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Cells go through a life cycle that includes growing to the right size, being equipped to perform its functions, and finally dividing into two new cells. The cell cycle is critical because it ensures the perpetuation of the cell population and by extension of the greater structure they are a part of — for example a tissue in the body.
The cell cycle itself is tightly regulated by checkpoints, which prevent errors like mutations or DNA damage from being passed onto the next generation of cells. Each checkpoint acts as a kind of quality-control monitor (a biological “checklist”) that ensures the order, integrity, and fidelity of the cell cycle. But checkpoints themselves often fail or are overridden after a prolonged stop of the cell cycle. If this happens in the human body, the result could be unregulated cell growth and division, which is what happens in cancer.
“Checkpoints monitor cells or whole organisms and can stop either the cell cycle or the organism’s development when they detect problems,” says Sahand Jamal Rahi at EPFL’s School of Basic Sciences. “But if cells or organisms are stuck with an error for a very long time, in many cases, they just continue dividing or growing; they don’t stop forever. There is a real risk of dying if checkpoints do not stop at all, but also waiting forever is effectively equivalent to dying.”
The math of checkpoint override
The question is then, how does the cell balance risk and speed when dividing? Although critical, checkpoint override is not very well understood, neither theoretically nor experimentally. But in a new paper, Rahi and his colleagues put forward the first mathematical theory to describe the process of checkpoint override. “Many organisms have to predict what’s going to happen,” he says. “You have a problem and you have to assess how bad that problem could be because the consequences are not certain. You could survive this or you might not survive this. So, the cell makes a bet either way. And in this study, we analyze the odds of that bet.”
For a real-life model organism, the researchers looked at the budding yeast Saccharomyces cerevisiae, which has been used in winemaking, baking and brewing for centuries. “There are systems that monitor organisms, and among these systems, possibly the best studied is the DNA damage checkpoint in yeast,” says Rahi. “So, we thought, let’s look at that and see whether we can make sense of checkpoint overrides. We started with a mathematical analysis behind which was a very simple question: what if these organisms are balancing risk and speed because they have to predict the future?”
The risk-speed tradeoff

In “proof of concept” experiments with mouse and human cells and tissues, Johns Hopkins Medicine researchers say they have designed tiny proteins, called nanobodies, derived from llama antibodies, that could potentially be used to deliver targeted medicines to human muscle cells. The researchers say the ability to more precisely target such tissues could advance the search for safer, more efficient ways to alleviate pain during surgery, treat irregular heart rhythms and control seizures.
Nanobodies are small versions of proteins called antibodies that mark potential pathogens for destruction by the immune system. Scientists do not know why they exist only in some species, such as the camelids and sharks, but since their discovery in the 1980s, researchers have studied them for use as a research tool and delivery system for anti-cancer drugs with mixed success.
Aware of such experiments, the researchers at Johns Hopkins suspected that nanobodies might be helpful as a tool to attach to a cell’s sodium ion channels, which act as a kind of switch that can conduct chemical signals that turn on or off muscle cells.
Nine varieties of these switches appear in the human body, each specific to a type of tissue such as muscle or nerve. Because the channel proteins have only small differences among themselves, most medications can not differentiate between them, posing safety hazards when trying to use them with drugs such as anesthetics. Existing drugs, say the researchers, block pain and sedate a patient by turning “off” the sodium ion channels in nerves and skeletal muscle, but also can dangerously lower heart rates and interfere with heart rhythms.
Other studies, the Johns Hopkins Medicine researchers say, have indeed shown that nanobodies can be used to carry a cargo, an ability that could advance efforts to deliver medications to specific sodium ion channels, eliminating such side effects.
“This is why clinicians and pharmaceutical companies are interested in finding drugs that can modulate these channels — either to turn on or off — distinctly,” says Sandra Gabelli, Ph.D., associate professor of medicine at the Johns Hopkins University School of Medicine.

