Culture

MINNEAPOLIS - The scientific community has long believed that beta-amyloid, a protein that can clump together and form sticky plaques in the brain, is the first sign of Alzheimer's disease. Beta-amyloid then leads to other brain changes including neurodegeneration and eventually to thinking and memory problems. But a new study challenges that theory. The study suggests that subtle thinking and memory differences may come before, or happen alongside, the development of amyloid plaques that can be detected in the brain. The study is published in the December 30, 2019, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"Our research was able to detect subtle thinking and memory differences in study participants and these participants had faster amyloid accumulation on brain scans over time, suggesting that amyloid may not necessarily come first in the Alzheimer's disease process," said study author Kelsey R. Thomas, PhD, of the VA San Diego Healthcare System in San Diego. "Much of the research exploring possible treatments for Alzheimer's disease has focused on targeting amyloid. But based on our findings, perhaps that focus needs to shift to other possible targets."

The study involved 747 people with an average age of 72. Researchers gave participants neuropsychological tests at the beginning of the study and measured their total scores and also their process scores to determine if they had subtle thinking and memory difficulties. What is a process score? While a person may score within the normal range on thinking and memory tests, process scores reflect how that person solves problems, measuring errors in their approach to completing tasks.

Looking at both total scores and process scores, researchers divided participants into three groups: 305 people with normal thinking and memory skills; 153 with subtle thinking and memory differences; and 289 people with mild cognitive impairment.

Participants had brain scans at the start of the study to determine levels of amyloid plaques in the brain, and then yearly scans for four years.

After adjusting for age, education, sex, genetic risk for Alzheimer's disease, and amyloid level at the start of the study, researchers found people with subtle thinking and memory differences had a more rapid accumulation of amyloid compared to people with normal thinking and memory skills. On a test that uses a dye to measure amyloid levels, where the average level was 1.16 for participants with subtle thinking and memory difficulties, amyloid levels in this group increased by .03 above and beyond the amyloid changes in those with normal thinking and memory skills over four years. People with subtle differences also had faster thinning of the entorhinal cortex, a brain region that is impacted very early in Alzheimer's disease.

On the other hand, researchers also found that, while people with mild cognitive impairment had more amyloid in their brains at the beginning of the study, they did not have faster accumulation of amyloid when compared to those with normal thinking and memory skills. However, they did have faster thinning of the entorhinal cortex as well as brain shrinkage of the hippocampus.

"From prior research, we know that another biomarker of Alzheimer's disease, a protein called tau, shows a consistent relationship with thinking and memory symptoms. Therefore, more research is needed to determine if tau is already present in the brain when subtle thinking and memory differences begin to appear," said Thomas.

"Finally, our study demonstrated a method to successfully detect subtle differences in thinking and memory either before or during the phase when amyloid is accumulating at a faster rate," Thomas said. "This could lead to non-invasive screenings that may be able to detect very early who is at risk of developing Alzheimer's disease."

A limitation of the study was that participants were mostly white and considered healthy, so the results may not be the same for other populations. It is also possible that the earliest stages of amyloid plaques forming in the brain are not detectable with brain scans.

Pregnant women exposed to persistent organic pollutants, or POPs, had slightly smaller fetuses than women who haven't been exposed to these chemicals, according to an analysis of ultrasound scans by researchers at the National Institutes of Health and other institutions. The researchers also found that the women in their study had lower levels of POPs than women in the 2003-2004 U.S. Health and Nutrition Survey, the most recent comprehensive study of these compounds in U.S. pregnant women. The latest findings suggest that the chemicals, which are no longer produced in the United States but persist in the environment, may have lasting health effects even at low levels.

The study appears in JAMA Pediatrics and was conducted by Pauline Mendola, Ph.D., an investigator in the Epidemiology Branch at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, and colleagues.

Persistent organic pollutants are chemicals once used in agriculture, disease control, manufacturing, and industrial processes. They include the pesticide DDT and dioxin, a byproduct of herbicide production and paper bleaching. POPs are slow to break down, may persist in water and air, and may be passed through the food chain. Their health effects vary, but some compounds have been linked to reproductive disorders and a higher risk of birth defects.

Earlier studies of the potential effects of POP exposure during pregnancy have produced conflicting results. According to the authors, most of these studies looked at infant birth weight and length, measures that could suggest impaired fetal growth but could also indicate genetic factors that lead to smaller birth size and weight. Moreover, previous studies have investigated POPs as individual chemicals, but people typically are exposed to a mix of these compounds.

"The differences we found in fetal growth measures may be more sensitive indicators, compared to birth size, of the potential effects of these compounds," said Dr. Mendola. "Even at low levels, there is evidence of a possible effect on fetal growth."

In the current study, researchers analyzed records, stored blood samples, and a series of ultrasound scans taken from weeks 16-40 of 2,284 pregnant women enrolled in the NICHD Fetal Growth Study from 2009 to 2013. The blood samples were tested for the presence of 76 POPs soon after the women began the study. The POP levels in each woman's blood were listed as percentiles, with the highest levels set at 100 and the lowest at 1. The researchers then compared growth measurements of head circumference, abdominal circumference, and femur (thigh bone) length of the fetuses of women in the 75th percentile to those of women in the 25th percentile.

They found that, compared to fetuses in the 25th percentile of exposure to organochlorine pesticides, the fetuses of women with exposure in the 75th percentile had the most widespread growth reductions, with head circumference reduced by an average of 4.7 mm, abdominal circumference reduced by 3.5 mm, and femur length reduced by 0.6 mm. High levels of dioxin-like polychlorinated biphenyls were associated with an average head circumference reduction of 6.4 mm and an abdominal circumference reduction of 2.4 mm. High levels of polybrominated diphenyl ethers--flame-retardant chemicals used in furniture, electronics and other consumer products--were associated with an average abdominal circumference reduction of 2.4 mm and an average femur length reduction of 0.5 mm.

