Bayreuth researchers develop a rapid test to detect quality and authenticity of olive oil

Extra virgin olive oil is extracted from cold-pressed, high-quality olives and is one of the most popular foods in Europe. However, inferior counterfeits are coming onto the market in increasing number.

A research team led by Prof. Dr. Stephan Schwarzinger at the University of Bayreuth has now developed a highly effective rapid test against this food fraud. Within one hour, the quality and authenticity of olive oils on the market can be clearly determined and counterfeits detected. Information on origin can also be checked for plausibility.

Increasingly, counterfeits of high-quality food are harming both customers and producers. The organisations responsible for the certification of foodstuffs are therefore emphatically calling for tougher legal measures. Until recently, however, comprehensive tests of the quality and authenticity of olive oils could only be carried out using different test procedures applied one after the other. They were therefore time-consuming and expensive.

A new method for a rapid test from Bayreuth now overcomes these obstacles with the help of nuclear magnetic resonance spectroscopy (NMR spectroscopy). Prof. Dr. Stephan Schwarzinger from the Northern Bavarian NMR Centre at the University of Bayreuth (NBNC) developed the test in cooperation with the University of Athens, the analytical laboratory ALNuMed GmbH, and partners from the olive oil industry.

"Over several years, we collected and systematically analysed more than 1,000 different samples of extra virgin olive oil. The NMR measurement provided us with an individual profile for each sample that includes all properties relevant to quality and authenticity," says Schwarzinger, who heads the Working Group for Quality and Authenticity of Food and Materials at NBNC.

The new rapid test is based on the special ability of NMR spectroscopy to detect ingredients that occur in very different amounts with high resolution and reproducibility. Practically, this means highly concentrated main ingredients, such as the fatty acids in olive oil, but also very low concentrated substances can be detected. These include in particular the polyphenols, which act as antioxidants in the human body and have a positive effect on health.

The quick test therefore indicates whether the oil examined is entitled, in principle, to bear a health claim according to the corresponding EU regulation. At the same time as the analysis of ingredients, taste impressions are also tested, which are important for consumer acceptance. In addition, a comparison with existing olive oil profiles can be used to check how credible the declaration of origin of the respective producer or trader is. NMR spectroscopy can be used to check whether the examined olive oil sample comes from Greece, Italy, or Spain, for example.Counterfeits of the popular extra virgin olive oil have been a problem for many years.

Cheap alternative vegetable oils are dyed green and sold as olive oil, rancid oil is mixed with good oil, or old oils are glossed over with special technologies and come back into circulation as extra virgin olive oil. These frauds damage the good reputation of this high-quality product, and could trigger a downward spiral that ultimately hits olive oil farmers via a drop in prices. And this, in turn, leads to the leaving fallow of large olive groves in the Mediterranean region with corresponding, negative ecological effects."

Prof. Dr. Stephan Schwarzinger, Northern Bavarian NMR Centre, University of Bayreuth (NBNC)

NMR spectroscopy, because it enables a rapid and simultaneous analysis of many parameters, is the tool of choice for detecting these forms of food fraud. Schwarzinger recently presented the basics of the new olive oil rapid test at BioFach in Nuremberg, the leading trade fair for the food industry.

"This year, due to the pandemic, the trade fair was held online. Nevertheless, our new test option met with broad interest. The olive oil experts were very impressed by how quickly and thoroughly the quality and authenticity of olive oils can be determined. It is already clear that this can significantly improve the transparency of olive oil supply chains and markets. We hope that our development will now be quickly implemented in contracting laboratories and brought to market," says the Bayreuth NMR expert.

In the past Schwarzinger and his group have made significant contributions to a method, also based on NMR spectroscopy, for checking the quality and authenticity of honey. Meanwhile, the University of Bayreuth is one of the world's leading research institutions for the authenticity of honey.

Source:

University of Bayreuth

Posted in: Life Sciences News | Biochemistry

Tags: Cold, Fatty Acids, food fraud, Honey, Laboratory, Olive Oil, Pandemic, Research, Spectroscopy

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A region within GLI1 gene could potentially be targeted as cancer treatment

Scientists from the Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital of Chicago found that a region within the DNA of the cancer-promoting GLI1 gene is directly responsible for regulating this gene's expression. These findings, published in the journal Stem Cells, imply that this region within GLI1 could potentially be targeted as cancer treatment, since turning off GLI1 would interrupt excessive cell division characteristic of cancer.

From previous research, we know that GLI1 drives the unrelenting cell proliferation that is responsible for many cancers, and that this gene also stimulates its own expression. We established in living human embryonic stem cells that removing the GLI1 regulatory region eliminated GLI1 expression and halted its activity. These findings are promising and could point to a therapeutic target for cancer."

Philip Iannaccone, MD, PhD, Co-Senior Author, Professor Emeritus at the Manne Research Institute, Lurie Children's and Northwestern University Feinberg School of Medicine

Dr. Iannaccone and colleagues used CRISPR gene editing technology to delete the binding region of the GLI1 DNA in human embryonic stem cells. They found that without this region, GLI1 remained turned off, which interfered with the gene's normal activity of driving embryonic development of blood, bone, and nerve cells.

"A surprising aspect of this work was that turning GLI1 off affected stem cell differentiation to all three embryonic lineages," says first author Yekaterina Galat, BS, Research Associate at the Manne Research Institute at Lurie Children's.

"The developmental function of GLI1 ends after birth, so if we manage to stop its expression in the context of cancer, it should not have negative consequences to normal biology," explains Dr. Iannaccone.

GLI1 expression is associated with about a third of all human cancers. In addition to promoting cell proliferation, GLI1 expression increases tumor cell migration and is associated with resistance to chemotherapy drugs.

