% but there has been a very gradual drop-off over the decade.There has been a slightly more marked drop in recent years to about 70% of pregnant women being vaccinated.”It’s really important, that because we haven’t seen in Wales very, very serious or fatal cases for some time, that we don’t become complacent and we keep those levels of protection high,” said Dr Johnson.He added babies under six months old were at most risk. “It can be very serious and lead to pneumonia and permanent brain damage. Young babies with whooping cough are at risk of dying from the disease.”He said vaccine protection passes on to the unborn baby and protected it until the first routine immunisation at two months old.How can I get vaccinated against it?Routine vaccination is included in inoculations for babies and pre-school childrenAbout half of cases last year in Wales were in the under 19s but it can affect any agePHW has urged pregnant women and parents of babies and young children to take up a vaccine offer or contact their GP or health visitor if they think they have not had itWhat about other winter illnesses?Seasonal viruses like flu have been stable so far this winter, although patients testing positive with flu or Covid in hospital have increased a little since the start of December.Respiratory syncytial virus (RSV) saw a winter peak in November among children – with cases in the community at a high intensity levels and hospital admissions peaking too. But numbers have been declining back to low levels.The latest sample test for various viruses taken by hundreds of patients attending hospital each week showed about 8% were positive for flu and 12% had Covid.BBC WalesAll the vaccines we offer routinely to children especially – but also those we offer to adults such as Covid and flu, they’re there because these illnesses are seriousDr Chris JohnsonPublic Health Wales, consultant epidemiologist And what about measles?With measles, there were nine cases in Wales in 2023, and none in the previous two years – and an outbreak in Cardiff ended in November.PHW said although cases were low it was important children were protected from it.”It’s very easy to think of them as just like any other childhood illness,” said Dr Johnson. “They aren’t. Steps have been taken globally to eliminate measles, because it is such a dangerous and highly infectious disease. “All the vaccines we offer routinely to children especially – but also those we offer to adults such as Covid and flu, they’re there because these illnesses are serious, and can result in really unpleasant hospitalisation and death, but they’re preventable.” More on this storyQ&A: Whooping coughPublished7 July 2006Why are measles cases rising and what is the MMR vaccine?Published3 days agoRelated Internet LinksPublic Health Wales: Whooping coughThe BBC is not responsible for the content of external sites.

The genetic treatment targeted a particular kind of congenital deafness and will soon be tried in children who are younger.Aissam Dam, an 11-year-old boy, grew up in a world of profound silence. He was born deaf and had never heard anything. While living in a poor community in Morocco, he expressed himself with a sign language he invented and had no schooling.Last year, after moving to Spain, his family took him to a hearing specialist, who made a surprising suggestion: Aissam might be eligible for a clinical trial using gene therapy.On Oct. 4, Aissam was treated at the Children’s Hospital of Philadelphia, becoming the first person to get gene therapy in the United States for congenital deafness. The goal was to provide him with hearing, but the researchers had no idea if the treatment would work or, if it did, how much he would hear.The treatment was a success, introducing a child who had known nothing of sound to a new world.“There’s no sound I don’t like,” Aissam said, with the help of interpreters during an interview last week. “They’re all good.”While hundreds of millions of people in the world live with hearing loss that is defined as disabling, Aissam is among those whose deafness is congenital. His is an extremely rare form, caused by a mutation in a single gene, otoferlin. Otoferlin deafness affects about 200,000 people worldwide.The goal of the gene therapy is to replace the mutated otoferlin gene in patients’ ears with a functional gene.Although it will take years for doctors to sign up many more patients — and younger ones — to further test the therapy, researchers said that success for patients like Aissam could lead to gene therapies that target other forms of congenital deafness.It is a “groundbreaking” study, said Dr. Dylan K. Chan, a pediatric otolaryngologist at the University of California, San Francisco, and director of its Children’s Communication Center; he was not involved in the trial.The one in which Aissam participated is supported by Eli Lilly and a small biotechnology firm it owns, Akouos. Investigators hope to eventually expand the study to six centers across the United States.Special earphones being used for Aissam’s hearing test. His form of deafness is rare, caused by a mutation in a single gene, otoferlin. Hannah Beier for The New York TimesAissam’s trial is one of five that are either underway (the others are in China and Europe) or about to start.Investigators from all five of the studies will be presenting their data on Feb. 3 at a meeting of the Association for Research in Otolaryngology.The studies, researchers said, mark a new frontier for gene therapy which, until now, had steered clear of hearing loss.“There has never been a biological or medical or surgical way to correct the underlying biological changes that cause the inner ear to not function,” Dr. Chan said.Although otoferlin mutations are not the most common cause of congenital deafness, there is a reason so many researchers started with it. That form of congenital deafness, said Dr. John A. Germiller, an otolaryngologist who is leading the CHOP study, is “low hanging fruit.”The mutated otoferlin gene destroys a protein in the inner ear’s hair cells necessary to transmit sound to the brain. With many of the other mutations that cause deafness, hair cells die during infancy or even at the fetal stage. But with otoferlin deafness, hair cells can survive for years, allowing time for the defective gene to be replaced with gene therapy.Aissam’s trial at the Children’s Hospital of Philadelphia is among five that are either underway (the others are in China and Europe) or about to start.Hannah Beier for The New York TimesThere’s an advantage in using gene therapy to allow children to hear. Most of the mutations that affect hearing — there are approximately 150 — do not affect any other part of the body. Some genes are actually unique to the ear.The inner ear is a small closed compartment, so gene therapy delivered there would not affect cells in other parts of the body, said Manny Simons, chief executive and co-founder of Akouos and senior vice president of gene therapy at Lilly.But getting the genes to the cochlea, a spiral-shaped cavity close to the center of the skull, is challenging. The cochlea is filled with fluid, is lined with 3,500 hair cells and is encased in a dense dome of bone with a tiny, round membrane. Sound sets off a wave of fluid in the cochlea and stimulates the hair cells to transmit signals to the brain. Each hair responds to a different frequency, enabling a person to hear the richness of sound.The gene therapy consists of a harmless virus carrying new otoferlin genes in two drops of liquid that are delicately injected down the length of the cochlea, delivering the genes to each hair cell.Yet despite the promise of otoferlin gene therapy, finding the right patients for the trial was difficult.One issue is the very idea of treating deafness.