PHILADELPHIA - Closing of local automotive assembly plants may lead to increases in deaths from opioid overdose, according to a study led by researchers at the Perelman School of Medicine at the University of Pennsylvania and the Massachusetts General Hospital. The findings highlight fading economic opportunity as a driving factor in the ongoing national opioid epidemic, and build on previous research that links declining participation in the labor force to increased opioid use in the U.S. The findings are published today in JAMA Internal Medicine.

"Major economic events, such as plant closures, can affect a person's view of how their life might be in the future. These changes can have a profound effect on a person's mental well-being, and could consequently influence the risk of substance use," said lead author Atheendar Venkataramani, MD, PhD, an assistant professor of Medical Ethics and Health Policy. "Our findings confirm the general intuition that declining economic opportunity may have played a significant role in driving the opioid crisis."

The study examined the number of opioid-related deaths over a 17-year period (1999-2016) in 112 manufacturing counties near major automotive manufacturing plants. Using a variety of data sources, the research team built a database of all automotive assembly plants in operation as of 1999, noting each plant's location and date of closing, where applicable. They then identified counties located within commuting zones that contained one or more of the plants that closed.

Of the manufacturing counties examined, 29 experienced an automotive assembly plant closure during the study period. Results showed that five years after the plants closed, opioid overdose mortality rates among adults ages 16 to 65 in those counties were 85 percent higher than anticipated compared to counties where plants remained open.

The group with the largest increase in opioid overdose mortality after an automotive plant closure was non-Hispanic white men between 18-34 years old, followed by non-Hispanic white men ages 35-65 years old. Increases in opioid overdose mortality rates after closures were also noted for younger non-Hispanic white women.

The authors note that although the study shows a robust and large association between plant closures and fatal opioid overdoses, the closures are not the only cause of the opioid crisis. They point to other factors such as prescription rates, which were at the forefront of the crisis in the early 2000s. The crisis, they say, can be attributed to both access to the drugs, and the forces that may lead people to take them and other opioids. Where initial access can be explained by the excessive prescribing rates, which have been in a decade-long decline since 2010, disentangling demand for opioids is more complicated.

"Our results are most relevant for the worsening population health trends in the industrial Midwest and South, regions that have experienced some of the largest increases in opioid overdose deaths and in which the automotive production and other manufacturing industries have long been economically and culturally significant," Venkataramani said. "While we as clinicians recognize and take very seriously the issue of overprescribing, our study reinforces that addressing the opioid overdose crisis in a meaningful way requires concurrent and complimentary approaches to diagnosing and treating substance use disorders in regions of the countries hardest hit by structural economic change."

"Until we can achieve structural change to address the fundamental drivers of the crisis, there are some health care system and health policy changes that can be implemented immediately," said senior author and co-study lead Alexander Tsai, MD, an associate professor of psychiatry at the Massachusetts General Hospital and Harvard Medical School. "There is an urgent need to rapidly lower the threshold for accessing evidence-based treatment for substance use disorders, for example, at the level of state Medicaid policy and private payor utilization management."

Researchers at the Biozentrum of the University have demonstrated how bacteria coordinate cell division with the replication of their genetic material. In an interdisciplinary study they explain why the current concept of the bacterial cell cycle has to be rewritten. The results were published in eLife.

Each living cell grows and divides, thus generating new offspring. This process is also known as the cell cycle. Strictly speaking, it describes a periodic repetition of two coordinated cycles: the duplication of a cell's genetic information on the one hand and cell division on the other. Although the cell cycle in plant and animal cells has been elucidated quite precisely in the past decades, it has remained unclear how these two processes are coordinated in bacteria.

DNA replication controls the cell cycle timing

Although it is natural to think that the cell cycle begins with the birth of the cell and ends with the next cell division, the new research argues for a major shift in this concept. Their findings show that, in bacteria, the cell cycle starts and ends with the initiation of DNA replication, with the cell division event occurring between two DNA replication events.

The researchers, led by Prof. Erik van Nimwegen at the Biozentrum of the University of Basel, used a highly interdisciplinary approach combining microfluidics, automated time-lapse microscopy, sophisticated image analysis, and computational modeling. They observed the behavior of individual E. coli cells over long periods of time and systematically quantified multiple variables describing growth, cell division and DNA replication for thousands of cell cycles in several growth conditions. Computational modelling was then applied to this data to uncover the control mechanisms of the cell cycle.

"Our model indicates that the cell cycle in E. coli starts with the initiation of DNA replication, at which point two different counters start running; one determining when the next cell division should occur, and the other determining when the next initiation of DNA replication should occur," explains Thomas Julou, head of the study. "Even though we have not yet identified the molecular basis of these two counters, the biomass produced since the last counter reset appears to be the variable controlling when the next division and replication events take place".

Studying fluctuations to reveal control mechanisms

In contrast to classical molecular biology approaches where the effects of mutations are analyzed, the current study uses a new approach in which analysis of the subtle fluctuations that normally growing cells exhibit is used to infer how the underlying process is controlled.

"A major challenge was to develop statistical methods to analyze the structure of the correlations in the fluctuations of cell cycle parameters such as cell size at birth," says Erik van Nimwegen. "A key new idea that we developed is that, instead of looking for correlations between variables, it is more informative to identify which variables appear to fluctuate independently of each other." This approach enabled the scientists to reveal the control mechanism of the bacterial cell cycle, but this method will be generally applicable to studying other biological processes and organisms.