"Our team plans to study GLI1 associated proteins that assist in regulation of GLI1 expression through its binding region," says Dr. Iannaccone. "Targeting these proteins as a means to stop GLI1 activity could prove to be a fruitful treatment strategy for cancer."

Source:

Ann & Robert H. Lurie Children's Hospital of Chicago

Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: Blood, Bone, Cancer, Cancer Treatment, Cell, Cell Division, Cell Migration, Cell Proliferation, Chemotherapy, Child Health, Children, CRISPR, DNA, Drugs, Embryonic Development, Embryonic Stem Cells, Gene, Hospital, Medicine, Nerve, Proliferation, Research, Stem Cells, Tumor

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Comparative analysis of SARS-CoV-2 antivirals leads to new potential treatment for COVID-19

A rapid spread of the virus that caused symptoms similar to severe pneumonia was first reported in Wuhan, China, in December 2019. Scientists found that this novel virus belonged to the family Coronaviridae and was later named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Worldwide, researchers are developing various vaccines, medicines, facemasks, and many other means to contain the SARS-CoV-2 infection.

Among various antiviral drugs, remdesivir has been approved for the treatment of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection. Remdesivir is a nucleoside analog that inhibits the SARS-CoV-2 RNA-dependent RNA-polymerase (RdRp). It is a virus polymerase inhibitor that involves the termination of both the viral transcript and newly synthesized viral genomes. However, there are some limitations that have escalated the need to develop other potential antiviral drugs that have minimal side effects and maximum efficacy.

Study: A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19. Image Credit: Ekaterina Bondaretc / Shutterstock

Researchers have discovered an alternate target site of SARS-CoV-2: the 3CLpro (Mpro), main protease. This protease plays a key role in the life cycle of the virus. After the virus enters into the host cell, the positive-stranded RNA genome of the virus gets rapidly translated into two polyproteins. These polyproteins are processed into functional protein by PL2 pro and 3CLpro viral protease. Two of the main functions of 3CLpro are governing proper assembly and folding of polymerase subunits required to develop into a properly functional polymerase complex. Thereby, inhibition of 3CLpro would effectively stop the viral life cycle. Further, the unique substrate preference of 3CLpro also makes it an effective target site.

To date, PF -07304814 is the only 3CLpro inhibitor that has reached the clinical trials. It is a ketone-based covalent cysteine protease inhibitor administered as a phosphate prodrug, thereby converting to its active form, PF-90 00835231. In 2003, PF-00835231 was developed in response to the previous coronavirus epidemic as an inhibitor for the 3CLpro. However, due to the rapid decline in the infection rate, it was not brought to clinical trials, and further study about its efficacy was stopped.

Scientists believe that PF-00835231 would be effective against the novel SARS-CoV-2. This is because of a 96% similarity at the amino acid level and 100% similarity within the catalytic pocket of the 3CLpro present in both SARS-CoV and SARS-CoV-2. A recent study demonstrated the effectiveness of PF-00835231 at high micromolar levels.

In a forthcoming paper in the Journal of Virology, scientists compared the in vitro efficacy and cytotoxicity profiles of PF-00835231 and remdesivir in two human model systems for SARS-CoV-2 infection; namely, A549+ACE2 cells and polarized human airway epithelial cultures. After the initial characterization of A549+ACE2 cells to study SARS-CoV-2, an in vitro study was carried out to evaluate the efficacy and cytotoxicity of PF-00835231, GC-376 (protease inhibitor at the preclinical stage), and remdesivir in A549+ACE2 cells.

The team also conducted time-of-drug-addition assays in A549+ACE2 cells to define and compare the action time of the antiviral drugs within the SARS-CoV-2 life cycle. The role of efflux transporter Multi-Drug Resistance Protein 1 (MDR1) on the antiviral efficacy of PF-00835231 was also studied. The main focus of the study was to provide in vitro evidence of the potential PF-00835231 as an effective antiviral drug for SARS-CoV-2 and also highlight its negative effects based on prior studies.

This research has shown that both PF-00835231 and remdesivir are similarly potent in studying a model of polarized human airway epithelial cultures (HAEC). However, in A549+ACE2 cell assay, PF-00835231 revealed better activity than the preclinical GC-376 and similar or marginally effect as remdesivir.

The optimal time to start antiviral drug treatment is the first week after the onset of symptoms, i.e. when the virus replication is actively ongoing. In the case of patients who are severely affected by COVID-19, the active replication of SARS-CoV-2 can be prolonged. This study revealed that intravenous treatment of PF-00835231 would remain effective for severely infected patients. Intravenous remdesivir treatment was also found to be effective against SARS-CoV-2.

Cell composition of polarized human airway epithelial cultures (HAEC), and cytotoxicity of PF-00835231 and remdesivir. a. Schematic representation of a transwell containing a polarized HAEC in air-liquid interface. Dark blue, cycling basal cells; light blue, basal cells; red, suprabasal cells; purple, secretory cells; yellow, microfold cells; green, ciliated cells; grey, mucus. To test for cytotoxicity, drugs were added to the media in the basolateral chamber. b. Clustered UMAP of single cells determined by single-cell RNA sequencing from n=3 uninfected HAEC. Clusters were determined by markers from the literature(37, 38) and by differentially expressed marker genes for each cluster determined by Wilcox test. c., d. Representative cross-sections of uninfected HAEC, 72 h post treatment with 10 µM PF-00835231 or 10 µM remdesivir. H&E (c.) or PAS-Alcian blue staining (d.). e. Trans-epithelial resistance (TEER) in drug1205 treated, uninfected HAEC over time as a measure of epithelial integrity. Means ? SEM from n=3 independent experiments. f. CellTiter-glo assay on undifferentiated, basal-like Bci-NS1.1 precursor cells. Means ? SEM from n=3 independent experiments.

