Culture

A new field of research in microbiology is transforming the way scientists see fungi, bacteria and other microorganisms. Microbiome research is so promising that it has drawn attention from funders and industry as well as scientists. In the United States alone, the market for microbiome-based agricultural products is expected to be worth more than $10 billion by 2025. Research on the human microbiome has surpassed $1.7 billion in the past decade.

Scientific study of microbiomes is growing exponentially, encompassing topics that range from the influence of gut microbiota on brain functioning in humans to the impact of marine bacteria on climate change. To address this extraordinary thematic diversity, agree on a definition of microbiome, and pursue guidelines for investment in research, the European Union-funded Microbiome Support project brought together a panel of experts from 28 institutions in various countries. The conclusions are published in the journal Microbiome.

Brazil was represented on the panel by the Genomics for Climate Change Research Center (GCCRC), one of the Engineering Research Centers (ERCs) funded by São Paulo Research Foundation - FAPESP. In this case, its partner is the Brazilian Agricultural Research Corporation (EMBRAPA). GCCRC is hosted by the University of Campinas (UNICAMP), and its principal investigator is Professor Paulo Arruda.

"The discussion reached conclusions that very clearly distinguish between the concepts of microbiota and microbiome. Microbiota is the community of microorganisms in a given environment, such as your office desk, plants, skin, or gut. Microbiota is everywhere. If you add the functions it performs in that environment, you're talking about microbiome," said Rafael Soares Correa de Souza, the leader of GCCRC's microbiome team. Souza is supported by FAPESP via a postdoctoral scholarship.

"When we speak of a plant's microbiome, for example, we're not referring only to the microorganism community present in the plant but also to all the functions performed by that community, such as absorption of nutrients, protection from pathogens and drought resistance, among many others," he said.

Advances in genetic sequencing and bioinformatics in recent decades have enabled scientists to discover not only that microorganisms such as bacteria, fungi, and protozoa are far more diverse than they thought but also that many of their functions have been poorly understood or simply unknown until recently.

These tools can now be used to identify the community of microorganisms and their "theater of activity", the term coined by the panel for the "whole spectrum" of molecules they produce, including their structural elements (nucleic acids, proteins, lipids, polysaccharides) and metabolites, and the "molecules produced by coexisting hosts and structured by the surrounding environmental conditions".

"The concept of microbiome is much more holistic than the concept of microbiota," Souza said.

Market and legislation

Many microbiome-based products have come to market, and defining concepts is important, among other reasons, to facilitate communication with society and offer a basis for lawmakers to legislate on the subject.

Meat from chickens whose diets have been supplemented with microbial agents that eliminate the need for antibiotics can be purchased in supermarkets even in Europe, a strictly regulated market. Fecal microbiota transplantation is an approved treatment for antibiotic-resistant infections in Brazil and the US.

Given the field's potential, Microbiome Support was set up to decide on research priorities for funding by Horizon Europe, the EU's scientific research and innovation initiative that will succeed Horizon 2020 and will invest €100 billion in all research fields between 2021 and 2027.

"Here at GCCRC we want to understand how to modulate the microbiome in order to improve the agricultural performance of plants, raise yields, and reduce fertilizer and agrochemical usage to enhance environmental safety and eliminate human health hazards. Brazil is one of the world's leading agricultural producers, so this is an opportunity for our science and industry," Souza said.

WASHINGTON -- Biometric authentication, which uses unique anatomical features such as fingerprints or facial features to verify a person's identity, is increasingly replacing traditional passwords for accessing everything from smartphones to law enforcement systems. A newly developed approach that uses 3D images of finger veins could greatly increase the security of this type of authentication.

"The 3D finger vein biometric authentication method we developed enables levels of specificity and anti-spoofing that were not possible before," said Jun Xia, from University at Buffalo, The State University of New York, research team leader. "Since no two people have exactly the same 3D vein pattern, faking a vein biometric authentication would require creating an exact 3D replica of a person's finger veins, which is basically not possible."

In the Optical Society (OSA) journal Applied Optics, the researchers describe their new approach, which represents the first time that photoacoustic tomography has been used for 3D finger vein biometric authentication. Tests of the method on people showed that it can correctly accept or reject an identity 99 percent of the time.

"Due to the COVID-19 pandemic, many jobs and services are now performed remotely," said research team member Giovanni Milione, from NEC Laboratories America, Inc. "Because our technique detects invisible features in 3D, it could be used to enable better authentication techniques to protect personnel data and sensitive documents."

Adding depth information

Although other biometric authentication approaches based on finger veins have been developed, they are all based on 2D images. The additional depth from a 3D image increases security by making it more difficult to fake an identity and less likely that the technique will accept the wrong person or reject the right one.

To accomplish 3D biometric authentication using the veins in a person's fingers, the researchers turned to photoacoustic tomography, an imaging technique that combines light and sound. First, light from a laser is used to illuminate the finger. If the light hits a vein, it creates a sound much in the same way that a grill creates a "poof" sound when it is first lit. The system then detects that sound with an ultrasound detector and uses it to reconstruct a 3D image of the veins.

"It has been challenging to use photoacoustic tomography for 3D finger vein biometric authentication because of the bulky imaging system, small field of view and inconvenient positioning of the hand," said Xia. "We addressed these issues in the new system design through a better combination of light and acoustic beams and custom-made transducers to improve the imaging field of view."