Due to the advantages such as large specific surface area, adjustable pore size and tunable functionality, metal-organic frameworks (MOFs) have shown great application potentials in the fields of gas adsorption and separation, catalysis, sensing and biomedicine. However, most metal-organic frameworks have pore sizes below 2 nm and are typical microporous structures, which limits pore structure and hinders mass transfer within the framework. In order to overcome this limitation, researchers introduced mesopores or macropores in microporous MOFs to generate multi-level pore structure through various strategies. These approaches have recently been reviewed by researchers at the Department of Chemistry, Texas A&M University, published in the National Science Review. Co-authors Liang Feng, Kun-Yu Wang, Xiu-Liang Lv, Tian-Hao Yan, Hong-Cai Zhou introduce recent methodology advances of hierarchically porous MOF synthesis. They also introduced the fabrication methods of HP-MOFs with intrinsic hierarchical pores, while approaches including modulated, templated and template-free synthetic strategies for HP-MOFs are further discussed in the review.

Nowadays, more and more multi-level pore MOFs have been reported by introducing template, etching, and construction of composites. For example, the team of Professor Zhou introduced linker lablization to selectively remove chemically labile organic linkers inside micropores. The trick is to selectively remove a certain number of linkers and clusters in the frameworks, and combine smaller pores into larger ones, while the overall framework intactness should be maintained, says Liang Feng, a graduate student at the Zhou group. He and his colleagues explored a series of bottom-up and top-down methods to create hierarchical pores in MOFs, especially robust MOF platforms for catalysis. The use of ligand instability to selectively remove a ligand from the framework can create larger pores, which also facilitate the guest diffusion during catalysis. This review also comments on the key factors that affect the generation of HP-MOF architectures and their applications in heterogeneous catalysis and guest encapsulation.

"The demands for hierarchical porosity in MOFs push the research of HP-MOFs for various applications including catalysis and storage." Prof. Hong-Cai Zhou said, "We envision that this review shall function as a roadmap that can guide the future design and development of HP-MOF materials with unusual precision and complexity in multiple scales. "

Holding particular biological resources, the Tibetan Plateau is a unique geologic-geographic-biotic interactively unite and hence plays an important role in the global biodiversity domain. The Tibetan Plateau has undergone vigorous environmental changes since the Cenozoic, and played roles as switching from "a paradise of tropical animals and plants" to "the cradle of Ice Age mammalian fauna". Recent significant paleontological discoveries have refined a big picture of the evolutionary history of biodiversity on that plateau against the backdrop of major environmental changes, and paved the way for the assessment of its far-reaching impact upon the biota around the plateau and even in more remote regions. Based on the newly reported fossils from the Tibetan Plateau which include diverse animals and plants, this paper presented general viewpoints of the biodiversity history on the Tibetan Plateau and its influence in a global scale.

This paper defined the Tibetan Plateau as an evolutionary junction of the history of modern biodiversity, whose performance can be categorized in the following three patterns: (1) Local origination of endemism; (2) Local origination and "Out of Tibet"; (3) Intercontinental dispersal via Tibet.

The first pattern is exemplified by the snow carps (schizothoracine fishes), the major component of the freshwater fish fauna on the plateau, whose temporal distribution pattern of the fossil schizothoracines approximately mirrors the spatial distribution pattern of their living counterparts. Through ascent with modification, their history reflects the biological responses to the stepwise uplift of the Tibetan Plateau.

The second pattern is represented by the dispersal history of some mammals since the Pliocene and some plants. The ancestors of some Ice Age mammals, e.g., the wholly rhino, Arctic fox, and argali sheep first originated and evolved in the uplifted and frozen Tibet during the Pliocene, and then migrated toward the Arctic regions or even the North American continent at beginning of the Ice Age; the ancestor of pantherines (big cats) first rose in Tibetan Plateau during the Pliocene, followed by the disperse of its descendants to other parts of Asia, Africa, North and South America to play as top predators of the local ecosystems. The early members of some plants, e.g., Elaeagnaceae appeared in Tibet during the Late Eocene and then dispersed and widely distributed to other regions.

The last pattern is typified by the history of the tree of heaven (Ailanthus) and climbing perch. Ailanthus originated in the Indian subcontinent, then colonized into Tibet after the Indian-Asian plate collision, and dispersed from the Tibetan Plateau to East Asia, Europe and even North America. The climbing perches among freshwater fishes probably rose in Southeast Asia during the Middle Eocene, dispersed to Tibet and then migrated into Africa via the docked India. These cases highlight the role of Tibet, which was involved in the continental collision, in the intercontinental biotic interchanges. The three evolutionary patterns above reflect both the history of biodiversity on the plateau as well as the biological and environmental effects of tectonic uplift.

Since the initiation of the Second Tibetan Plateau Scientific Expedition in 2017, this review is the first comprehensive conclusions on the relationship between the uplift of the Tibetan Plateau and the evolution of biota based on latest numerous fossil records. It provides important scientific evidence for the influence of the uplift of the Tibetan Plateau on the environment and biota.

Researchers from HSE University have shown that the 2010 happiness level of citizens from Tunisia, Libya, Egypt, and other Arab countries could provide a much more accurate forecast of the Arab Spring events than purely economic indices, such as GDP per capita and unemployment rate.