The current research has also demonstrated a significant synergistic effect between PF-00835231 and remdesivir in inhibiting SARS-CoV-2. Researchers believe that the use of multiple antiviral drugs with different modes of action or target sites would efficiently circumvent cross-resistance caused by mutations. Hence, the development of antiviral treatments using multiple antiviral drugs would significantly improve antiviral therapy in COVID -19.

To summarize, the team's research reveals the significance of the novel antiviral drug, PF–00835231, against SARS-CoV-2 with the help of 3D in vitro models of human airway epithelium. This would help to decrease the mortality rate of COVID-19 and also pave the way to explore new treatment methods for other harmful viruses.

Journal reference:
  • Maren de Vries, Adil S. Mohamed, Rachel A. Prescott, Ana M. Valero Jimenez, Ludovic Desvignes, Rebecca O'Connor, Claire Steppan, Joseph C. Devlin, Ellie Ivanova, Alberto Herrera, Austin Schinlever, Paige Loose, Kelly Ruggles, Sergei B. Koralov, Annaliesa S. Anderson, Joseph Binder, Meike Dittmann. A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19, Journal of Virology Feb 2021, JVI.01819-20; DOI: 10.1128/JVI.01819-20 https://jvi.asm.org/content/early/2021/02/19/JVI.01819-20

Posted in: Medical Science News | Medical Research News | Disease/Infection News | Healthcare News | Pharmaceutical News

Tags: ACE2, Amino Acid, Antiviral Drug, Assay, Cell, Coronavirus, Coronavirus Disease COVID-19, Cysteine, Cytotoxicity, Drug Repurposing, Drugs, Efficacy, Genome, in vitro, Mortality, Nucleoside, Pneumonia, Polymerase, Preclinical, Protein, Remdesivir, Research, Respiratory, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Virology, Virus

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Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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Retroviruses invading the koala germline contribute to high cancer rates

Koalas are facing multiple environmental and health issues which threaten their survival. Along with habitat loss – accelerated by last year’s devastating bush fires – domestic dog attacks and road accidents, they suffer from deadly chlamydial infections and extremely high frequency of cancer.

An international team of scientists led by the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) now demonstrate that a retrovirus invading the koala germline explains the high frequency of koala cancer. The results are reported in the journal Nature Communications.

The koala retrovirus (KoRV) is a virus that, like other retroviruses such as HIV, inserts itself into the DNA of an infected cell. At some point in the past 50,000 years, KoRV has infected the egg or sperm cells of koalas, leading to offspring that carry the retrovirus in every cell in their body.

The entire koala population of Queensland and New South Wales in Australia now carry copies of KoRV in their genome. All animals, including humans, have gone through similar "germline" infections by retroviruses at some point in their evolutionary history and contain many ancient retroviruses in their genomes.

These retroviruses have, over millions of years, mutated into degraded, inactive forms that are no longer harmful to the host. Since in most animal species this process occurred millions of years ago, the immediate health effects on the host at that time are unknown but it has been suspected for some time that the invasion of a genome by a retrovirus may have considerable detrimental health effects.

The koala is at a very early stage of this process when the retrovirus is still active and these health effects can be studied.

Since retroviruses can cause cancer, it was thought that there is a link between KoRV and the high frequency of lymphoma, leukaemia and other cancers in koalas from northern Australia. To investigate this link, scientists at the Leibniz-IZW sequenced DNA from wild koalas suffering from cancer.

This allowed them to accurately detect the number of copies of KoRV in the koala genomes and identify the precise locations where the retrovirus had inserted its DNA. By comparing this information between healthy and tumour tissues in single koalas, and by comparing insertion sites between koala individuals, they found multiple links between KoRV and genes known to be involved in the kind of cancers to which koalas are prone.

"Each koala carries around 80 – 100 inherited copies of KoRV in its genome. The genomic locations of most of these are not shared between koalas, indicating a rapid expansion and accumulation of KoRV copies in the population. Each time a retrovirus copies and re-inserts itself into the genome, it causes a mutation, potentially disrupting gene expression, which could be detrimental to the host," says Prof Alex Greenwood, Head of Department of Wildlife Diseases at the Leibniz-IZW.

This means that by frequently copying itself to new locations in the genome, KoRV is currently conferring a high mutational load on the koala population. Tumour tissues contain many new copies of KoRV, indicating that KoRV is more active in tumour cells.

These copies generally were located close to genes associated with cancer. New KoRV insertions in tumour tissues affected the expression of genes in their vicinity. Such changes in gene expression associated with cancer can cause increased cell growth and proliferation, which leads to tumours.

Although other factors may also contribute to cancer in koalas, the mutational burden from KoRV likely increases the frequency of cells becoming cancerous and may shorten the time for cancer to develop.

In one koala, a copy of KoRV was found that had incorporated an entire cancer-related gene from the koala genome into its DNA sequence. This greatly increased the expression of this gene and most likely caused cancer in this particular koala.

If this mutated virus is transmissible, it would be of grave concern for koala conservation efforts. Comparing the genomic location of KoRVs between koalas also suggests that KoRV may predispose related koalas to particular tumours, with koalas sharing KoRV insertions in specific cancer-related genes suffering from similar types of cancer which they can pass on to their offspring.

Across all koalas studied, there were "hot spots" in the genome where KoRV frequently inserts itself. These hot spots were also located in proximity to genes associated with cancer.

In summary then, we find multiple links at the genomic level between cancer-related genes and KoRV, revealing ways in which KoRV underlies the high frequency of cancer in koalas."

Gayle McEwen, Scientist, Leibniz Institute for Zoo and Wildlife Research (IZW)

The results highlight the detrimental health consequences that wildlife species can suffer following germline infection by retroviruses.

