bluuebunny/crossref_metadata_2025 huggingface dataset:
Bifidobacterium adolescentis shows potential to strengthen host defence against gastrointestinal infection via inhibition of the opportunistic pathogen Candida albicans and stimulation of human-isolated macrophages killing capacity in vitro
Authors: Ricci Liviana , Mackie Joanna , Lenardon Megan D. , Jukes Caitlin , Hegazy Ahmed N. , Brown Alistair J.P. , Duncan Sylvia H. , Walker Alan W.
Published: July 2020

The human gut microbiota enhances the host’s resistance to enteric pathogens via colonisation resistance, a phenomenon that is driven by multiple mechanisms, such as production of antimicrobial metabolites and activation of host immune responses. However, there is limited information on how individual gut bacterial species, particularly many of the dominant anaerobes, might impact the host’s defence.

This study investigated the potential of specific human gut isolates to bolster the host’s resistance to infection. First, by antagonising the opportunistic fungal pathogen Candida albicans, and secondly, by modulating the killing capacity of human-isolated macrophages in vitro.

Co-culturing C. albicans with faecal microbiota from different healthy individuals revealed varying levels of fungal inhibition. In vitro assays with a panel of representative human gut anaerobes confirmed that culture supernatants from certain bacterial isolates, in particular of Bifidobacterium adolescentis, significantly inhibited C. albicans growth. Mechanistic studies revealed that microbial fermentation acids including acetate and lactate, in combination with the associated decrease in pH, were strong drivers of this inhibitory activity.

In the second in vitro assay, human-isolated macrophages were exposed to bacterial supernatants, and subsequently tested for their capacity to eliminate adherent-invasive Escherichia coli. Among the gut anaerobes tested, B. adolescentis was revealed to exert the strongest immunostimulatory and killing effect when compared to the unstimulated macrophages control.

B. adolescentis is known to be stimulated by dietary consumption of resistant starch andmay therefore represent an attractive target for the development of probiotic and prebiotic interventions tailored to enhancethe host’s natural defences against infection.
Air pollution induces an adaptive response in Staphylococcus aureus and alters host-pathogen interaction
Authors: Purves Jo , Corscadden Louise , Purser Lillie , Selley Liza , Monks Paul , Ketley Julian , Andrew Peter , Morrissey Julie
Published: July 2020

Air pollution is a major global health problem, with around 91% of the world’s population living in areas that exceed the WHO air pollution guidelines. This complex mix of pollutants almost always includes particulate matter (PM), and this has the greatest impact on human health. PM exposure contributes to a range of diseases such as COPD, heart disease and respiratory infections. Our recent publication was the first to document that as well as damaging the host, PM has a direct impact on bacteria that can cause respiratory infections. We showed that Black Carbon (BC) exposure results in species-specific alterations in biofilm structure in both Streptococcus pneumoniae and Staphylococcus aureus, altered biofilm protectivity against antibiotic exposure, and S. pneumoniae bacterial colonisation in vivo.

Following on from this ground-breaking work, our current data show that the bacterial response to BC occurs at the genetic level, altering the transcription of key genes involved in biofilm formation, colonisation and virulence. Bacterial adhesion to and invasion of human epithelial cells is significantly increased when S. aureus are pre-exposed to BC prior to infection compared to naïve S. aureus cells. In a murine respiratory colonisation model, both S. aureus co-infected alongside BC, and crucially S. aureus pre-exposed to BC, show increased colonisation of the nasopharynx and lungs. These data suggest that the bacteria are responding and adapting to exposure to air pollution, and this has an impact on how the bacteria infect the host.
Regulation of Rhodobacter capsulatus gene transfer agent production
Authors: Duncan Ian , Sherlock David , Fogg Paul
Published: July 2020