Designing a practical system

To better integrate light illumination and acoustic detection, the researcher fabricated a new light- and acoustic-beam combiner. They also designed an imaging window that allows the hand to be naturally placed on the platform, similar to a full-size fingerprint scanner. Another critical development was a new matching algorithm, developed by Wenyao Xu from the Computer science and Engineering department that allows biometric identification and matching of features in 3D space.

The researchers tested their new system with 36 people by imaging their four left and four right fingers. The tests showed that the approach was not only feasible but also accurate, especially when multiple fingers were used.

"We envision this technique being used in critical facilities, such as banks and military bases, that require a high level of security," said Milione. "With further miniaturization 3D vein authentication could also be used in personal electronics or be combined with 2D fingerprints for two-factor authentication."

The researchers are now working to make the system even smaller and to reduce the imaging time to less than one second. They note that it should be possible to implement the photoacoustic system in smartphones since ultrasound systems have already been developed for use in smartphones. This could enable portable or wearable systems that perform biometric authentication in real time.

In an article published in Nature Genetics, researchers confirm that about 14% of all cases of cerebral palsy, a disabling brain disorder for which there are no cures, may be linked to a patient's genes and suggest that many of those genes control how brain circuits become wired during early development. This conclusion is based on the largest genetic study of cerebral palsy ever conducted. The results led to recommended changes in the treatment of at least three patients, highlighting the importance of understanding the role genes play in the disorder. The work was largely funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

"Our results provide the strongest evidence to date that a significant portion of cerebral palsy cases can be linked to rare genetic mutations, and in doing so identified several key genetic pathways involved," said Michael Kruer, M.D., a neurogeneticist at Phoenix Children's Hospital and the University of Arizona College of Medicine - Phoenix and a senior author of the article. "We hope this will give patients living with cerebral palsy and their loved ones a better understanding of the disorder and doctors a clearer roadmap for diagnosing and treating them."

Cerebral palsy affects approximately one in 323 children in the United States. Signs of the disorder appear early in childhood resulting in a wide range of permanently disabling problems with movement and posture, including spasticity, muscle weakness, and abnormal gait. Nearly 40% of patients need some assistance with walking. In addition, many patients may also suffer epileptic seizures, blindness, hearing and speech problems, scoliosis, and intellectual disabilities.

Since its first official description in 1862, scientists have hotly debated whether cerebral palsy is caused by problems at birth. For instance, it is known that babies born prematurely or who experience a lack of blood flow or oxygen during birth have a greater chance of suffering from the disorder. Later though, researchers concluded that a majority (85-90%) of all cases are congenital, or born with the disease, and some studies had suggested that cerebral palsy could be inherited. Despite this, the causes of many children's cases had remained elusive.

Then in 2004, scientists discovered the first genetic mutation known to cause cerebral palsy. Since then several more mutations have been identified and depending on how an experiment was performed, scientists have estimated that anywhere from 2 to 30% of all cases may be linked to a misspelling in a patient's DNA. In this study, the researchers provided support for a previous estimate and highlighted which genes may play a critical role in the disorder.

"Cerebral palsy is one of neurology's oldest unresolved mysteries. The results from this study show how advances in genomic research provide scientists with the hard evidence they need to unravel the causes behind this and other debilitating neurological disorders," said Jim Koenig, Ph.D., program director at NINDS.

The study was led by Sheng Chih (Peter) Jin, Ph.D., assistant professor of genetics at Washington University School of Medicine, St. Louis, and Sara A. Lewis, Ph.D., a post-doc in the lab Dr. Kruer leads.

The researchers searched for what are known as "de novo," or spontaneous, mutations in the genes of 250 families from the United States, China, and Australia through a collaboration made possible by the International Cerebral Palsy Genomics Consortium. These rare mutations are thought to happen when cells accidentally make mistakes copying their DNA as they multiply and divide. An advanced technique, called whole exome sequencing, was used to read out and compare the exact codes of each gene inscribed in the chromosomes of the patients with that of their parents. Any new differences represented de novo mutations that either happened while a parent's sperm or egg cell multiplied or after conception.

Initially the researchers found that the cerebral palsy patients had higher levels of potentially harmful de novo mutations than their parents. Many of these mutations appeared to be concentrated in genes that are highly sensitive to the slightest changes in the DNA letter code. In fact, they estimated that about 11.9% of the cases could be explained by damaging de novo mutations. This was especially true for the idiopathic cases which had no known cause and represented the majority (62.8%) of cases in the study.

Approximately another 2% of the cases appeared to be linked to recessive, or weaker, versions of genes. This raised the estimate of cases that could be linked to genetic problems from 11.9% to 14%, as has been previously reported.

Moreover, the results led to recommendations for more tailored treatments of three patients.

"The hope of human genome research is that it will help doctors find the best, most personalized, matches between treatments and diseases. These results suggest that this may be possible for some patients with cerebral palsy," said Chris Wellington, program director in the Division of Genome Sciences at the NIH's National Institute of Human Genome Research, which also provided support for the study.

When the researchers looked more closely at the results, they found that eight genes had two or more damaging de novo mutations. Four of these genes, labeled RHOB, FBXO31, DHX32, and ALK, were newly implicated in CP while the other four had been identified in previous studies.

The researchers were especially surprised by the RHOB and FBXO31 results. Two cases in the study had the same spontaneous mutation in RHOB. Likewise, two other cases had the same de novo mutation in FBXO31.

"The odds of this randomly happening are incredibly low. This suggests that these genes are highly linked to cerebral palsy," said Dr. Jin.