Germline invasions have been repeatedly experienced during vertebrate evolution and have shaped vertebrate genomes, including the lineage leading to modern humans. These were most likely associated with severe detrimental health effects, which must be endured and overcome to ensure species survival.

The scientists at the Leibniz-IZW have previously shown that old retroviruses present in the koala genome aid the rapid degradation of KoRV. The koala finds itself in a race to survive the effects of KoRV long enough for the virus to be degraded. Considering the many threats to koalas, it is a race they need to win.

Source:

Leibniz Institute for Zoo and Wildlife Research (IZW)

Journal reference:

McEwen, G. K., et al. (2021) Retroviral integrations contribute to elevated host cancer rates during germline invasion. Nature Communications. doi.org/10.1038/s41467-021-21612-7.

Posted in: Genomics | Life Sciences News

Tags: Cancer, Cell, DNA, Evolution, Frequency, Gene, Gene Expression, Genes, Genome, Genomic, Germline, HIV, Leukemia, Lymphoma, Mutation, Proliferation, Research, Retrovirus, Sperm, Virus

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Study describes the sequencing of 64 full human genomes

Researchers at the University of Maryland School of Medicine (UMSOM) co-authored a study, published today in the journal Science, that details the sequencing of 64 full human genomes. This reference data includes individuals from around the world and better captures the genetic diversity of the human species.

Among other applications, the work will enable population-specific studies on genetic predispositions to human diseases as well as the discovery of more complex forms of genetic variation.

Twenty years ago this month, the International Human Genome Sequencing Consortium announced the first draft of the human genome reference sequence.

The Human Genome Project, as it was called, required 11 years of work and involved more than 1000 scientists from 40 countries. This reference, however, did not represent a single individual, but instead was a composite of humans that could not accurately capture the complexity of human genetic variation.

Building on this, scientists have conducted several sequencing projects over the last 20 years to identify and catalog genetic differences between an individual and the reference genome. Those differences usually focused on small single base changes and missed larger genetic alterations.

Current technologies now are beginning to detect and characterize larger differences – called structural variants – such as insertions of new genetic material. Structural variants are more likely than smaller genetic differences to interfere with gene function.

The new finding in Science announced a new and significantly more comprehensive reference dataset that was obtained using a combination of advanced sequencing and mapping technologies.

The new reference dataset reflects 64 assembled human genomes, representing 25 different human populations from across the globe. Importantly, each of the genomes was assembled without guidance from the first human genome composite. As a result, the new dataset better captures genetic differences from different human populations.

We've entered a new era in genomics where whole human genomes can be sequenced with exciting new technologies that provide more substantial and accurate reads of the DNA bases. This is allowing researchers to study areas of the genome that previously were not accessible but are relevant to human traits and diseases."

Scott Devine, PhD, Study Co-Author and Associate Professor, Medicine, University of Maryland School of Medicine

Scott Devine is also the Faculty Member of IGS. Institute of Genome Science (IGS)'s Genome Resource Center (GRC) was one of three sequencing centers, along with Jackson Labs and the University of Washington, that generated the data using a new sequencing technology that was developed recently by Pacific Biosciences. The GRC was one of only five early access centers that was asked to test the new platform.

Dr. Devine helped to lead the sequencing efforts for this study and also led the sub-group of authors who discovered the presence of "mobile elements" (i.e., pieces of DNA that can move around and get inserted into other areas of the genome).

Other members of the Institute for Genome Sciences (IGS) at the University of Maryland School of Medicine are among the 65 co-authors. Luke Tallon, PhD, Scientific Director of the Genomic Resource Center, worked with Dr. Devine to generate one of the first human genome sequences on the Pacific Bioscences platform that was contributed to this study. Nelson Chuang, a graduate student in Dr. Devine's lab also contributed to the project.

"The landmark new research demonstrates a giant step forward in our understanding of the underpinnings of genetically-driven health conditions," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "This advance will hopefully fuel future studies aimed at understanding the impact of human genome variation on human diseases."

Source:

University of Maryland School of Medicine

Journal reference:

Ebert, P., et al. (2021) Haplotype-resolved diverse human genomes and integrated analysis of structural variation. Science. doi.org/10.1126/science.abf7117.

Posted in: Molecular & Structural Biology | Genomics

Tags: Bases, DNA, Gene, Genetic, Genome, Genomic, Genomics, Medical Research, Medical School, Medicine, Research

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Study provides new insight into the genetics of coronary artery disease

According to a new study published in The American Journal of Human Genetics, more than one third of genetic variants that increase the risk of coronary artery disease regulate the expression of genes in the liver. These variants have an impact on the expression of genes regulating cholesterol metabolism, among other things. The findings provide valuable new insight into the genetics of coronary artery disease. The study was conducted in collaboration between the University of Eastern Finland, Kuopio University Hospital, the University of California Los Angeles, and the University of Arizona.

In this study, promoter capture Hi-C, ChIP-Seq, STARR-Seq and CRISPR technologies were used to study the action of coronary artery disease risk variants in hepatocyte cells of the liver. Photographer: UEF/ Raija Törrönen

Coronary artery disease (CAD) and its most important complication myocardial infarction (MI) are among the leading causes of death in the Western world. Both genetic and environmental factors contribute to the disease and recent genome-wide association studies have identified approximately 200 risk loci for CAD. However, the vast majority of such variants are located in the non-coding regions of the genome and have no known biological function. Even though the functional characterization of such variants has been difficult in the past, thanks to new and advanced genomics techniques such as RNA-seq, ChIP-seq, STARR-seq and HiC, and computational analysis, understanding the variants’ functions is now possible.

The involvement of the liver in the progression of coronary artery disease is not completely understood. In the new study, the researchers show that over one third of risk variants for CAD are located in regulatory elements specific to liver, and they act to regulate the expression of genes implicated in traditional risk factors, such as glucose and cholesterol related traits.