Horizontal gene transfer (HGT) enables the spread of antimicrobial resistance, virulence, metabolic and other genes conferring an advantage to the organism. HGT is enhanced in biofilms because of increased cell-cell contact (conjugation), and eDNA in the biofilm matrix causing development of competence and providing material for transformation. Production of the Rhodobacter capsulatus gene transfer agent (RcGTA), another mechanism of HGT, could also increase in biofilm as high cell density increases the proportion of GTA particles produced that encounter a target cell. RcGTA is a phage-like particle that packages ∼4.5 kb pieces of random DNA from the producing cell’s genome and transfers it to a recipient cell. Five loci comprise the RcGTA genome: a 15kb cluster containing most of the RcGTA structural genes, a cell lysis locus, two structural loci encoding head spikes and tail fibres, and a maturation/regulation locus that includes that master regulator, gafA.

I assayed RcGTA production using gene transfer bioassays and biofilm using a 96 well plate assay. I will present data showing that deletion of four GTA-related genes, including gafA itself, all lead to reduced biofilm production. All four gene knock-outs also strongly reduce GTA-mediated gene transfer, suggesting GTA production and biofilm are co-regulated. I will also present work to characterize GTA production in biofilms, for example by monitoring the transfer of fluorescent protein genes through confocal microscopy, and assessing how specific regulators control this process. Biofilms are ubiquitous in the environment so studying the spread of antimicrobial resistance genes by GTAs is important.
Identifying drivers of microbial community composition associated with aquatic primary producers: metagenomic analysis of cyanobacterial cultures
Authors: Green David , Rad-Menendez Cecilia , De Boever Frederik
Published: July 2020

The energy derived from aquatic primary production is fundamental to driving Earth’s life support systems – but they don’t achieve all this by themselves. Heterotrophic bacteria found in the photic zones of aquatic environments have a fundamental role in this too. Our group’s interest is in understanding how heterotrophs help autotrophs: who in these communities are important, and how and why they are important. Answering this is important in both natural and manmade environments so we can model these environments, and as appropriate, manipulate them, such as applying designer microbiomes to aid industrialisation of algal cultivation. Metagenomic analysis of 31 marine and freshwater cyanobacterial cultures from the Culture Collection of Algae & Protozoa resulted in assembly of >400 bacterial metagenomes (MAGs) with ca. 14 unique MAGs per culture. Community composition was clearly partitioned by salinity as a driver but collectively niche accounted for most community taxonomic variation. No universal core microbiome was identified, but taxonomic composition of marine cultures bore notable similarities to marine eukaryotic algal communities and to a natural cyanobacterial mat community found next to a northern Chilean geyser. Stable taxonomic associations imply that these taxa may have functional importance to their algal host. Functional analysis of the MAGs is underway and we will test whether the relative taxonomic variability contrasts with low functional variation between communities. If true, this implies that primary producers drive community assembly in a functionally predictable way, and that function, not taxonomy, is the more important parameter to understand.
Investigating the impact of M1 protein from Group A Streptococcus on fibrin clot formation, structure and fibrinolytic potential
Authors: Cherrington Sophie , Hardy Lewis , J. Francis Robert , Maqbool Azhar , Philippou Helen , Thelwell Craig
Published: July 2020

Background: Fibrin formation is an essential part of innate immunity, sealing off infections to limit bacterial spreading.The surface-anchored M1 protein is a major virulence determinant of Group A streptococcus (GAS). During early infection M1 is cleaved from the cell surface by SpeB, a streptococcal protease regulated by CovR/S. M1 forms a supramolecular complex with fibrinogen however the impact on fibrin formation is not known.

Methods: The effects of recombinant M1 (rM1) were assessed in fibrin clots made from plasma or purified fibrinogen incubated with thrombin, by confocal microscopy and scanning electron microscopy. Clotting and lysis profiles (with plasminogen activators and plasminogen) were investigated kinetically using thromboelastography (ROTEM).

Results: rM1 (0.47-60 μg/ml) increased clotting rates to produce heterogeneous clots with irregular fibre bundles and compacted fibrin. Formation of the protective fibrin biofilm was also disrupted by rM1. Furthermore, mechanical strength of fibrin clots was reduced with increasing rM1 concentrations and was undetectable above 15.5 μg/ml. Purified and plasma clots formed with rM1 were more susceptible to lysis by plasmin, with a 1.4 – 2-fold reduction in lysis times.