“There is an internal Deaf community that doesn’t see itself as needing to be cured,” said Dr. Robert C. Nutt, a developmental and behavioral pediatrician in Wilmington, N.C., who is deaf.Some Deaf parents, he added, celebrate when their newborn baby’s hearing test indicates that the baby is deaf too and so can be part of their community.Making the issue of gene therapy even more complicated is the standard intervention for otoferlin hearing loss: a cochlear implant. The device, which uses electrodes to stimulate auditory nerves in the inner ear, allows patients to hear sounds, especially those needed to understand speech. But the implant does not provide the full richness of sound — and is said to assist in hearing but without restoring it completely.Dr. John Germiller, an otolaryngologist who is leading the CHOP study.Hannah Beier for The New York TimesMost babies born with otoferlin deafness get cochlear implants in infancy and are therefore ineligible for the trial. The implants somewhat alter the cochlea, which could hamper the interpretation of gene therapy results.The Food and Drug Administration, which allowed the CHOP study to go forward, asked that, for safety reasons, the researchers start with older children, not infants, and treat only one ear.The challenge for the U.S. study was to find older children whose parents would agree to the study, who had otoferlin deafness and who did not have cochlear implants.Aissam never had cochlear implants. He never had schooling in Morocco to help him develop communication skills. But three years ago, when he was 8, his father, Youssef Dam, a construction worker, got a job in Barcelona, Spain. For the first time, Aissam went to school, enrolling in a school for the deaf, where he learned Spanish Sign Language. Soon after, his family learned of the gene therapy trial.When Aissam was deemed eligible to be patient No. 1, Lilly and Akouos paid for him and his father to live in Philadelphia for four months, while Aissam received gene therapy and follow-up hearing tests.No one knew whether the nerve cells that communicate with the hair cells of the cochlea would still be intact and functional in someone who had been deaf for 11 years, Dr. Simons of Lilly said.It was not even clear what dose of the new genes to give. All that the researchers had to go on were studies with mice. “We were flying blind,” Dr. Germiller said.Aissam’s results, his doctors said, were remarkable. In an interview at CHOP, his father said through an interpreter — he speaks a North African language from the Amazigh family, commonly known as Berber — that Aissam was hearing traffic noises just days after the treatment. When Aissam had a hearing test two months later, his hearing in the treated ear was close to normal.But no matter how well the gene therapy works, the researchers recognize that Aissam may never be able to understand or speak a language, Dr. Germiller said. The brain has a narrow window for learning to speak beginning around ages 2 to 3, he explained. After age 5, the window for learning spoken language is permanently shut.Hearing can still help patients even if they never learn to speak, he noted. They can hear traffic or know when someone is trying to communicate. The ability to hear also can help with lip reading.Aissam signing to an interpreter during an interview at the children’s hospital.Hannah Beier for The New York TimesNow that gene therapy has proved safe for Aissam and for another child in Taiwan treated two months after him, researchers at the hospital in Philadelphia are able to move on to younger children. They have two lined up, a 3-year-old boy from Miami and a 3-year-old girl from San Francisco, both of whom got cochlear implants in only one ear, so that the other could be treated with gene therapy.If the Lilly trial of otoferlin gene therapy is proved to be effective and safe, “there will be a lot of interest in other genes” that cause deafness, said Dr. Margaret A. Kenna, an otolaryngologist at Boston Children’s Hospital and professor of otolaryngology at Harvard Medical School.Dr. Kenna, an investigator in the Lilly trial, added, “It’s been a long time coming.”“For decades people have been saying, ‘When is this going to work?’” Dr. Kenna said. “I didn’t think gene therapy would begin in my practice lifetime. But here it is.”Of the other studies, two are in China where investigators are treating younger children and in both ears. Results from one, supported by the National Natural Science Foundation of China and Shanghai Refreshgene Therapeutics, will be reported Wednesday in the journal The Lancet. The other is supported by Otovia Therapeutics and various programs in China.A third study is sponsored by Regeneron and Decibel Therapeutics. Researchers in Europe so far have treated one child, who is younger than 2, and in one ear. Another study by Sensorion is expected to start this month.On a recent frigid morning, Aissam sat in a conference room at CHOP and, with the help of three translators, patiently answered questions about his remarkable experience. He’s a solemn child with a round face and big brown eyes. There was an interpreter for his father, and the sign language team had a Certified Deaf Interpreter — a person who is deaf translated his signs into American Sign Language — and an interpreter who knew American Sign Language and spoke his words.Their system worked to a certain extent but robbed the conversation of spontaneity and forced Aissam to answer in short sentences or phrases, minimizing the expression of his personality.But Aissam managed to convey the wonder of hearing.Noises and voices frightened him initially, he said. But then, as the world of sound opened up, he began to enjoy every sound he heard — elevators, voices, the sound of scissors snipping his hair at a barbershop.And there was music, which he heard for the first time one day while getting his hair cut.Asked if there was a sound he particularly liked, Aissam did not hesitate.“People,” he signed.