Subjective memory disorders in conjunction with conspicuous levels of beta-amyloid proteins in the cerebrospinal fluid are a strong indication of developing Alzheimer’s disease. This is the conclusion of a DZNE study involving about 1,000 older adults. A team led by dementia researcher Frank Jessen reports on these findings in the scientific journal Alzheimer’s & Dementia. The study results could contribute to the early detection and treatment of Alzheimer’s disease.
When people feel that their memory or other mental abilities are declining, but objective tests do not reveal any deterioration, this is referred to in medicine as “subjective cognitive impairment,” or SCD for short. The phenomenon has been a topic of research for several years. “The affected individuals report cognitive problems that cause them serious concern, but which are not measurable with current techniques,” explains Prof. Frank Jessen, a DZNE scientist and director of the Department of Psychiatry at University of Cologne. By now it has turned out: SCD is a risk factor, but not a conclusive warning sign for upcoming dementia. “In many individuals with SCD, there is no progressive loss of cognitive performance. To assess the individual risk more accurately, other factors have to be taken into account,” the researcher says. “We have now been able to specify these. If, in addition to SCD, there is also evidence that certain proteins accumulate in the brain, then taken together that’s a strong sign for a developing Alzheimer’s disease.”
A Nationwide Study
This assessment is based on a long-term DZNE study called DELCODE, which comprises ten study centers across Germany and involves several university hospitals. Within this framework, cognitive performance of almost 1,000 older women and men has been recorded annually since several years. This is done by means of established neuropsychological test procedures. In addition, the cerebrospinal fluid of many study participants is analyzed and brain volume determined by means of magnetic resonance imaging (MRI).
Jessen and his colleagues now evaluated measurement series of the individual subjects, each data set covered a period of up to five years. Mean age of the study participants was around 70 years, they were originally recruited through memory clinics at the participating university hospitals and through newspaper advertisements. The cohort included more than 400 people with SCD at baseline and around 300 individuals who had measurable cognitive impairments — up to symptoms of dementia due to Alzheimer’s disease. In addition, the cohort comprised more than 200 adults whose cognitive performance was within the normal range and who did not exhibit SCD at baseline: These “healthy” persons served as a control group. All in all, this represents one of the most comprehensive studies on SCD to date.
Biomarkers in the Cerebrospinal Fluid
The protein beta-amyloid, which accumulates in the brain in the course of Alzheimer’s disease, played an important role in the investigations. Accumulation in the brain can be assessed indirectly — on the basis of the level of the protein in the cerebrospinal fluid: if the reading is beyond a threshold value, this is regarded as evidence that beta-amyloid is concentrating in the brain. These individuals are then considered “amyloid-positive.” 83 study participants with SCD and 25 volunteers from the control group had this status. “Deposition of beta-amyloid, like SCD, is a risk factor for Alzheimer’s disease. On their own, however, neither phenomenon is a clear indicator of disease. But the picture sharpens, as evidenced by our study, when these phenomena are considered together and over a longer time period,” Jessen says.

Currently, treatment systems let, on average, half of the emerging contaminants found in wastewater go through. However, scientists are developing new technologies to make infrastructure more efficient and remove the remaining contaminants that would otherwise be discharged into waterways. Jean-François Blais, water treatment and environmental decontamination expert at the Institut national de la recherche scientifique (INRS), collaborated with Canadian scientists to review current and emerging treatment technologies. Through this review, the team determined the removal efficiency of a particular type of contaminant that causes hormonal disruption: endocrine disruptors.
Efficient technologies
One of the most promising technologies is ozonation. Ozone, a powerful oxidizing gas, breaks down pollutants through a chemical reaction. This very technology was chosen for the Jean-R.-Marcotte wastewater treatment plant, where all of Montréal’s wastewater converges. Another promising method in water treatment is adsorption with activated carbon. In addition to being inexpensive, this material can effectively filter and absorb contaminants regardless of whether it is in powder or granular form.
In his review, Professor Blais also focused on electro-oxidation processes and membrane bioreactors. The first method uses two electrodes to degrade pollutants. The second combines a membrane (to filter out some of the contaminants) and biological organisms (to degrade what passes through it).