The researchers also looked at the genes behind other brain development disorders and found that about 28% of the cerebral palsy genes identified in this study have been linked to intellectual disability, 11% to epilepsy and 6.3% to autism spectrum disorders. In contrast, the researchers found no significant overlap between cerebral palsy genes and those involved with the neurodegenerative disorder Alzheimer's disease which attacks the brain later in life.

"Our results support the idea that cerebral palsy is not one narrow disease but a spectrum of overlapping neurodevelopmental problems," said Dr. Lewis.

Further analysis of the results suggested that many of the genes they found in this study, including six of the eight genes that had two or more de novo mutations, control the wiring of neural circuits during early development. Specifically, these genes are known to be involved in either the construction of protein scaffolds that line the perimeters of neural circuits or in the growth and extension of neurons as they wire up.

Experiments on fruit flies, formally known as Drosophila melanogaster, supported this idea. To do this, the researchers mutated fly versions of the wiring genes they identified in the cerebral palsy patients. They found that mutations in 71% of these genes caused flies to have problems with movement, including walking, turning, and balancing. The results suggested that these genes play a critical role in movement. They estimated that there was only a 3% chance these problems would happen if they had blindly mutated any gene in the fly genome.

"Treatments for cerebral palsy patients have not changed for decades," said Dr. Kruer. "In the future, we plan to explore how these results can be used to change that."

Because gastrointestinal stromal tumors (GIST) are sensitive to the targeted small molecule therapy imatinib, oncologists tend to treat all patients with metastatic GIST with this drug. However, because this rare type of cancer is caused by different genetic mutations, imatinib does not help all patients equally.

To determine whose cancer may be most responsive, the National Comprehensive Cancer Network suggests that patients undergo genetic testing to identify each individuals' tumor mutations. And yet, only 30 percent of patients have genetic testing at the time of diagnosis, likely due to concerns over cost and utility of testing, said Jason Sicklick, MD, professor of surgery in the Division of Surgical Oncology at University of California San Diego School of Medicine.

"We recommend that all patients with a new diagnosis of metastatic GIST undergo genetic testing prior to the initiation of first-line chemotherapy," said Sicklick, surgical oncologist and co-leader of the Sarcoma Disease Team at Moores Cancer Center at UC San Diego Health. "In doing so, those who are unlikely to benefit from imatinib can be given a treatment better suited for their individual tumor."

In a paper published online on September 29, 2020 in the journal JAMA Network Open, Sicklick and colleagues reported that genetic testing is cost-effective and beneficial for newly diagnosed patients with metastatic GIST, a type of soft tissue sarcoma that develops in specialized nerve cells in the wall of the digestive system, most often occurring in the stomach or small intestine.

The team developed a model to compare the cost effectiveness of targeted gene testing and personalized therapy to patients with metastatic GIST who were prescribed imatinib (marketed as Gleevec). Data analyses were conducted October 2019 to January 2020.

"Genetic testing is cost-effective as it allows clinicians to prescribe chemotherapy in a tumor-specific manner. Patients who would not benefit from imatinib, because of primary tumor resistance, are given alternative therapy," said first author Sudeep Banerjee, MD, who did the research while in the Sicklick lab at Moores Cancer Center and who is now chief resident at David Geffen Medical School at UCLA. "Avoiding ineffective treatment and reduced rates of disease progression are the reasons why genetic testing is cost-effective."

Although the most common sarcoma, GIST is rare with an estimated annual incidence of 6.8 cases per million people in the United States. Eventually this cancer becomes highly resistant to existing drug therapies.

Clinicians fight the growth with progressively aggressive drugs, the downside being that each line of therapy has diminishing effectiveness and higher toxicity for patients. More than 95 percent of patients eventually succumb to drug-resistant GIST, underscoring the importance of starting patients on the most effective available drug not only because it is most cost-effective, but crucial for maintaining and improving quality of life in these patients, said Sicklick, co-corresponding author on the paper.

"The treatment of cancer is becoming an increasingly personalized process," said Banerjee. "There is a rapidly expanding body of research around gene-specific and even mutation-specific therapies that can be effective independent of the site of origin of a given tumor. Genetic testing provides the necessary information for patients to potentially benefit from those novel therapies."

Simultaneous heatwaves and droughts are becoming increasingly common in western parts of the Unites States, according to a new study led by researchers from McGill University. Periods of dry and hot weather, which can make wildfires more likely, are becoming larger, more intense, and more frequent because of climate change.

In a study published by Science Advances, the researchers analyzed heat and drought events across the contiguous United States over the past 122 years. They found that combined dry and hot events have not only increased in frequency, but also in size geographically. Where such events were once confined to small parts of the United States, now they cover whole regions, such as the entire west coast and parts of the Northeast and Southeast.

"Dry-hot events can cause large fires. Add wind and a source of ignition, and this results in 'megafires' like the 2020 fires across the west coast of the United States. Drought and record-breaking heatwaves, coupled with a storm that brought strong winds and 12,000 lightning events in a span of 72 hours, caused more than 500 wildfires," says lead author Mohammad Reza Alizadeh, a PhD student under the supervision of Professor Jan Adamowski in the Department of Bioresource Engineering at McGill University.

The researchers also found that dry and hot weather events are intensifying, with longer periods of drought and higher temperatures. These dual "dry-hot extremes" are not only self-intensifying - more heat causes more drought and vice versa - but are also self-propagating, meaning they are able to move from region to region. "As increased temperatures are driving and expanding aridity, droughts and heatwaves move from one region to downwind regions," says Alizadeh. These extremes can be particularly damaging for agricultural production and ecosystems, they warn.