Our results not only confirm the correlation of cholesterol levels and the risk of coronary artery disease but also pinpoint for the first time the causal single nucleotide polymorphisms and the potential target genes that mediate the risk.”

Minna Kaikkonen-Määttä, Associate Professor, Academy Research Fellow at University of Eastern Finland

Another important finding was the discovery that risk variant-containing regulatory elements often seem to regulate many genes, not just one.

Overall, our findings expand the list of genes and regulatory mechanisms acting in the liver and governing the risk of CAD development. Deciphering gene regulatory networks is becoming increasingly important in understanding disease mechanisms and developing next generation drug therapies.”

Minna Kaikkonen-Määttä

The study was largely funded by the European Research Council through an ERC Starting Grand awarded to Associate Professor Kaikkonen-Määttä. Other supportive funding to the research groups was provided by the National Institutes of Health, the Academy of Finland, Jane and Aatos Erkko Foundation, Sigrid Jusélius Foundation, the Finnish Foundation for Cardiovascular Research, the Finnish Diabetes Research Foundation, and Kuopio University Hospital project grants.

Source:

University of Eastern Finland

Journal reference:

Selvarajan, I., et al. (2021) Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease. The American Journal of Human Genetics. doi.org/10.1016/j.ajhg.2021.02.006.

Posted in: Genomics

Tags: Cholesterol, Coronary Artery Disease, Diabetes, Gene, Genes, Genetic, Genetics, Genome, Genomics, Glucose, Hospital, Liver, Metabolism, Myocardial Infarction, Next Generation, Nucleotide, Research, RNA, Single Nucleotide Polymorphisms

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Electronic doctors’ notes could help hospitals plan for surges in COVID-19 cases

A new study, published today in Nature Digital Medicine, found that 'natural language processing' (NLP) of information routinely recorded by doctors – as part of patients' electronic health records – reveal vital trends that could help clinical teams forecast and plan for surges in patients.

The researchers from King's College London, King's College Hospital NHS Foundation Trust (KCH), and Guy's and St Thomas' Hospital NHS Foundation Trust (GSTT), used NLP algorithms to translate the electronic notes made by doctors into a standardized, structured set of medical terms that could be analyzed by a computer.

Tracking trends in patients

In the same way social media posts can be tracked and aggregated by 'hashtags', the researchers detected words or phrases that were 'trending' in electronic health records at KCH and GSTT, during key stages of the COVID-19 pandemic last year. For instance, they tracked the number of patient records containing keywords for symptomatic COVID-19, such as 'dry cough', 'fever' or 'pneumonia'. Throughout the pandemic, hospital doctors have entered patient symptoms and test results into electronic health records, which are used to track the spread of COVID-19 at a national level.

However, these records often contain incomplete and unstructured data, that is difficult to access and analyze.

By analyzing the text as a 'bag of words', the researchers were able to produce real-time maps of trending 'signals' (i.e., symptoms that were most frequently recorded by doctors), and these signals closely mirrored patterns of positive laboratory tests reported by each hospital. Clear spikes were visible in March 2020, for instance, during the first wave of COVID-19 cases, and in subsequent waves.

Providing advance warning for hospitals

The study indicates that these signals provide a real-time situational report of reflecting current activity levels in a hospital and up to four days advance warning for hospitals helping them to prepare for surges in COVID-19 admissions.

The study authors also reported a strong association between the trending signals and regional tracking of COVID-19 admissions in London hospitals. In addition, they found that as new COVID-19 symptoms emerged nationally, these symptoms were also recorded more frequently by doctors at KCH and GSTT.

Dr James Teo, Clinical Director of AI at King's College Hospital and Guy's and St Thomas' Hospital, said: "By teaching computers how to read and understand doctors' notes, we hope to reveal important patterns and trends that could help in the fight against COVID-19 and other diseases.

Tracking word trends in electronic health records offers an additional method for studying disease and healthcare activity, in a way that is very easy and cost-effective to run. While this method was shown to be effective in two individual hospital Trusts, the approach could be scaled up to a regional or even national level with the right privacy safeguards".

CogStack

The CogStack platform used in this study allows researchers to interrogate complex sets of data extremely rapidly, providing a real-time feed of what is happening in a particular hospital, allowing clinical teams to prepare for incoming patients.

The CogStack platform allows us to extract information from deep within hospital records at King's College Hospital NHS Foundation Trust in near real time. This means we can anticipate likely increases in pressure on the system before receiving information such as test results, giving clinical teams time to react and prepare in advance."

Professor Richard Dobson, Head of the Department of Biostatistics & Health Informatics, NIHR Maudsley BRC

Source:

NIHR Maudsley Biomedical Research Centre

Journal reference:

Teo, J.T.H., et al. (2021) Real-time clinician text feeds from electronic health records. npj Digital Medicine. doi.org/10.1038/s41746-021-00406-7.

Posted in: Device / Technology News | Disease/Infection News | Healthcare News

Tags: Artificial Intelligence, Cough, Fever, Healthcare, Hospital, Imaging, Laboratory, Language, Medical Imaging, Medicine, Pandemic, Pneumonia, Research

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After billions of dollars and dozens of wartime declarations, why are vaccines still in short supply?

The U.S. government has invested billions of dollars in manufacturing, used a wartime act dozens of times to boost supplies and yet there's still not enough covid vaccine on the way to meet demand — or even the government's own goals for national immunization.

President Joe Biden, in remarks at the National Institutes of Health this month, said the nation is "now on track to have enough supply for 300 million Americans by the end of July." But at the current rate of production, Pfizer and Moderna will miss their targets of providing at least 100 million doses each by the end of March, let alone 200 million more doses each has promised by July.