These two approaches are being developed at INRS, in Professor Patrick Drogui’s Laboratory of Environmental Electrotechnologies and Oxidative Processes.
“All of these emerging technologies have the advantage of being able to be added to existing treatment plants, mostly downstream of the current systems,” explains Professor Blais.
Ultimately, they could improve the performance of existing water treatment technologies without requiring major changes to municipal facilities.
The issue of Lac Saint-Charles
These different wastewater treatment options have real-world implications for municipalities. The City of Québec, in particular, quickly became interested in these innovative treatment methods following concerns about the water quality of its main water supply, Lac Saint-Charles. It therefore mandated the INRS team to find effective solutions to this problem, as well as to connect its sewer system.
“Many remote residences are using septic tanks and absorption fields,” says Blais. We wanted to identify alternatives, like stand-alone treatment systems for homes, to connect them without sacrificing the health of our bodies of water.”
In April 2021, Professor Blais, Professor Sophie Duchesne, Research Officer Geneviève Rioux, and Priscille Ahossi, master’s student in Professional Studies in Water Sciences, submitted an assessment and recommendation report outlining solutions the City could implement.
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Materials provided by Institut national de la recherche scientifique – INRS. Original written by Audrey-Maude Vézina. Note: Content may be edited for style and length.

Using anti-inflammatory drugs and steroids to relieve pain could increase the chances of developing chronic pain, according to researchers from McGill University and colleagues in Italy. Their research puts into question conventional practices used to alleviate pain. Normal recovery from a painful injury involves inflammation and blocking that inflammation with drugs could lead to harder-to-treat pain.
“For many decades it’s been standard medical practice to treat pain with anti-inflammatory drugs. But we found that this short-term fix could lead to longer-term problems,” says Jeffrey Mogil, a Professor in the Department of Psychology at McGill University and E. P. Taylor Chair in Pain Studies.
The difference between people who get better and don’t
In the study published in Science Translational Medicine, the researchers examined the mechanisms of pain in both humans and mice. They found that neutrophils — a type of white blood cell that helps the body fight infection — play a key role in resolving pain.
“In analyzing the genes of people suffering from lower back pain, we observed active changes in genes over time in people whose pain went away. Changes in the blood cells and their activity seemed to be the most important factor, especially in cells called neutrophils,” says Luda Diatchenko a Professor in the Faculty of Medicine, Faculty of Dentistry, and Canada Excellence Research Chair in Human Pain Genetics.
Inflammation plays a key role in resolving pain
“Neutrophils dominate the early stages of inflammation and set the stage for repair of tissue damage. Inflammation occurs for a reason, and it looks like it’s dangerous to interfere with it,” says Professor Mogil, who is also a member of the Alan Edwards Centre for Research on Pain along with Professor Diatchenko.
Experimentally blocking neutrophils in mice prolonged the pain up to ten times the normal duration. Treating the pain with anti-inflammatory drugs and steroids like dexamethasone and diclofenac also produced the same result, although they were effective against pain early on.
Thesefindings are also supported by a separate analysis of 500,000 people in the United Kingdom that showed that those taking anti-inflammatory drugs to treat their pain were more likely to have pain two to ten years later, an effect not seen in people taking acetaminophen or anti-depressants.
Reconsidering standard medical treatment of acute pain
“Our findings suggest it may be time to reconsider the way we treat acute pain. Luckily pain can be killed in other ways that don’t involve interfering with inflammation,” says Massimo Allegri, a Physician at the Policlinico of Monza Hospital in Italy and Ensemble Hospitalier de la Cote in Switzerland.
“We discovered that pain resolution is actually an active biological process,” says Professor Diatchenko. These findings should be followed up by clinical trials directly comparing anti-inflammatory drugs to other pain killers that relieve aches and pains but don’t disrupt inflammation.”
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Materials provided by McGill University. Note: Content may be edited for style and length.