According to the researchers, the trigger for these hot-dry events is shifting. Looking back at the catastrophic Dust Bowl of the 1930s, they explain that the dust storms were driven by a lack of rainfall coupled with poor land management practices. In recent decades, however, dry-hot disasters are driven more often by excess heat than a lack of rainfall.

The future will bring us more of these disasters, if the current warming trends continue, the researchers caution. They suggest their findings could be used to inform climate mitigation and adaptation efforts. "We need to understand how things are changing in order to adapt," says Professor Jan Adamowski.

Results of recent studies involving valproic acid, used for decades as an anti-convulsant drug, show that it can interact with the conformation of DNA and regulate gene expression.

These are some of the key findings from a project led by biologist Maria Luiza S. Mello at the University of Campinas (UNICAMP) in the state São Paulo, Brazil, with the collaboration of Benedicto de Campos Vidal, Emeritus Professor in the Biology Institute’s Department of Structural and Functional Biology.

The group has been studying the functions of valproic acid, or sodium valproate (VPA), for over a decade and have demonstrated the compound’s action on the expression of genes associated with diabetes in cellular models (read more at: agencia.fapesp.br/23819).

Its interaction with DNA is reported in an article published in the International Journal of Biological Macromolecules. The study was part of a Thematic Project supported by FAPESP to study the action of VPA. “Elucidating the drug’s action mechanisms is important because it paves the way for novel pharmaceutical research,” Mello said.

Changes in histones and DNA

The epigenetic action of VPA – its capacity to influence gene expression without changing the subject’s DNA – was already well-known. “In 2017, Iranian researchers mooted the possibility of an action mechanism that was not only epigenetic but also involved direct interaction with the structure of histone H1,” Mello said. “So we decided to study how histones and DNA itself respond to VPA.” Histones are cell nucleus proteins and key components of chromatin, the substance of chromosomes. These are made up of DNA tightly wound around histones.

The group tested samples containing VPA-DNA and VPA-histone mixtures. They analyzed the interactions between H1, H3, and VPA by means of high-performance polarization microscopy and Fourier-transform infrared microspectroscopy, using equipment previously acquired by FAPESP for Campos Vidal.

“The samples with DNA, histones, and VPA were analyzed first under the polarization microscope and then under the infrared microspectroscope” Mello said. This type of measurement, performed with a spectroscope coupled to a special microscope, produces a spectral signature of molecular structure – a graphical record of how the molecules are organized.

The graph of the signature displays curves with peaks and troughs. “The frequency of the peaks points to a specific chemical group,” Mello said.

The group then compared histone and DNA organization with and without VPA. “We found that VPA can cause changes in the conformation, or spatial arrangement, of the two histones of interest, H1 and H3. In addition, we observed changes in DNA superstructure and molecular order,” he said. The next step will be to confirm whether the effect also occurs in cells treated with VPA in vitro.

Tumor gene expression

Besides this discovery, as part of the master’s research of Marina Amorim Rocha, in December 2019 the group published in Scientific Reports another important finding about the epigenetic action of VPA in laboratory-grown HeLa cells, which are derived from human cervical cancer cells. The focus for the investigation was a specific kind of epigenetic alteration known as DNA methylation.

Methylation occurs when a methyl group (CH3) is added to the carbon 5 position in the DNA nitrogenous base cytosine. “When this happens in the promoter of a gene, the functioning of the gene itself is altered,” Mello explained. If large-scale methylation occurs in the promoter of a tumor suppressor gene, for example, the gene can become inactive and cease performing its function.

The process can be manipulated, passively by inhibiting an enzyme involved in methylation or actively via a recently discovered pathway. “In this case a group of enzymes from the TET family lets these methylated cytosines transform themselves into other derived molecules until demethylation is complete,” Mello said.

In their study, the UNICAMP researchers found that the mechanism induced by VPA in HeLa cells was predominantly but not exclusively active. “It also acts via the passive pathway, and this finding can enhance the expertise of scientists dedicated to drug development,” Mello said. In other words, the fact that the compound reduces methylation in cultured cells during the stationary phase of the life cycle suggests that in future it can be tested as a candidate to reverse this process in cells that have stopped dividing.

Researcher Steven Emslie encountered a puzzle at Cape Irizar, a rocky cape located just south of the Drygalski Ice Tongue on the Scott Coast, Ross Sea. He found both ancient and what appeared to be fresh remains of Adelie penguins, mostly of chicks, which frequently die and accumulate at these colonies. However, the "fresh" remains were puzzling, he says, because there are no records of an active penguin colony at this site since the first explorers (Robert Falcon Scott) in 1901-1903 came to the Ross Sea.

Emslie found abundant penguin chick bones scattered on the surface, along with guano stains, implying recent use of the site, but that wasn't possible, says Emslie. Some of the bones were complete chick carcasses with feathers, now falling apart from decay as at a modern colony, as well as intact mummies. Emslie and his colleagues collected some of these surface remains for further analysis and radiocarbon dating to try and figure out what was going on there.

The team found old pebble mounds scattered about the cape. These mounds are former nesting sites of Adélie penguins because they use pebbles to build their nests. When they abandon a site, the pebbles become scattered and stand out on the landscape, since they are all about the same size.