Moderna would need to more than double its vaccine production rate from January — when it made roughly 19 million doses — to meet its contractual obligations. Pfizer supplied 40 million vaccine doses by Feb. 17. It has roughly six weeks left to deliver the first 120 million doses it has promised.

Biden and officials from the two companies say they are rapidly expanding production capacity. But critics are lining up. They want to know whether the government did enough, fast enough, to guarantee that companies would meet the urgent challenges of the pandemic. As for the manufacturers bolstered by extraordinary sums of taxpayer money, why did they not share technology and know-how sooner, or move more quickly into strategic production partnerships?

Experts say it's complicated, noting that the output of raw materials and assembly lines can't be ratcheted up 10,000-fold at the push of a button — and that the effort thus far has been close to miraculous. They cite bottlenecks in at least three areas: the production of specialty lipids, fatty materials that are a primary component of the Moderna and Pfizer-BioNTech vaccines; the hundreds of millions of glass vials that hold the vaccine; and the sterile automated assembly lines where vaccine moves from bulk containers into vials before shipment.

U.S. officials have run headlong into the limits of the Defense Production Act, a Korean War-era law that allows the federal government to ramp up supplies of critical materials in times of national emergency. The vaccine manufacturing process relies on a complex supply chain, from sourcing raw materials and equipment to designing chemical processes, building production lines and hiring and training workers.

Also, experts note, no one knew which vaccines would prove effective.

"A year ago there was no commercial market for mRNA product. There was scientific research and pharma making small-volume clinical lots. Now we need billions of doses, in the space of a year. That's overloading the supply infrastructure," said Kevin Gilligan, a senior consultant with Biologics Consulting and a former official with the Biomedical Advanced Research and Development Authority, or BARDA, a federal agency created in 2006 to deal with pandemics and bioterrorism.

As of December, the Trump administration through its Operation Warp Speed initiative had obligated nearly $14 billion for vaccine development and manufacturing, including investments to expand U.S. capacity, according to a Government Accountability Office report in January. The administration invoked the Defense Production Act on at least 23 vaccine-related contracts, in part to prioritize the government's contracts over others, according to a KHN review of the federal contracts database, contracts obtained by the nonprofit group Knowledge Ecology International, GAO and government news releases.

They include the December contract that the Department of Health and Human Services signed with Pfizer for another 100 million doses, on top of the initial 100 million it committed to last summer. That contract, worth $1.95 billion, included DPA provisions to give the company priority access to raw materials and spare parts for factories, according to a former administration official.

The DPA has also been used in vaccine contracts with Moderna, Johnson & Johnson and other drug companies for hundreds of millions of doses. On top of that, the law has been invoked for at least 10 contracts with companies making needles or syringes. It's been used to require glass makers Corning and SiO2 Materials Science to prioritize vial production for vaccine production, and in contracts for aspects of manufacturing with companies like Emergent BioSolutions, Fujifilm Diosynth Biotechnologies and Grand River Aseptic Manufacturing.

Operation Warp Speed awarded Emergent BioSolutions $648 million last year to boost the manufacturing capacity it needed to enter agreements with Johnson & Johnson and AstraZeneca — worth at least $615 million and $261 million, respectively — to help make their vaccines. Grand River Aseptic Manufacturing won a $160 million award from BARDA and has contracted with Johnson & Johnson to fill vials and finish packaging of its single-shot covid vaccine, which is expected to get emergency authorization from the Food and Drug Administration as soon as this month but will only have a few million doses available initially.

The Biden administration has expanded its use of the wartime act to prioritize equipment like filling pumps and filtration systems for Pfizer. "We told you that when we heard of a bottleneck on needed equipment, supplies or technology related to vaccine supply, that we would step in and help," Tim Manning, the White House official leading the administration's covid supply efforts, said during a February press briefing.

Yet it can do only so much, according to medical supply chain experts. Prashant Yadav, a senior fellow at the Center for Global Development at Harvard University, said it could take months for the impact of that DPA action to be felt because of the time it takes to procure equipment and get it installed, with each step tightly regulated.

The U.S. is unlikely to get a meaningful bump in capacity "unless we think about co-production deals," in which a drug company agrees to manufacture a competitor's vaccine, said Tinglong Dai, an associate professor at Johns Hopkins University's Carey Business School.

So far, such arrangements have proliferated in Europe — which has less capacity to produce drugs than the United States does. Deals with other major vaccine manufacturers have been less common on the U.S. side of the pond.

"Though we have not partnered with, say, another large pharma for production, we have built strategic partnerships with a number of organizations that have been instrumental to our scaling up and meeting supply and commercialization plans," Moderna spokesperson Ray Jordan said in an email.

Moderna this month said that its manufacturing process would scale up rapidly in the coming weeks, that it would provide the U.S. between 30 million and 35 million doses in February and March and between 40 million and 50 million doses monthly from April to July. The company declined to elaborate on what made the boost possible.

Vaccine manufacturers long ago should have been sharing technology and expertise to boost production in the U.S. and Europe, and especially in developing countries, said James Love, director of Knowledge Ecology International, a nonprofit focused on patent rights.

"We've wasted about a year by not doing some of the obvious things," he said. "The rhetoric is that it's an emergency. But on the scale-up of manufacturing, you just don't see it."

It's not that simple, others say. "There wasn't any excess capacity available in the United States a year ago. Zero," Paul Mango, a former HHS official heavily involved in Operation Warp Speed, said regarding vaccines. "It's getting the equipment. It's quality control. It's getting the employees. People make it sound like this is easy. You can't just push 400 workers and say, go at it."

Each Pfizer-BioNTech or Moderna shot contains billions of lipid nanoparticles, each particle containing four lipids and a strand of the nucleic acid RNA, the five pieces assembled in a way that allows the RNA to enter our cells and create a particle that stimulates the immune system to defend against the covid virus.