Motifs for action

At the beginning of the 2010s, a new wave of political protests swept through North Africa and Middle East. The disturbances broke out in Tunisia in December 2010, resulting in the president dismissing the government and fleeing the country on January 15, 2011. Two days before, on January 13, political protests began in Libya, leading to the overthrow of Gaddafi's regime, followed by a military intervention and a civil war. At that time, unrests and riots started in Syria, Egypt, and Yemen, and by the end of February, as many as 19 nations had been involved in the event of the Arab Spring.

The Arab Spring is not the first example of the 'revolution wave' in human history. In the middle of the 19th century, a similar series of political upheavals happened in Europe (the Spring of Nations). This leads to the conclusion that the society seeking a wide confrontation with the existing authorities possesses particular characteristics which can be identified by demographic, sociological, economical, or any other type of monitoring.

In the 1960s, street rallies may have been driven by relative deprivation, that is moral dissatisfaction of the people who feel they lack resources they believe they deserve. For example, this deprivation may be caused if the elected authorities fail to keep their promises, while citizens aspire to the quality of life comparable with that of other nations.

According to HSE Professor Andrey Korotayev, relative deprivation is a psychological term denoting the subjective feeling of a gap between expected and actual welfare. Relative deprivation should not be confused with absolute deprivation, as the latter means real lack of immediate basic resources, such as shelter, food, etc., i.e. it is an economic rather than psychological metric.

The theory of relative deprivation--without quantitative assessments--has been widely used to analyze political processes in many countries, including Russia. However, there is no common opinion on the role of relative deprivation in generating social and political events, as it is still quite unclear how to measure it accurately.

The sociologist proposed a 10-point scale to measure Subjective Feeling of Happiness (SFH). According to Veenhoven, a typical happy person is a citizen of an economically successful state that guarantees stable democracy and freedom; a representative of the dominant majority, occupying the top positions on the social ladder; and a supporter of moderately conservative views.

Arab Spring Reasons

Russian sociologists Andrey Korotayev and Alisa Shishkina searched to verify subjective happiness efficiency as a relative deprivation metric based on the Arab Spring countries data. They ranked the countries according to the sociopolitical destabilization index. The index can be evaluated in points--from 1 to 7--depending on the scale and consequences of the protests in the country. The sociopolitical destabilization index equals 1 in the countries with very few low-intensity separate protests, such as Qatar and the United Arab Emirates, while 7 is given to the nations suffered from revolutions (Egypt, Libya, Tunisia).

Having compared the index with the 2010 SFH values, the researchers found that in the countries with a low-intensity protest activity people were subjectively happier than inhabitants of the states where demonstrations and riots lasted for quite a while. These people were also happier than citizens of the countries with a higher GDP per capita. For example, the highest SFH level (7.2) was recorded in the United Arab Emirates, with its 2010 GDP per capita exceeding $ 57,000; while Morocco appeared to have the lowest SFH level (4.66) and GDP per capita of $ 6,000.

In addition, the researchers analyzed correlation between GDP on the eve of the Arab Spring and the sociopolitical destabilization index. The findings prove that the average protest activity was much lower in affluent Arab countries than in their poor neighbours.

Jobs, money, and something else

On the face of it, the findings seem to suggest that revolutionary sentiments are driven by economic factors, not socio-psychological reasons. However, subsequent multiple regression analyses, applying the sociopolitical destabilization index, the change in the level of the subjective feeling of happiness between 2009 and 2010, GDP per capita and unemployment rate, clearly show that more weight should be placed on socio-psychological rather than purely economic explanation of the genesis of the Arab revolutions.

Meanwhile, the researchers point out that the subjective feeling of happiness cannot be seen as the ultimate predictor of protests. We should remember that a number of political, social, demographic, historical, religious, and economic factors played their role in sociopolitical destabilization. Relative deprivation appears to be one of many possible reasons.

Andrey Korotayev says that the researches are planning to apply a similar approach to analyze political processes in other countries across the globe. By doing so, the researchers will try to measure the threshold level of relative deprivation that forces people to take part in protests, including peaceful demonstrations, mass strikes, or terrorist acts.

Grizzly bears spend many months in hibernation, but their muscles do not suffer from the lack of movement. In the journal "Scientific Reports", a team led by Michael Gotthardt reports on how they manage to do this. The grizzly bears' strategy could help prevent muscle atrophy in humans as well.

A grizzly bear only knows three seasons during the year. Its time of activity starts between March and May. Around September the bear begins to eat large quantities of food. And sometime between November and January, it falls into hibernation. From a physiological point of view, this is the strangest time of all. The bear's metabolism and heart rate drop rapidly. It excretes neither urine nor feces. The amount of nitrogen in the blood increases drastically and the bear becomes resistant to the hormone insulin.

A person could hardly survive this four-month phase in a healthy state. Afterwards, he or she would most likely have to cope with thromboses or psychological changes. Above all, the muscles would suffer from this prolonged period of disuse. Anyone who has ever had an arm or leg in a cast for a few weeks or has had to lie in bed for a long time due to an illness has probably experienced this.

A little sluggish, but otherwise fine

Not so the grizzly bear. In the spring, the bear wakes up from hibernation, perhaps still a bit sluggish at first, but otherwise well. Many scientists have long been interested in the bear's strategies for adapting to its three seasons.

A team led by Professor Michael Gotthardt, head of the Neuromuscular and Cardiovascular Cell Biology group at the Max Delbrueck Center for Molecular Medicine (MDC) in Berlin, has now investigated how the bear's muscles manage to survive hibernation virtually unharmed. The scientists from Berlin, Greifswald and the United States were particularly interested in the question of which genes in the bear's muscle cells are transcribed and converted into proteins, and what effect this has on the cells.