"We excavated into three of these mounds, using methods similar to archaeologists, to recover preserved tissues of penguin bone, feather, and eggshell, as well as hard parts of prey from the guano (fish bones, otoliths). The soil was very dry and dusty, just as I've found at other very old sites I've worked on in the Ross Sea, and also had abundant penguin remains in them. Overall, our sampling recovered a mixture of old and what appeared to be recent penguin remains implying multiple periods of occupation and abandonment of this cape over thousands of years. In all the years I have been doing this research in Antarctica, I've never seen a site quite like this."

The analyses reported in Emslie's recent paper published in Geology indicate at least three occupation periods of the cape by breeding penguins, with the last one ending at about 800 years ago. When that occupation ended, either due to increasing snow cover over the cape or other factors (the Little Ice Age was beginning about then too), the "fresh" remains on the surface were covered in snow and ice and preserved intact until recent exposure from snowmelt.

Global warming has increased the annual temperature in the Ross Sea by 1.5-2.0 °C since the 1980s, and satellite imagery over the past decade shows the cape gradually emerging from under the snow. Thus, says Emslie, "This recent snowmelt revealing long-preserved remains that were frozen and buried until now is the best explanation for the jumble of penguin remains of different ages that we found there."

Acta Pharmaceutica Sinica B publishes special issue on 'Research on Emerging COVID-19 (Target, Mechanism, and Therapeutics)' edited by Hai-Bin Luo, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China; Shilin Chen, Institute of Chinese Materia Medica, Beijing, China and Peiqing Liu, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. In recent months, due to its high infectivity and pathogenicity, SARS-CoV-2 has gradually spread to more than 200 countries and regions, resulting in more than 500,000 deaths globally. There is an urgent need for effective prevention and treatment (drugs and vaccines) against this highly pathogenic coronavirus. This special issue includes original five research articles, three review articles, and two letters to the editor covering topics around the identification of readily available drugs or natural products as a rapid way to provide clinical treatment in COVID-19 therapy.

Featured papers in this issue are:

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19 by authors Xiaoyan Liu, Zhe Li, Shuai Liu, Jing Sun and Hai-Bin Luo (https://doi.org/10.1016/j.apsb.2020.04.008). Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, the authors found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, the authors identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro.

Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites by authors Sisi Kang, Mei Yang, Zhongsi Hong, Liping Zhang and Shoudeng Chen (https://doi.org/10.1016/j.apsb.2020.04.009). The structural information of SARS-CoV-2 nucleocapsid protein remains unclear. The authors have determined the 2.7 Å crystal structure of the N-terminal RNA binding domain of SARS-CoV-2 nucleocapsid protein and revealed potential unique drug targeting sites, which can help guide the design of novel antiviral agents targeting SARS-CoV-2.

D3Targets-2019-nCoV: a webserver for predicting drug targets and for multi-target and multi-site based virtual screening against COVID-19 by authors Yulong Shi, Xinben Zhang, Kaijie Mu, Cheng Peng and Weiliang Zhu (https://doi.org/10.1016/j.apsb.2020.04.006). The authors have developed a molecular docking-based web server D3Targets-2019-nCoV to accelerate drug discovery against COVID-19. The server has two functions; one, to predict targets for active compounds, and two, to identify potent compounds via virtual screening. The webserver is useful to medical chemists, pharmacologists and clinicians for efficiently discovering or developing effective drugs against SARS-CoV-2.

Other articles published in the issue include:

Review articles

Combating COVID-19 with integrated traditional Chinese and Western medicine in China
Liqiang Ni, Lili Chen, Xia Huang, Chouping Han, Hongzhuan Chen
https://doi.org/10.1016/j.apsb.2020.06.009

Bioactive natural compounds against human coronaviruses: a review and perspective
Yanfang Xian, Juan Zhang, Zhaoxiang Bian, Hua Zhou, Hongxi Xu
https://doi.org/10.1016/j.apsb.2020.06.002

Highly pathogenic coronaviruses: thrusting vaccine development in the spotlight
Chunting He, Ming Qin, Xun Sun
https://doi.org/10.1016/j.apsb.2020.05.009

Original articles

Analysis on herbal medicines utilized for treatment of COVID-19
Lu Luo, Jingwen Jiang, Cheng Wang, Martin Fitzgerald, Shilin Chen
https://doi.org/10.1016/j.apsb.2020.05.007

Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model
Cheng Cui, Miao Zhang, Xueting Yao, Siqi Tu, Dongyang Liu
https://doi.org/10.1016/j.apsb.2020.04.007

Letters to the Editor
Comment on GLP-1-based drugs and COVID-19 treatment
Tianru Jin, Mingyao Liu
https://doi.org/10.1016/j.apsb.2020.05.006

Anti-RAS drugs and SARS-CoV-2 infection
Jingwei Bian, Rongsheng Zhao, Suodi Zhai, Zijian Li
https://doi.org/10.1016/j.apsb.2020.04.013

Keywords: SARS-CoV-2; COVID-19; Prevention; Treatment

DENVER, CO - A new editorial accompanying a study published in the Journal of the American College of Cardiology is bringing attention to the underappreciated and often overlooked issue of malnutrition among those who are obese. Malnutrition is defined as faulty nutrition due to inadequate or unbalanced intake of nutrients. It is often incorrectly perceived as an illness that primarily affects those who are underweight, yet a recent study examining acute coronary disease (ACD) found malnourishment is an important underlying factor in the disease. In fact, about half of those found to be malnourished were overweight or obese.