The lipids, which are made only in a handful of factories, have been a major supply problem. "No one has ever thought of a scenario where we would use lipid nanoparticle formulation for [billions of] doses," Yadav said. "We have not invented a process for doing lipid nanoparticles at scale."

Two of the lipids in the vaccine, cholesterol and DSCP, have long been used in industry to shape and buffer chemical formulations. A third lipid prevents the particles from clumping together. A fourth enables the lipid shell of the vaccine to fuse with human cells and, once inside the cell, to crack open so the RNA can move to a structure called a ribosome and make proteins that stimulate immunity.

All of these raw materials are produced under regulated conditions — in Massachusetts, Missouri, Colorado and Alabama by companies under license with Moderna, Pfizer or Acuitas Therapeutics, which was co-founded by Pieter Cullis, a University of British Columbia professor who is considered the grandfather of lipid nanoparticle technology.

Before the pandemic, these companies produced meager amounts for use in small clinical trials, laboratory experiments or in one licensed drug, patisiran, which is used to treat a rare genetic disease in about a thousand people worldwide. Now they are producing thousands of kilograms of the stuff, said Stefan Randl, a vice president at Evonik, a lipid maker. Evonik recently announced it would scale up production at two German sites, possibly in the second half of the year, to be used in the Pfizer-BioNTech vaccine. The company last year bought a U.S. lipid manufacturer in Alabama.

"All of a sudden the quantities had to be ramped up a thousand-fold or more," Randl said. "This is the biggest bottleneck."

Several elements of the vaccine, including lipids and enzymes used in making the mRNA, until recently were produced using animal products such as sheep's wool, said Andrew Geall, chief scientific officer at Precision NanoSystems, which designs equipment for mixing the mRNA and lipids. Animal products could cause contamination or disease, even in minute quantities, so manufacturers now use synthetic chemicals.

Luckily, the cosmetic industry — a major user of some of the same lipids used in the vaccines — has been switching from animal products in recent decades, noted Julia Born, an Evonik spokesperson.

Still, only a limited number of companies globally have expertise and facilities to make the lipids, said Thomas Madden, CEO and a co-founder of Acuitas, and they've all struggled to move from quantities produced in a laboratory to industrial-scale production. For instance, he said, hazardous solvents and chemicals used in laboratory procedures need to be avoided in industrial processes, where they could give rise to workplace safety issues.

"This is a hugely complex supply chain," Madden said. "Once you address a bottleneck at one point, you identify the next bottleneck in the process. It's a bit of a game of whack-a-mole."

Although it's not particularly difficult to make the lipids used in vaccines, it takes time to get FDA authorization of a facility that can make them in high quantities, said Cullis, the UBC professor. It would take two to three years to start such a factory from scratch, so instead, Moderna and Pfizer-BioNTech have been hooking up with existing manufacturers and getting them to convert to lipid production, he said.

Another bottleneck is "fill/finish" — getting the finished vaccine into vials or syringes so the shots can be shipped to customers. Vaccine filling lines require extremely high levels of efficiency and sterility, and few companies in the world have this capacity, said Mike Watson, former president of Valera, a Moderna subsidiary. Moderna has hired Catalent, a contract manufacturer that recently experienced delays that slowed the release of some doses, to fill and finish U.S. doses at its facility in Bloomington, Indiana. At least two other companies will do the same for Moderna's vaccine supply abroad.

In January, the French multinational Sanofi — whose own covid vaccine has been delayed by poor performance in producing immunity — agreed to offer its fill/finish line in Germany for the Pfizer-BioNTech vaccine. That line isn't expected to be running until July.

In the U.S., the number of vaccine doses shipped to states has ticked up in recent weeks, partly because Pfizer said its five-dose vials actually provide six shots. Moderna is seeking FDA permission to add up to five doses to its 10-dose vials.

Pfizer has said it is manufacturing raw materials in St. Louis, the active ingredients for the vaccine in Andover, Massachusetts, and filling vials in Kalamazoo, Michigan.

CEO Albert Bourla, with Biden at his side in Kalamazoo on Friday, said the company added lipid production capabilities at plants in Michigan and Connecticut, as well as fill/finish lines in Kansas. He said it has significantly cut the average time it takes to make doses — from 110 days to 60 days.

"Today, during this meeting, the president challenged us to identify additional ways in which his administration could help us potentially accelerate even further the delivery of the full 300 million doses earlier than July," Bourla said. "The challenge is accepted, and we will try to do our best."

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation.

This article was reprinted from khn.org with permission from the Henry J. Kaiser Family Foundation. Kaiser Health News, an editorially independent news service, is a program of the Kaiser Family Foundation, a nonpartisan health care policy research organization unaffiliated with Kaiser Permanente.

Posted in: Healthcare News

Tags: Cell, Cholesterol, Contamination, Coronavirus, Drugs, Genetic, Health and Human Services, Health Care, Immune System, Immunization, Laboratory, Lipids, Manufacturing, Mole, Nanoparticle, Nanoparticles, Nucleic Acid, Pandemic, Pharmaceuticals, Public Health, Research, Ribosome, RNA, Running, Therapeutics, Vaccine, Virus

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Three decades-old antibiotics could offer an alternative to opioid-based painkillers

Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, UT Southwestern researchers report. The finding, published online today in PNAS, could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the U.S.

Over 100 million Americans are affected by chronic pain, and a quarter of these experience pain on a daily basis, a burden that costs an estimated $600 billion in lost wages and medical expenses each year. For many of these patients – those with cancer, diabetes, or trauma, for example – their pain is neuropathic, meaning it's caused by damage to pain-sensing nerves.