A six-year study of nearly 100,000 women in Botswana has provided new evidence that relatively inexpensive daily diet supplementation of iron, folic acid and vitamin supplementation in pregnancy can reduce complications at birth. Researchers found that iron and folic acid supplementation (IFAS), as well as iron and folic acid plus essential vitamins and trace minerals (multiple micronutrient supplementation, or MMS), are associated with significantly lower rates of babies born at low birthweight and other complications at birth, compared to iron or folic acid alone. For example, the rate of low-birthweight birth was under 10.5 percent for women supplementing their diets with multiple micronutrients, the lowest rate of any comparison group.
Published in Lancet Global Health, the study was led by Ellen Caniglia, ScD, an assistant professor of Epidemiology in the Department of Biostatistics, Epidemiology, and Informatics at the Perelman School of Medicine at the University of Pennsylvania, as well as investigators at the Botswana-Harvard AIDS Institute Partnership and Harvard T.H. Chan School of Public Health. The results represent a broad, real-world confirmation of earlier clinical trial results. The study, the largest ever of its kind, also included a substantial cohort of pregnant women with HIV, and found that IFAS and MMS appeared to have even larger benefits in this group.
“Our results support the current World Health Organization recommendation that pregnant women should take iron and folic acid supplementation daily, but also provide compelling evidence that multiple micronutrient supplementation has further advantages over IFAS,” Caniglia said.
About 15 to 20 percent of children born every year around the world have low birthweight, defined as a weight less than 2.5 kg at birth. Commonly occurring with preterm birth, low birthweight is associated with significantly increased risks of childhood illnesses and death, and diseases later in life such as diabetes and cardiovascular disease. The highest rates of low-birthweight births occur in South Asia and Sub-Saharan Africa.
To help reduce the rate of babies born at low birthweight and related complications at birth, the World Health Organization (WHO) recommends daily IFAS throughout pregnancy, in all settings, based on substantial clinical trial evidence. There is also clinical trial evidence that daily prenatal MMS, which includes iron and folic acid plus vitamins (A, C, D, E, B1, B2, B3, B6, B12) and minerals/metals (iodine, selenium, zinc, copper), may be superior to IFAS.
However, there has been a need for more evidence for MMS’s benefits, especially with respect to IFAS, in real-world settings, and in high-risk women such as women with HIV. The new study provides proof that the approach can help.

A new study suggests that antidepressant use by mothers during the first trimester of pregnancy does not increase the chances of epilepsy and seizures in babies. The research is published in the May 11, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“The findings of this study are very important,” said study author Ayesha Sujan, PhD, of Indiana University in Bloomington, Indiana. “Pregnancy can be a trying time, and the addition of depression, anxiety, and other mental health conditions can add to this burden. These findings may provide reassurance to women and their doctors considering the risks and benefits to medication.”
The study looked at over 1.7 million children born in Sweden over a 17-year period. Researchers identified more than 24,000 children who had been exposed to antidepressants during the first trimester of pregnancy and compared them to those who were not exposed.
Antidepressants included medications to treat anxiety and depression, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitor (SNRIs).
Researchers then looked at hospital admissions and outpatient specialist visits to identify children who had seizures during the first month of life or epilepsy in the first years of life. Among 1,551,906 children followed for one month after birth, 0.12%, or 1,864 children had neonatal seizures; and among 1,367,087 children followed for two to 17 years, 0.40%, or 5,424 children were diagnosed with epilepsy.
Though seizures in the first month of life were rare, they were more common among children who had been exposed to SSRIs or SNRIs during pregnancy compared to children who were not exposed to these antidepressants. Before adjusting for factors in the mothers such as age, epilepsy, socioeconomic status, and tobacco use, there were 1.7 per 1,000 exposed children having a neonatal seizure versus 1.2 per 1,000 unexposed children having a neonatal seizure. Similarly, while 5.4 per 1,000 exposed children had been diagnosed with epilepsy by the age of five, 4.1 per 1,000 unexposed children had been diagnosed with epilepsy by age five.
While the authors found a higher prevalence of neonatal seizures and epilepsy among exposed children compared to unexposed children, after adjusting for factors in the mothers associated with an increase in the risk of seizures in their newborn, they found no link between antidepressant use by mothers during the first trimester and a child’s risk of seizures or epilepsy.