"Malnutrition is a largely under-recognized and undertreated condition in patients with increased body mass index, as increased abdominal girth is too often mistaken for overnutrition rather than undernutrition," said Andrew Freeman, MD, director of cardiovascular prevention and wellness at National Jewish Health and co-author of the editorial. "It's important to dispel the thought that weight is correlated with food quality and that obese patients are not at risk of malnutrition."

The ACD study is just the latest evidence that underscores the prevalence of malnutrition among obese individuals and how it contributes to serious health complications. In fact, the World Health Organization reports that malnutrition affects more than four times more overweight or obese individuals than those who are underweight.

"It is imperative that individuals undergo nutritional assessments and are offered counseling and resources to ensure they are taking in the right nutrients to adequately fuel their body," Dr. Freeman said. "If left untreated, malnutrition leads to serious health conditions including diabetes, hypertension and heart disease."

While it is well-documented in the scientific community that malnutrition causes these health concerns, obese patients who are seen for these conditions often do not undergo nutritional screening, especially in cardiology. Recognizing that overweight patients often have poor diet quality can help shift the conversation in the patient-physician visit toward improving nutritional status.

"Paying lip service with the usual phrases, such as 'Be sure to exercise and eat right,' simply doesn't cut it. It behooves us as a profession to ensure adequate training and competency in the delivery of care in the lifestyle space," Dr. Freeman said. "Clinicians should be well-versed in the dietary patterns known to reduce or even reverse cardiovascular disease, as well as physical activity guidelines and self-care practices such as stress relief, mindfulness and good, quality sleep."

Monitoring each of these lifestyle components can lead to marked improvements in many chronic diseases. This new paper highlights an urgent call to action: it is time for the medical community to arm itself with the most cost effective and powerful tool in the battle against heart disease and other common health conditions: nutrition and lifestyle medicine.

Studies have previously shown that eating whole grains, legumes, fruits, vegetables, nuts, and seeds are beneficial in reducing blood pressure, blood glucose, cholesterol and inflammatory markers. Treatment of at-risk patients must include counseling on how to shift toward a diet that is rich in these healthier food options. In fact, many hospitalizations for life-threatening events can be valuable teaching moments to truly affect care and change treatment trajectories.

Long after a COVID-19 vaccination is developed and years after the coronavirus death toll is tallied, the impact on mental health will linger, continuing to inflict damage if not addressed, according to new research. Michael Zvolensky, University of Houston Hugh Roy and Lillie Cranz Cullen Distinguished University Professor of Psychology and director of the Anxiety and Health Research Laboratory/Substance Use Treatment Clinic, has published two papers discussing the psychological, addictive and health behavior issues related to the COVID-19 pandemic from a behavioral science perspective.

"The impact of COVID-19 on psychological symptoms and disorders, addiction and health behavior is substantial and ongoing and will negatively impact people's mental health and put them at greater risk for chronic illness and drug addiction," reports Zvolensky in Behaviour Research and Therapy. "It will not equally impact all of society. Those at greater risk are those that have mental health vulnerabilities or disorders."

For instance, those who 'catastrophize' the pandemic amplify the actual stress impact, increasing their symptoms and creating the possibility for substance abuse.

"That sets in motion a future wave of mental health, addiction and worsening health problems in our society. It's not going to go away, even with a vaccination, because the damage is already done. That's why we're going to see people with greater health problems struggling for generations," said Zvolensky

Zvolensky offers a model of how the COVID-19 stress burden may be associated with addictive problems and health behaviors, and how these may be associated with later chronic illness and psychological problems.

In Psychiatry Research, Zvolensky presents findings linking worry and fear about the pandemic to drug use and abuse.

Zvolensky evaluated a group of 160 participants to find if COVID-19-related worry and fear differed between substance abstainers, pre-COVID-19 users and those who initiated drug use for the first time during the pandemic.

"Results generally suggest the persons using substance experience the highest levels of COVID-19-related worry and fear," said Zvolensky. "Additionally, worry about COVID-19 is related to coping motives for substance use."

These results provide preliminary evidence that COVID-19-related worry and fear may be putative risk factors for substance use initiation in the face of COVID-19, and these results may provide critical clinical information for helping individuals cope with this pandemic," he said.

A team of researchers in the United States and Japan reports that spinal cord stimulation (SCS) measurably decreased pain and reduced motor symptoms of Parkinson's disease, both as a singular therapy and as a "salvage therapy" after deep brain stimulation (DBS) therapies were ineffective.

Writing in the September 28, 2020 issue of Bioelectronic Medicine, first author Krishnan Chakravarthy, MD, PhD, assistant professor of anesthesiology at University of California San Diego School of Medicine, and colleagues recruited 15 patients with Parkinson's disease, a neurodegenerative disorder that is commonly characterized by physical symptoms, such as tremors and progressive difficulty walking and talking, and non-motor symptoms, such as pain and mental or behavioral changes.

The mean age of the patients was 74, with an average disease duration of 17 years. All of the patients were experiencing pain not alleviated by previous treatments. Eight had undergone earlier DBS, a non-invasive, pain therapy in which electrical currents are used to stimulate specific parts of the brain. Seven patients had received only drug treatments previously.

Researchers implanted percutaneous (through the skin) electrodes near the patients' spines, who then chose one of three types of electrical stimulation: continuous, on-off bursts or continuous bursts of varying intensity.

Following continuous programmed treatment post-implantation, the researchers said all patients reported significant improvement, based on the Visual Analogue Scale, a measurement of pain intensity, with a mean reduction of 59 percent across all patients and stimulation modes.