Understanding and copying the tricks of nature

"Muscle atrophy is a real human problem that occurs in many circumstances. We are still not very good at preventing it," says the lead author of the study, Dr. Douaa Mugahid, once a member of Gotthardt's research group and now a postdoctoral researcher in the laboratory of Professor Marc Kirschner of the Department of Systems Biology at Harvard Medical School in Boston.

"For me, the beauty of our work was to learn how nature has perfected a way to maintain muscle functions under the difficult conditions of hibernation," says Mugahid. "If we can better understand these strategies, we will be able to develop novel and non-intuitive methods to better prevent and treat muscle atrophy in patients."

Gene sequencing and mass spectrometry

To understand the bears' tricks, the team led by Mugahid and Gotthardt examined muscle samples from grizzly bears both during and between the times of hibernation, which they had received from Washington State University. "By combining cutting-edge sequencing techniques with mass spectrometry, we wanted to determine which genes and proteins are upregulated or shut down both during and between the times of hibernation," explains Gotthardt.

"This task proved to be tricky - because neither the full genome nor the proteome, i.e., the totality of all proteins of the grizzly bear, were known," says the MDC scientist. In a further step, he and his team compared the findings with observations of humans, mice and nematode worms.

Non-essential amino acids allowed muscle cells to grow

As the researchers reported in the journal "Scientific Reports", they found proteins in their experiments that strongly influence a bear's amino acid metabolism during hibernation. As a result, its muscle cells contain higher amounts of certain non-essential amino acids (NEAAs).

"In experiments with isolated muscle cells of humans and mice that exhibit muscle atrophy, cell growth could also be stimulated by NEAAs," says Gotthardt, adding that "it is known, however, from earlier clinical studies that the administration of amino acids in the form of pills or powders is not enough to prevent muscle atrophy in elderly or bedridden people."

"Obviously, it is important for the muscle to produce these amino acids itself - otherwise the amino acids might not reach the places where they are needed," speculates the MDC scientist. A therapeutic starting point, he says, could be the attempt to induce the human muscle to produce NEAAs itself by activating corresponding metabolic pathways with suitable agents during longer rest periods.

Tissue samples from bedridden patients

In order to find out which signaling pathways need to be activated in the muscle, Gotthardt and his team compared the activity of genes in grizzly bears, humans and mice. The required data came from elderly or bedridden patients and from mice suffering from muscle atrophy - for example, as a result of reduced movement after the application of a plaster cast. "We wanted to find out which genes are regulated differently between animals that hibernate and those that do not," explains Gotthardt.

However, the scientists came across a whole series of such genes. To narrow down the possible candidates that could prove to be a starting point for muscle atrophy therapy, the team subsequently carried out experiments with nematode worms. "In worms, individual genes can be deactivated relatively easily and one can quickly see what effects this has on muscle growth," explains Gotthardt.

A gene for circadian rhythms

With the help of these experiments, his team has now found a handful of genes whose influence they hope to further investigate in future experiments with mice. These include the genes Pdk4 and Serpinf1, which are involved in glucose and amino acid metabolism, and the gene Rora, which contributes to the development of circadian rhythms. "We will now examine the effects of deactivating these genes," says Gotthardt. "After all, they are only suitable as therapeutic targets if there are either limited side effects or none at all."

A study in Botswana by Columbia University Mailman School of Public Health scientists finds that spikes in cases of life-threatening diarrhea in young children are associated with La Niña climate conditions. The findings published in the journal Nature Communications could provide the basis for an early-warning system that would allow public health officials to prepare for periods of increased diarrhea cases as long as seven months ahead of time.

In low- and middle-income countries, diarrhea is the second leading cause of death in children younger than five years of age, with 72 percent of deaths occurring in the first two years of life. Rates of under-5 diarrhea in Africa are particularly high, with an estimated incidence of 3.3 episodes of diarrhea per child each year and one-quarter of all child deaths caused by diarrhea.

The El Niño-Southern Oscillation (ENSO) is a coupled ocean-atmosphere system spanning the equatorial Pacific Ocean that oscillates in a 3-to-7-year cycle between two extremes, El Niño (warmer ocean temperatures) and La Niña (cooler ocean temperatures). The ENSO cycle affects local weather patterns around the world, including temperatures, winds, and precipitation.

Researchers analyzed associations between ENSO and climate conditions and cases of under-5 diarrhea in the Chobe region in northeastern Botswana. They found that La Niña is associated with cooler temperatures, increased rainfall, and higher flooding during the rainy season. In turn, La Niña conditions lagged 0-7 months are associated with about a 30-percent increase in incidence of under-5 diarrhea in the early rainy season from December through February

"These findings demonstrate the potential use of the El Niño-Southern Oscillation as a long-lead prediction tool for childhood diarrhea in southern Africa," says first author Alexandra K. Heaney, a former doctoral student in environmental health sciences at Columbia Mailman and now a postdoc at University of California, Berkeley. "Advanced stockpiling of medical supplies, preparation of hospital beds, and organization of healthcare workers could dramatically improve the ability of health facilities to manage high diarrheal disease incidence."

Previously, El Niño events have been linked to diarrhea outbreaks in Peru, Bangladesh, China, and Japan, but until now studies of the effects of ENSO on diarrheal disease in Africa have been limited to cholera--a pathogen responsible for only a small fraction of diarrheal cases in Africa.

Infectious diarrhea is caused by many different pathogens (viruses, bacteria, and protozoa) and meteorological conditions can have a critical influence on pathogen exposures, in particular, those associated with waterborne transmission. For example, extreme rainfall events may contaminate drinking water by flushing diarrhea-causing pathogens from pastures and dwellings into drinking water supplies, and drought conditions can concentrate animal activity increasing the movement of diarrhea-causing pathogens into surface water resources.