To treat chronic pain, prescriptions for opioid painkillers have increased exponentially since the late 1990s, leading to a rise in abuse and overdoses. Despite the desperate need for safer pain medications, development of a new prescription drug typically takes over a decade and more than $2 billion according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, M.D., associate professor of anesthesiology and pain management at UTSW.

Seeking an alternative to opioids, Kandil and her UT Southwestern colleagues – including Hesham A. Sadek, M.D., Ph.D., professor of internal medicine, molecular biology, and biophysics; Mark Henkemeyer, Ph.D., professor of neuroscience; Mahmoud S. Ahmed, Ph.D., instructor of internal medicine; and Ping Wang, Ph.D., a postdoctoral researcher – explored the potential of drugs already approved by the Food and Drug Administration (FDA).

The team focused on EphB1, a protein found on the surface of nerve cells, which Henkemeyer and his colleagues discovered during his postdoctoral training nearly three decades ago. Research has shown that this protein is key for producing neuropathic pain. Mice genetically altered to remove all EphB1 don't feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting EphB1's promise as a target for pain-relieving drugs. Unfortunately, no known drugs inactivate EphB1.

Exploring this angle further, Ahmed used computer modeling to scan a library of FDA-approved drugs, testing if their molecular structures had the right shape and chemistry to bind to EphB1. Their search turned up three tetracyclines, members of a family of antibiotics used since the 1970s. These drugs – demeclocycline, chlortetracycline, and minocycline – have a long history of safe use and minimal side effects, Ahmed says.

To investigate whether these drugs could bind to and inactivate EphB1, the team combined the protein and these drugs in petri dishes and measured EphB1's activity. Sure enough, each of these drugs inhibited the protein at relatively low doses. Using X-ray crystallography, Wang imaged the structure of EphB1 with chlortetracycline, showing that the drug fits neatly into a pocket in the protein's catalytic domain, a key portion necessary for EphB1 to function.

In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted reactions to painful stimuli such as heat or pressure, with the triplet achieving a greater effect at lower doses than each drug individually. When the researchers examined the brains and spinal cords of these animals, they confirmed that EphB1 on the cells of these tissues had been inactivated, the probable cause for their pain resistance. A combination of these drugs might be able to blunt pain in humans too, the next stage for this research, says Kandil.

Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic. This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We're opening the window to something new."

Enas S. Kandil, M.D., Associate Professor, Anesthesiology and Pain Management, UT Southwestern

Source:

UT Southwestern Medical Center

Posted in: Medical Science News | Medical Research News | Pharmaceutical News

Tags: Anesthesiology, Animal Model, Antibiotic, Cancer, Cardiology, Chronic, Chronic Pain, Crystallography, Diabetes, Drugs, Education, heat, Medicine, Minocycline, Molecular Biology, Nerve, Neuropathic Pain, Neuroscience, Opioids, Pain, Pain Management, pH, Prescription Drug, Protein, Receptor, Research, Tetracycline, Trauma, X-Ray

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Vaccination programs combined with physical distancing could contain COVID-19 resurgence

A combination of robust vaccination programs and strict physical distancing rules could avoid recurring peaks of COVID-19 without the need to rely on stay-at-home restrictions, according to a new study by epidemiologists and demographers from WorldPop at the University of Southampton, in collaboration with The Chinese University of Hong Kong.

This research used anonymized mobile phone geolocation data with epidemiological and coronavirus case data from China to model the potential impact of vaccination and physical distancing on virus transmission. They predicted the effect of different combinations of interventions on low, medium and high density cities in the country.

The impact of physical distancing in containing future resurgences of COVID-19 depends greatly on the intensity of measures, population density, and the availability of vaccines across geographical areas and time. The researchers set out to gain a greater understanding of the relationship between these factors.

The findings are published in the journal Nature Human Behaviour.

The team predicts that in most cities, vaccination programmes and physical distancing combined will be enough to contain virus resurgence without the need to greatly restrict population mobility. Containment in this study was defined as maintaining a low transmission rate, or 'R' below one.

The researchers report cities with medium and high density populations will need both vaccination and distancing to prevent future intense waves of COVID-19, until herd immunity is reached. However, they suggest cities with low populations and effective vaccination could fully interrupt transmission without the need for physical distancing. In all cities, full 'stay-at-home' lockdowns would no longer be necessary.

The team's results also suggest strong physical distancing interventions implemented for short periods of time may be more effective than mild, longer term ones.

The author and spatial epidemiologist, Dr Shengjie Lai, Senior Research Fellow in Geography and Environmental Sciences at the University of Southampton comments: "Our research provides a framework and set of outputs that can be used by policy-makers and public health authorities to identify appropriate levels of intervention to keep COVID-19 outbreaks in check over time. Although our study was based on data from China, our methods and findings are applicable to cities worldwide with similar levels of population density and social contact patterns."

Director of WorldPop, Professor Andy Tatem, added: "Previous studies have assumed that when people reduce mobility, they proportionately reduce their social contacts, but this isn't necessarily the case and as more SARS-CoV-2 vaccines come online, there is an urgent need to understand the relationship between these factors, so we can adjust and tailor interventions and open up sections of society in a safer way."

The researchers recognize some limitations to their study, for example, the absence of data on the contribution of handwashing and face masks and challenges of vaccine supply, but emphasize that their approach can be quickly adapted to provide near real-time data to address emerging, time critical needs.

Source:

University of Southampton

Journal reference:

Huang, B., et al. (2021) Integrated vaccination and physical distancing interventions to prevent future COVID-19 waves in Chinese cities. Nature Human Behaviour. doi.org/10.1038/s41562-021-01063-2.

Posted in: Medical Research News | Disease/Infection News | Healthcare News

Tags: Coronavirus, Education, Public Health, Research, SARS, SARS-CoV-2, students, Vaccine, Virus

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