“While several studies have shown a possible link between antidepressant use by mothers during pregnancy and seizures in newborns and toddlers, our study suggested that antidepressant exposure in the first trimester of pregnancy does not increase the risk of seizures and epilepsy in children,” Sujan said. “This could mean that the slightly elevated risk for such seizures documented in previous studies could be due to other factors such as other diseases or tobacco use during pregnancy.”
A limitation of the study was that use of antidepressants was based on women reporting their own use only during the first trimester of pregnancy. The authors also note that they examined first trimester exposure, while some previous studies documented the strongest associations with antidepressant use and seizures or epilepsy in babies toward the end of pregnancy.
The study was funded by National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, National Institute on Drug Abuse, the National Science Foundation, the Swedish Research Council for Health, Working Life and Welfare, and the Swedish Research Council.

People who have been hospitalized for a major traumatic brain injury (TBI) may have a higher risk of developing dementia when compared to people who do not have a TBI, according to a new study published in the May 11, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. Major TBI was defined as having bleeding in the brain and a hospital stay of three or more days. Researchers did not find an increased risk for people who had minor TBI, which was defined as a concussion with no more than a one-day hospital stay.
“Traumatic brain injury has been identified as a possible risk factor for dementia, and due to increasing numbers of people living with dementia, it is imperative to identify risk factors that might be modifiable to decrease the number of people who develop dementia in the future,” said study author Rahul Raj, MD, PhD, of the University of Helsinki in Finland. “The goal of our study was to assess the association between TBI and dementia while adjusting for other relevant dementia risk factors like high blood pressure, smoking, alcohol consumption and physical activity.”
For the study, researchers used a Finnish national database that includes health surveys collected every five years. Focusing on a 20-year period, they identified 31,909 people who completed one or more surveys that included details on lifestyle factors such as physical activity, smoking and alcohol use.
Researchers then looked at national health registries. Of the study group, they identified 288 people hospitalized due to a major TBI and 406 hospitalized due to a minor TBI who did not have dementia within one year of their injury. A total of 976 people developed dementia over an average 16-year follow-up period.
Of those with a major TBI, 27 people, or 9%, developed dementia. Of those with a minor TBI, nine people, or 2%, developed dementia. And of those with no TBI, 940 people, or 3% developed dementia.
After adjusting for age and sex, researchers found that people who were hospitalized due to a major TBI had a 1.5 times greater risk of dementia than those without a TBI.
But after further adjustment for other relevant dementia risk factors such as education, smoking, alcohol consumption, physical activity and high blood pressure, the association weakened. Raj explained that alcohol use and physical activity appeared to play the biggest role in weakening the association.
Researchers found no increased risk of dementia for people hospitalized for minor TBI.
“Approximately one in 10 people in our study who had major TBI did develop dementia,” said Raj. “Considering that there is no cure for dementia or TBI, the results of our study suggest that prevention of other dementia risk factors such as excess alcohol consumption and physical inactivity could possibly reduce the risk of dementia in people with major TBI. More research is needed in larger groups of people.”
A limitation of the study was that it included only people hospitalized for TBI, so people who did not seek care for a mild TBI were not included.
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Materials provided by American Academy of Neurology. Note: Content may be edited for style and length.

A new study published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) finds that two common herpesviruses may contribute to impaired glucose metabolism and an increase the risk of developing type 2 diabetes (T2D) among infected individuals. The research was conducted by Dr Tim Woelfle at Ludwig-Maximilians University and Helmholtz Munich, Germany, and colleagues.
Herpesviruses are one of the most prevalent viruses in humans, with eight types currently known: herpes simplex viruses (HSV) 1 and 2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesviruses (HHV) 6, 7 and 8. All of them cause lifelong latent infections in their hosts after an initial, usually mild or asymptomatic primary infection.
T2D is one of the most widespread and important metabolic diseases with an estimated 9.3% of the world’s population having the condition as of 2019, exerting a high mortality burden primarily due to resultant cardiovascular disease. There are many known behavioural, environmental, and genetic risk factors for T2D but until recently, viruses had only been proposed as playing a role in the development of type 1 diabetes, in which the pancreas stops producing enough insulin.