Water Treatment Systems Appear To Be Strained

The researchers speculate that centralized water disinfection processes currently used in the Chobe region may be insufficient to deal with changes in water quality brought on by extremes of wet and dry weather, although they caution that further confirmatory studies are needed.

Earlier research by Columbia Mailman researchers in the Chobe region found that cases of diarrhea in young children spiked during extreme climate conditions, in both the wet and dry seasons. A second study reported on a method to forecast childhood diarrheal disease there. Because climate conditions vary from region to region, forecasts for infectious diseases must be region-specific. In other studies, the scientists have created forecasts for influenza, Ebola, and West Nile Virus. During the influenza season in the United States, they publish weekly regional forecasts with predictions on whether cases are expected to rise or fall and by how much.

Insights Into a Changing Climate in Southern Africa

Research into links between climate systems and infectious disease in Botswana also provides insights into long-term changes in weather patterns coming as a result of climate change.

"In Southern Africa, precipitation is projected to decrease," says Jeffrey Shaman, PhD, co-author and professor of environmental health sciences at the Columbia Mailman School. "This change, in a hydrologically dynamic region where both wildlife and humans exploit the same surface water resources, may amplify the public health threat of waterborne illness. For this reason, there is an urgent need to develop the water sector in ways that can withstand the extremes of climate change."

BUFFALO, N.Y. -- As the world warms, a new study is helping scientists understand how cone-bearing trees like pines and junipers may respond to drought.

The research addresses a classic question in the field: When conditions are dry for long periods of time, do trees survive by growing new roots to tap water sources, or by relying on established roots that already go deep?

The answer, at least for some cone-bearing trees, known as conifers, may be the latter, says Scott Mackay, PhD, professor of geography in the University at Buffalo College of Arts and Sciences. Mackay is an expert in ecohydrology and how trees take up water.

In the new study, he led a team that used computational modeling to investigate how pines and junipers access water sources during prolonged dry spells.

In simulations, trees of both species survived a five-year drought when they entered the dry period with deep roots already reaching into fractured bedrock, where water can be found. These modeled trees also used water in ways that matched well with observations of real trees that successfully weathered drought conditions at the Los Alamos Survival-Mortality (SUMO) experiment site in New Mexico.

"When the model was set up with roots in the groundwater, none of the trees died off," Mackay says. "When the model required the trees to grow the roots into the bedrock after simulations started, all the trees died off. Growing new roots, which itself requires water, took too long."

The study was a collaboration between scientists at UB, Duke University, the Swiss Federal Institute for Forest, Snow and Landscape Research (WSL), Pacific Northwest National Laboratory, Oklahoma State University and the University of Utah.

The research, published online in New Phytologist in July 2019, appears in the journal's January 2020 issue, along with a more recent commentary on the paper's importance by Louis Santiago, PhD, a professor of botany and plant sciences at the University of California, Riverside.

"Mackay et al. (2020) were able to distinguish between two major hypotheses regarding the dynamics of root function during drought, and essentially establish theory, which can now be validated or refuted in other systems," Santiago writes in the commentary.

The study's results could help explain why some pines and junipers are able to survive droughts while other trees around them, including those of the same species, perish.

What's happening underground?

The inability to see underground -- to peer through soil and bedrock -- is a topic of frustration for scientists who research trees. Mackay's research addresses this conundrum, providing a new tool for deducing what might be happening down below.

"It's very difficult to see what's happening with a tree's roots. Digging these trees up is very difficult, and you would kill them in the process," Mackay says. "The model provides us with an additional lens of seeing below the surface. Below-ground is kind of a frontier, an area of research that's becoming more and more important."

The model his team employed in the study simulates the behavior of trees, including how they use water and carbon, both of which are needed to grow new tissue, including roots.

As Mackay explains, "Carbon is obtained through photosynthesis, and it has to be transported down from the canopy of the trees to grow roots. Water is needed as part of this transport process. So if the tree's roots are in dry soil and they can't obtain water, this can affect the tree's ability to move carbon around, which can in turn impair the growth of new roots. Our model captures this feedback."

By helping scientists understand the traits that set some pines and junipers up to survive droughts, the study could provide insights into how coniferous forests will respond to the pressures of climate change.

"Scientists are trying to forecast what's going to happen to the world's biomes under climate change, and models need to be physiologically realistic," Mackay says. "During past droughts, there's lots of evidence of what we might think of as hydrologic refugia -- pockets of woody species that have survived droughts by tapping into deeper water resources. Some models tend to overestimate tree mortality because they're not able to capture some of these refugia. If we can learn more about these refugia and how they're established, we can use that knowledge to create better models."

New York is the fifth largest producer of onion bulbs in the United States, producing over 110,000 metric tons from over 2,800 hectares. Most of these onions are grown on high organic matter soils, where foliar disease management is crucial to productivity and profitability. These foliar diseases include Botrytis leaf blight, purple blotch, downy mildew, and Stemphylium leaf blight.

Stemphylium leaf blight (SLB) initially appears as small, tan to brown lesions that coalesce and extend the length of the leaves. These lesions become dark olive brown to black, contributing to the loss of green leaf area, which may affect bulb size and quality and prevents the plant tops from lodging naturally when the bulbs are fully matured.

Until recently, SLB has been considered a minor foliar disease as it has not done much damage in New York since the early 1990s. However, onion growers in New York have recently seen an increase in the dieback of their crops, and scientists at Cornell University were surprised to discover that SLB was the cause.