Conclusions: At sites of GAS infection, cleaved M1 may bind to fibrinogen generating fibrin clots which: lack the protective film at the clot surface; are mechanically weaker; and are less resistant to lysis by plasmin. GAS strains of M1-type are commonly associated with invasive infections; the impact of M1 on fibrin structure could contribute to the severity of GAS infection by compromising the fibrin barrier that limits bacterial proliferation and migration.
Human host cell entry restriction of Lassa and other arenaviruses
Authors: Stott Robert , Strecker Thomas , Foster Toshana
Published: July 2020

Arenaviruses are the largest family of viral haemorrhagic fever causing viruses. They have worldwide distribution and are divided into Old World (OW) and New World (NW) viruses based on their phylogeny, geographical distribution and serological cross-reactivity. Endemic to West Africa and South America, these emerging RNA viruses jump the species barrier from their natural rodent hosts to humans, resulting in illnesses ranging from mild flu-like syndromes to severe and highly fatal haemorrhagic zoonoses. Recent increased frequency of outbreaks and associated high fatality rates of the most common arenavirus, Lassa, in Nigeria has emphasised that these viruses should no longer be treated as causes of sporadic epidemics. The immense impact of these outbreaks on human health is further exacerbated by the lack of vaccines and effective treatments and makes it imperative to understand the molecular basis of viral pathogenesis and immune evasion.

Virus entry is a key determinant of viral host range, cellular tropism and disease outcome, hence, targeting this step of the arenavirus lifecycle could have significant impact on the control of viral infection. Our data demonstrate for the first time a synergistic restriction activity against arenavirus entry by two cellular host factors known for their control of enveloped virus infections. This co-operative restriction activity appears to conserved and we have evidence that arenaviruses may have evolved strategies to escape inhibition, through entry receptor switching, thus alluding to an understanding of the dynamics of arenavirus infection and adaptations that the viruses have made to escape host restriction pressures.
Diverse mutational routes to the restoration of motility in a soil bacterium
Authors: Flanagan Louise , Horton James , Taylor Tiffany
Published: July 2020

Restoration of a phenotype following insertion of a crippling mutation gives us insights into the adaptability of an organism. Mutational routes to the restoration of phenotypes can be diverse. Deletion of the master regulator (fleQ) for flagellar synthesis genes renders Pseudomonas fluorescens immotile, but after being put under strong selection to swim, it reliably re-evolves motility.

In order to uncover how the immotile bacteria regain their ability to swim they are inoculated into swimming agar plates and sampled from the leading edge of the motile zone. These samples are sequenced at a range single locus sites, predicted to be where causative mutations for the restoration of motility will be found (as indicated from previous research).

In the engineered immotile strain Pf0-2x, a huge variety of mutations, consisting of SNPs, multi-codon deletions, and frameshifts are observed across all candidate loci. In a complex environment (LB) 50% of initial restorative mutations occur in glnA, a glutamine synthetase gene. In a minimal media environment (M9) 45% of these mutations occur in ntrB, a gene for a kinase that forms part of a two component system. These findings contrast strongly with similar work in the related P. fluorescens strain SBW25, where the same SNP is repeatedly found across all environments. Interestingly, this SNP has never been seen in Pf0-2x.