An individual may be diagnosed as having prediabetes when they exhibit impaired fasting glucose (IFG) or an impaired glucose tolerance (IGT). Previous studies have found that incidence rate of T2D is much higher in people with prediabetes (7.6% per person-year) than among individuals with normal glucose tolerance (0.6% per person-year).
The research was based on health data for 1967 subjects in the KORA (Cooperative Health Research in the Augsburg Region) population-based health research platform in the south of Germany. Participants underwent detailed health examinations at baseline (2006-2008) and at follow-up (2013-2014), which included testing for the presence of human herpesviruses, oral glucose tolerance tests (OGTT), and measurement of glycated haemoglobin (HbA1c) (a measure of blood sugar control over the previous 3 months).
The study group had a median age of 54 years at baseline, 962 (49%) were men and 999 (51%) were women. Incidence analysis for the development of (pre)diabetes used the data for those 1257 participants with normal glucose tolerance at baseline (median age 49 years, 42% male and 58% female [528 and 729 individuals, respectively]).

Maternal obesity impairs heart health and function of the fetus according to a new study in mice. The study, published in The Journal of Physiology found that maternal obesity causes molecular changes in the heart of the fetus and alters expression of genes related to nutrient metabolism, which greatly increases offspring’s risk of cardiac problems in later life.
This is the first study to show that the heart is ‘programmed’ by the nutrients it receives in fetal life. Changes in the expression of genes alter how the heart normally metabolises carbohydrates and fats. They shift the heart’s nutrient preference further toward fat and away from sugar. As a result, the hearts of fetuses of obese female mice were larger, weighed more, had thicker walls and showed signs of inflammation. This impairs how efficiently the heart contracts and pumps blood around the body.
The researchers from University of Colorado, US, used a mouse model that replicates human maternal physiology and placental nutrient transport in obese women. Female mice (n=31) were fed a diet with a high fat content together with a sugary drink, which is equivalent to a human regularly consuming a burger, chips and a fizzy drink (1500kcal). The female mice ate this diet until they developed obesity, putting on about 25% of their original body weight. 50 female mice were fed a control diet.
Mouse pups (n=187) were studied in utero, as well as after birth at 3, 6, 9 and 24 months using imaging techniques, including echocardiography and positron emission tomography (PET) scans. Researchers analysed genes, proteins and mitochondria of the offspring.
The changes in offspring cardiac metabolism strongly depended on sex. The expression of 841 genes were altered in the hearts of female foetuses and 764 genes were altered in male foetuses, but less than 10% genes were commonly altered in both sexes. Interestingly, although both male and female offspring from mothers with obesity had impaired cardiac function, there were differences in the progression between sexes; males were impaired from the start, whereas females’ cardiac function got progressively worse with age.
The sex-difference in the lasting impairments of cardiovascular health and function could be due to oestrogen. Higher levels in young females may protect cardiovascular health, the protection diminishes as oestrogen levels deplete as the females age. The molecular cause for the sex difference is not yet understood.
Lead author, Dr Owen Vaughan, University of Colorado, US said:
“Our research indicates a mechanism linking maternal obesity with cardiometabolic illness in the next generation. This is important because obesity is increasing rapidly in the human population and affects almost one third of women of childbearing age. By improving our understanding of the mechanisms involved, this research paves the way for treatments that could be used in early life to prevent later-life cardiometabolic illnesses, which are costly for health services and affect many people’s quality of life. For example, we could offer more tailored advice on nutrition to mothers or children based on their body mass index or sex, or develop new drugs that target metabolism in the heart of the fetus.”
Mice have shorter pregnancies, more offspring and different diets to humans so further studies in human volunteers would be required to extrapolate the findings to women’s health. Loss-of-function studies also need to be carried out to prove this mechanism linking maternal obesity and offspring heart function and pinpoint the exact molecules responsible.
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Materials provided by The Physiological Society. Note: Content may be edited for style and length.