"We set out to determine the cause of the dieback problem," said Frank Hay, one of the Cornell University scientists. "A surprise was that Stemphylium leaf blight had long been considered a minor disease of onion but had become the dominant foliar disease in New York onion crops."

Hay and his colleagues discovered that the re-emergence of SLB occurred as the disease developed resistance to fungicides. Their research has resulted in the removal of some fungicides from commercial production as widespread field resistance has developed.

Citrus greening disease, or Huanglongbing (HLB), is deadly, incurable, and the most significant threat to the citrus industry. Most HLB research focuses on the tree canopy, but scientists in California studied the impact of HLB on root systems. They recently published the first study to report on the response of two different varieties of citrus to the causal bacterium, 'Candidatus Liberibacter asiaticus' using metabolomics and microbiome technologies.

"Metabolomics is a cutting-edge field of study that provides snapshot information about the metabolism of living things," explains author Emily M. T. Padhi, "while microbiome studies provide valuable information about the microbial communities living in a particular ecological niche - some microbes are beneficial to the host, while others can be harmful."

Padhi and colleagues wanted to see how the root system of two varieties of citrus responded to HLB. They collected roots from healthy and infected Lisbon lemon and Washington Navel orange trees grown in greenhouses at the same time and under the same conditions.

They found that both varieties experienced a reduction in root sugars and amino acids when exposed to HLB. However, they also found differences. While the concentration of malic acid and quinic acid (two metabolites involved in plant defense) increased in the navel roots, they decreased in the lemon roots. They also found that the beneficial bacteria Burkholderia increased substantially in navel plants but not in lemons, which contradicts previous studies.

"Overall, this is the first study to compare two varieties of citrus using a combined metabolomics and microbiome approach and demonstrates that scion influences root microbial community composition and, to a lesser extent, the root metabolome."

There is evidence to suggest that the causal bacterium moves to the root system soon after a plant becomes infected. A key strategy for preserving the health of an infected tree is root system management and research on different responses to HLB may help devise new variety-specific preventative and treatment measures.

COLUMBUS, Ohio - A growing number of Chinese scientists working in the United States and other parts of the world are returning to their homeland, enhancing China's research productivity.

In a new study, researchers found that more than 16,000 researchers have returned to China from other countries since that nation has opened up to international engagement. More than 4,500 left the United States for China in 2017 - nearly double the number who left in 2010.

These foreign-trained researchers are helping grow China into a scientific powerhouse, said Caroline Wagner, co-author of the study and associate professor in the John Glenn College of Public Affairs at The Ohio State University.

"In our lifetime, China has joined the global scientific community to become world-class in a number of critical fields, such as AI and materials science," Wagner said.

"As more of their researchers return home, that rise is going to continue."

The study was published online this month in the journal Science and Public Policy.

For the study, the researchers made use of a scientific publisher's (Elsevier) database that allowed them to track researchers based on their publications in scientific journals.

The study's authors traced the paths of Chinese authors who first published in China and then subsequently in a different country, or, first published abroad and then in China, to track individual mobility.

Results showed that the number of Chinese researchers going to the United States is larger than the number going to Europe. Chinese scientists are more likely to return to their home from Europe than from the United States.

"The most elite Chinese scientists are more likely to stay in the United States than go home - and that's good for the United States," Wagner said.

"But increasingly, we found that people are going back. The U.S. has been lucky that many top scientists have stayed. But China has programs to attract them back to their homeland."

The study showed the returning scientists' value to China.

Overall, Wagner and her colleagues found that 12 percent of studies published by researchers in China were by those who had worked in other countries - and that is probably an underestimation, she said.

More importantly, those who worked abroad and returned to China published more high-impact research than scientists who didn't work abroad, according to the study.

"Once they go home, those who worked elsewhere are more productive at the international level than people who stayed in China," she said.

One reason for the success of the mobile researchers was that they published more studies with foreign-based collaborators. In previous research, Wagner has found that the more open a country is to cross-country scientific cooperation, the stronger its scientific impact.

That's also one reason why China is fine with the fact that many of its scientists stay in the United States, Europe or elsewhere.

"Chinese leaders value the connections. It is a way to create linkages with the worldwide scientific community," she said.

A variety of indicators suggest that China's science and technology capabilities are on a sharply rising trajectory. For one, China's spending on research and development as tracked by the Organisation for Economic Co-operation and Development has increased faster than overall economic growth in the country.

And by one measure, China ranked second in the world in the number of papers published in indexed scientific journals in 2017.

Wagner said that returning scientists have helped build China's scientific community, which in turns attracts more of the country's scientists to come back home. But she said it is still in America's best interest to try to retain as many of China's best scholars as possible, and be welcoming to those who visit.

"The U.S. has retained its dynamism in science and technology because excellent scientists from other countries come here," she said.

"If we lose that attraction, if we discourage people from coming here, it will take a toll on the U.S. scientific system."

One of the wonders of cell biology is its symmetry. Mammalian cells have one nucleus and one cell membrane, and most humans have 23 pairs of chromosomes. Trillions of mammalian cells achieve this uniformity -- but some consistently break this mold to fulfill unique functions. Now, a team of Johns Hopkins Medicine researchers have found how these outliers take shape.

In experiments with genetically engineered mice, a research team has ruled out a mechanism that scientists have long believed controls the number of hairlike structures, called cilia, protruding on the outside of each mammalian cell. They concluded that control of the cilia count might rely instead on a process more commonly seen in non-mammalian species.