Seventy-three percent of patients showed improvement in the 10-meter walk, a test that measures walking speed to assess functional mobility and gait, with an average improvement of 12 percent.

And 64 percent of patients experienced improvements in the Timed Up and Go (TUG) test, which measures how long it takes a person to rise from a chair, walk three meters, turn around, walk back to the chair and sit down. TUG assesses physical balance and stability, both standing and in motion. Average TUG improvement was 21 percent.

The authors said the findings suggest SCS may have therapeutic benefit for patients with Parkinson's in terms of treatment for pain and motor symptoms, though they noted further studies are needed to determine whether improved motor function is due to neurological changes caused by SCS or simply decreased pain.

"We are seeing growing data on novel uses of spinal cord stimulation and specific waveforms on applications outside of chronic pain management, specifically Parkinson's disease," said Chakravarthy, pain management specialist at UC San Diego Health. "The potential ease of access and implantation of stimulators in the spinal cord compared to the brain suggests that this is a very exciting area for future exploration."

Irvine and Pasadena, CA - Sept. 28, 2020 - Early results of an experimental vaping study have shown significant lung injury from E-cigarette (eC) devices with nickel-chromium alloy heating elements. The findings were consistent, with or without the use of nicotine, vitamin E oil or tetrahydrocannabinol (THC), which have previously been thought to contribute to the life-threatening respiratory problem.

The early results, published in the Journal of the American Heart Association by researchers from the University of California, Irvine (UCI) School of Medicine and the Huntington Medical Research Institutes (HMRI), were observed during a larger study designed to explore the effect of e-cigarette and other vaping product use on the cardiovascular system. While conducting experiments, researchers observed eC or vaping product use-associated lung injury (EVALI) immediately after switching from a vaping device with a stainless steel heating element, to one that used nickel-chromium alloy (NC).

"The results were so impactful, we felt it imperative to release the initial findings early so that electronic cigarette users could be cautioned sooner, especially considering E-cigarette users are at increased risk of COVID-19," stated senior author Robert A. Kloner, MD, PhD, chief science officer for HMRI and professor of medicine at USC.

The switch in devices occurred in September 2019, when the eC device the team was using went off market and a substitute device was offered as an alternative. The new device was physically compatible with the original exposure system, but the heating element changed from stainless steel (SS) to a nickel?chromium alloy (NC).

"Within an hour of beginning an experiment, we observed evidence of severe respiratory distress, including labored breathing, wheezing and panting," said Michael Kleinman, PhD, professor of occupational and environmental medicine at UCI School of Medicine and member of the UCI Center for Occupational and Environmental Health. "After analyzing lung tissue from subjects in the study, we found them to be severely compromised and observed other serious changes such as lung lesions, red blood cell congestion, obliteration of alveolar spaces, and pneumonitis in some cases."

The current research aimed to study the impacts of breathing in E-cigarette vapors on heart function in a well- established pre-clinical experimental model. Over the course of nearly a year, none of the subjects exposed to vapors from the stainless steel devices, both with and without additives, contracted respiratory distress and only one showed a less than 10% area of inflammation in the lungs. Once the new eC device was introduced, affected subjects showed severe respiratory distress, with labored breathing, wheezing and panting. The lung injury occurred without nicotine, THC, or Vitamin E additives; and may also have been related to higher wattage of power settings on the E-cigarette devices. These preliminary studies will be followed up with additional future studies to systematically try to determine the cause of the lung problem.

"While further research is needed, these results indicate that specific devices and power settings may play a key role in the development of EVALI as much as the additives do," said Kloner. "The harms associated with E-cigarettes and vaping simply cannot be overstated."

Vaping has been proven to cause increased blood pressure, endothelial dysfunction, and the risk of myocardial infarction and stroke. Heating elements in commercially available eC are usually made of stainless steel, nickel?chromium or nichrome, Kanthal nickel, or titanium.

A condition, which was dubbed "E?cigarette or vaping product use-associated lung injury" (EVALI) was recognized in the United States in June 2019 and peaked in September 2019. In March 2020, there were 2,800 US cases of EVALI and 68 deaths reported. Patients were typically found to be young males and users of E-cigarettes or vaping products whose CT scans revealed lung inflammation and injury. Of note, EVALI can mimic many of the features of COVID-19 pneumonia.

WOODS HOLE, Mass. -- The dialogue between neurons is of critical importance for all nervous system activities, from breathing to sensing, thinking to running. Yet neuronal communication is so fast, and at such a small scale, that it is exceedingly difficult to explain precisely how it occurs. A preliminary observation in the Neurobiology course at the Marine Biological Laboratory (MBL), enabled by a custom imaging system, has led to a clear understanding of how neurons communicate with each other by modulating the "tone" of their signal, which previously had eluded the field. The report, led by Grant F. Kusick and Shigeki Watanabe of Johns Hopkins University School of Medicine, is published this week in Nature Neuroscience.

In 2016 Watanabe, then on the Neurobiology course faculty, introduced students to the debate over how many synaptic vesicles can fuse in response to one action potential (see this 2-minute video for a quick brush-up on neurotransmission). To probe this controversy, they used a "zap-and-freeze" imaging technology conceived by co-authors M. Wayne Davis, Watanabe and Erik Jorgensen, and built by Leica for testing in the Neurobiology course. They zapped a neuron with electricity to induce an action potential, then quickly froze the neuron and took an image. They saw multiple vesicles fusing at once at many synapses, the first novel finding of this Nature Neuroscience report.