The experiments, described Dec. 2 in Nature Cell Biology and led by Andrew Holland, Ph.D., associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine, may eventually help scientists learn more about human diseases related to cilia function, such as respiratory infections, infertility and hydrocephaly.

Cilia are ancient structures that first appeared on single-celled organisms as small hairlike "fingers" that act as motors to move the cell or antennae to sense the environment. Nearly all human cells have at least one cilium that senses physical or chemical cues. However, some specialized cell types in humans, such as those lining the respiratory and reproductive tracts, have hundreds of cilia on their surface that beat in waves to move fluids through the system.

"Our main question was how these multicilliated cells become so dramatically different than the rest of the cells in our body," says Holland. "Most cells make exactly one cilium per cell, but these highly specialized cells give up on this tight numerical control and make hundreds of cilia."

In an effort to answer the question, Holland and his team took a closer look at the base of cilia, the place where the organelles attach and grow from the surface of the cell. This base is a microscopic, cylinder-shaped structure called a centriole.

In single-ciliated cells, Holland says, centrioles are created before a cell divides. A cell contains two-parent centrioles that each duplicate so that both new cells gets one pair of centrioles -- the oldest of these two centrioles then goes on to form the base of the cilium. However, multicilliated cells create unique structures, called deuterosomes, that act as a copy machine to enable the production of tens to hundreds of centrioles, allowing these cells to create many cilia.

"Deuterosomes are only present in multicilliated cells, and scientists have long thought they are central for determining how many centrioles and cilia are formed," says Holland.

To test this, Holland and his team developed a mouse model that lacked the gene that creates deuterosomes. Then, they analyzed the tissues that carry multicilliated cells and counted their cilia.

The researchers were surprised to find that the genetically engineered mice had the same number of cilia on cells as the mice with deuterosomes, ruling out the central role of deuterosomes in controlling the number of cilia. For example, the multicilliated cells lining the trachea all had 200-300 cillia per cell. The researchers also found that cells without deuterosomes could make new centrioles just as quickly as cells with them.

With this surprising result in hand, the researchers engineered mouse cells that lacked both deuterosomes and parent centrioles, and then counted the number of cilia formed in multicilliated cells.

"We figured that with no parent centrioles and no deuterosomes, the multicilliated cells would be unable to create the proper number of new cilia," says Holland.

Remarkably, Holland says, even the lack of parent centrioles had no effect on the final cilia number. Most cells in both normal and genetically engineered groups created between 50 and 90 cilia.

"This finding changes the dogma of what we believed to be the driving force behind centriole assembly," explains Holland. "Instead of needing a platform to grow on, centrioles can be created spontaneously."

While uncommon in mammals, the so-called de novo generation of centrioles is not new to the animal kingdom. Some species, such as the small flatworm planaria, lack parent centrioles entirely, and rely on de novo centriole generation to create the cilia they use to move.

In further experiments on genetically engineered mice, Holland found that all the spontaneously created centrioles were assembled within a region of the cell rich with fibrogranular material -- the protein components necessary to build a centriole.

He says he suspects that proteins found in that little-understood area of the cell contain the essential elements necessary to construct centrioles and ultimately control the number of cilia that are formed. Everything else, the deuterosomes and even the parent centrioles, are "not strictly necessary," he says.

"We think that the deuterosomes function to relieve pressure on the parent centrioles from the demands of making many new centrioles, freeing up parent centrioles to fulfill other functions," says Holland.

A better understanding of mechanisms that limit cilia number in human cells could potentially advance efforts to treat cilia-related disorders, he said, by identifying targets for drugs.

Researchers at the University of Toronto have identified a key protein that supports the growth of many colorectal cancers. The study, which will be published December 27 in the Journal of Cell Biology, reveals that a protein called Importin-11 transports the cancer-causing protein βcatenin into the nucleus of colon cancer cells, where it can drive cell proliferation. Inhibiting this transport step could block the growth of most colorectal cancers caused by elevated βcatenin levels.

Around 80% of colorectal cancers are associated with mutations in a gene called APC that result in elevated levels of the βcatenin protein. This increase in βcatenin is followed by the protein’s accumulation in the cell nucleus, where it can activate numerous genes that drive cell proliferation and promote the growth and maintenance of colorectal tumors. But how βcatenin enters the cell nucleus after its levels rise is poorly understood. “Because the molecular mechanisms underlying βcatenin nuclear transport remain unclear, we set out to identify genes required for continuous βcatenin activity in colorectal cancer cells harboring APC mutations,” says Stephane Angers, a professor in the Department of Pharmaceutical Sciences at the University of Toronto’s Leslie Dan Faculty of Pharmacy.

Using CRISPR DNA editing technology, Angers and colleagues, including graduate student Monika Mis, developed a new technique that allowed them to screen the human genome for genes that support βcatenin’s activity in colorectal cancer cells after its levels have been elevated by mutations in APC. One of the main genes they identified was IPO11, which encodes a protein called Importin-11 that is known to be involved in nuclear import.

Angers and colleagues found that Importin-11 binds to βcatenin and escorts it into the nucleus of colorectal cancer cells with mutations in APC. Removing Importin-11 from these cells prevented βcatenin from entering the nucleus and activating its target genes.

The researchers discovered that Importin-11 levels are often elevated in human colorectal cancers. Moreover, removing Importin-11 inhibited the growth of tumors formed by APC mutant cancer cells isolated from patients.

“We conclude that Importin-11 is required for the growth of colorectal cancer cells,” Angers says. Learning more about how Importin-11 transports βcatenin into the nucleus may help researchers develop new therapies that block this process and reduce the growth of colorectal cancers caused by mutations in APC.