But there was more. Back at Johns Hopkins, Kusick and Watanabe decided to walk through the neurotransmission process with zap-and-freeze, taking images every 3 milliseconds after the action potential. That's when they found an answer to an even larger question - how do neurons change the tone of their neurotransmission signal?

At any given time, only a few synaptic vesicles are in "docked" position, meaning loaded and ready to release neurotransmitter. Immediately after an action potential, the number of docked vesicles decreases by 40 percent, so after 2 to 3 action potentials, the docked vesicles would be depleted. (That is, their signal or "voice" would become weaker and weaker, as more action potentials are induced.) But they found that, within 14 milliseconds following an action potential, new vesicles are swiftly recruited to the docked pool that can fuse and release neurotransmitter, and this recruitment is transient such that neurotransmission can be strong or weak on a millisecond time scale. This is the first close-up look at neural communication that adds up from a temporal perspective.

"What this means is that we have identified a mechanism that neurons use to communicate through intonations," Watanabe says. "Each docked vesicle is like a word that neurons can use for communication at any given moment. It has been known for decades that neurons can speak more than a few words at a time, and they can also change the tone of these words. The question was how. We've shown that neurons continuously bring in more words, but by simply changing the number of vesicles, they can raise or lower the voice. If you are asking a question, you will raise the intonation at the end of a sentence - neurons do so by changing the number of docked vesicles ready to go."

The "zap and freeze" electron microscopy technology is the 21st-century version of the "freeze slammer" developed by John Heuser, Tom Reese et al., and used at MBL nearly 50 years ago to demonstrate how neurons communicate with each other.

The emergence of jaws in primitive fish allowed vertebrates to become top predators. What is less appreciated is another evolutionary innovation that may have been just as important for the success of early vertebrates: the formation of covers to protect and pump water over the gills. In a new study published in the Proceedings of the National Academy of the Sciences (PNAS), USC Stem Cell scientists and their collaborators have identified a key modification to the genome that led to the evolution of gill covers more than 430 million years ago.

The scientists started by creating zebrafish with mutations in a gene called Pou3f3. Strikingly, fish lacking this gene, or the DNA element controlling its activity in the gills, failed to form gill covers. Conversely, zebrafish producing too much Pou3f3 developed extra rudimentary gill covers.

Intrigued by these findings, co-corresponding authors Gage Crump and Lindsey Barske collaborated with scientists from several universities to explore whether changes in Pou3f3 might account for the wide variation in gill covers across vertebrates. Crump is a professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC. Barske initiated the study in the Crump Lab, and is now an assistant professor at Cincinnati Children's Hospital Medical Center.

In jawless fish such as sea lampreys, which lack gill covers, the scientists found that the control element to produce Pou3f3 in the gill region is missing.

In contrast, in cartilaginous fish such as sharks and skates, the control element for Pou3f3 is active in all gills. Correspondingly, nearly all cartilaginous fish have a separate cover over each gill. In bony fish, including zebrafish, the control element produces Pou3f3 in one particular region, leading to a single cover for all gills.

"Remarkably, we have identified not only a gene responsible for gill cover formation," said Crump, "but also the ancient control element that allowed Pou3f3 to first make gill covers and then diversify them in cartilaginous versus bony fish."

Barske and Crump even showed that humans retain this control element, reflecting the presence of gill cover-like structures in human embryos that are inherited from our distant fish ancestors.

Newly released study results present a strong case for lung cancer screening in New Zealand - particularly for Māori whose mortality rates are between three and four times higher than other ethnic groups.

Around 450 Māori are diagnosed with lung cancer each year and approximately 300 die from it.

Waitematā and Auckland DHBs have collaborated with University of Otago researchers on a study to assess whether low dose computerised tomography (LDCT) might be a cost-effective way to catch the disease in its early stages and improve health outcomes for Māori and, ultimately, other ethnic groups.

LDCT is a computerised x-ray that produces very clear three dimensional images by using only a small amount of radiation.

The study, led by Associate Professor Sue Crengle (Kāi Tahu, Kāti Mamoe, Waitaha) from the University of Otago and just published online by medical journal BMJ Open, used scientific modelling to estimate the benefits and costs of LDCT screening in a high-risk population.

Multiple factors need to be considered before any kind of screening programme goes ahead but an answer to the question of cost-effectiveness is a significant step forward.

"Having clarity about the cost-effectiveness of lung cancer screening provides further impetus to get this work started," Associate Professor Crengle says. "If this works for Māori, then it will work for everyone else as well."

Study findings show that:

a national biennial lung cancer screening programme is likely to be cost-effective for Māori and the total population in New Zealand.

screening is likely to reduce population inequities relating to lung cancer among Māori.

Screening trials have been completed overseas where they have resulted in a 20-26 per cent reduction in lung cancer deaths.

The DHBs and University of Otago are now planning to trial an invitation process with up to 50 general practices across the Auckland and Waitematā catchments. The trial will be aimed at Māori patients and the results will help shape any future screening roll-out across New Zealand.

Waitematā DHB and Auckland DHB Director of Health Outcomes Dr Karen Bartholomew says deaths from lung cancer are the single-greatest contributor to the higher mortality rate for Māori compared with NZ Europeans / other ethnicities.

"Around 75 per cent of early-stage lung cancer may be curable." Dr Bartholomew says. "If lung cancer is caught early enough, the impact of screening could go a long way towards helping us save lives and eliminate the unacceptable inequities we currently see in mortality between Māori and non-Māori."