These results highlight how preferential mutational routes can vary across environments, and that strain-to-strain differences can have a major impact types of mutations that are uncovered and selected for by evolution.
Molecular identification of antibiotic resistance genes of bacteria isolates from ready to eat food and drinking water sold in Imo State University
Authors: Dike Kelechi , Obiukwu Charles , Ekwomadu Moses , Nnagbo Pauline
Published: July 2020

Food and water are fundamental need of human as its quality is of great concern to the generality of consumers, despite quality control measures during their production, unacceptable microbiological load often makes them unsafe. In this study, we analyzed various ready to eat food and water for presence of coliform bacteria, fungi count, antibiotic resistance gene and plasmid DNA, Samples were found to be positive for various antibiotic resistance genes namely, Sul1, Sul2, Tet A and TetB, interestingly, considerable total coliform bacteria were found from isolates and this result was further confirmed using illumina sequencing of the 16SrRNA gene. All Samples were negative for plasmid DNA, These finding deserve attention as the presence of coliform bacterial and antibiotic resistance genes potentiate health risk to members of university community and as such calls for strigent supervision and saftety and implementation of food safety regulations.
M1CR0B1AL1Z3R—a user-friendly web server for the analysis of large-scale microbial genomics data
Authors: Avram Oren , Rapoport Dana , Portugez Shir , Pupko Tal
Published: July 2020

Large-scale mining and analysis of bacterial datasets contribute to the comprehensive characterization of complex microbial dynamics within a microbiome and among different bacterial strains, e.g., during disease outbreaks. The study of large-scale bacterial evolutionary dynamics poses many challenges. These include data-mining steps, such as gene annotation, ortholog detection, sequence alignment, and phylogeny reconstruction. These steps require the use of multiple bioinformatics tools and ad-hoc programming scripts, making the entire process cumbersome, tedious and error-prone due to manual handling. This motivated us to develop the M1CR0B1AL1Z3R web server, a ‘one-stop shop’ for conducting microbial genomics data analyses via a simple graphical user interface (Avram, et al., Nucleic Acids Res., 2019). Some of the features implemented in M1CR0B1AL1Z3R are: (i) extracting putative open reading frames and comparative genomics analysis of gene content; (ii) extracting orthologous sets and analyzing their size distribution; (iii) analyzing gene presence-absence patterns; (iv) reconstructing a phylogenetic tree based on the extracted orthologous set; (v) inferring GC-content variation among lineages. M1CR0B1AL1Z3R facilitates the mining and analysis of dozens of bacterial genomes using advanced techniques, with the click of a button. M1CR0B1AL1Z3R is freely available at https://microbializer.tau.ac.il/ [https://microbializer.tau.ac.il/].
Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas
Authors: Hu Xin , Estecio Marcos R. , Chen Runzhe , Reuben Alexandre , Wang Linghua , Fujimoto Junya , Carrot-Zhang Jian , McGranahan Nicholas , Ying Lisha , Fukuoka Junya , Chow Chi-Wan , Pham Hoa , Godoy Myrna C.B. , Carter Brett W. , Behrens Carmen , Zhang Jianhua , Antonoff Mara B. , Sepesi Boris , Lu Yue , Pass Harvey , Kadara Humam , Scheet Paul , Vaporciyan Ara A. , Heymach John V. , Wistuba Ignacio I. , Lee J. Jack , Futreal P. Andrew , Su Dan , Issa Jean-Pierre J. , Zhang Jianjun
Published: July 2020

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8+ T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and allelic imbalance burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas.
Effects of environmental factors on severity and mortality of COVID-19
Authors: Kifer Domagoj , Bugada Dario , Villar-Garcia Judit , Gudelj Ivan , Menni Cristina , Sudre Carole , Vučković Frano , Ugrina Ivo , Lorini Luca F , Posso Margarita , Bettinelli Silvia , Ughi Nicola , Maloberti Alessandro , Epis Oscar , Giannattasio Cristina , Rossetti Claudio , Kalogjera Livije , Peršec Jasminka , Ollivere Luke , Ollivere Benjamin J , Yan Huadong , Cai Ting , Aithal Guruprasad P. , Steves Claire J , Kantele Anu , Kajova Mikael , Vapalahti Olli , Sajantila Antti , Wojtowicz Rafal , Wierzba Waldemar , Krol Zbigniew , Zaczynski Artur , Zycinska Katarina , Postula Marek , Lukšić Ivica , Čivljak Rok , Markotić Alemka , Brachmann Johannes , Markl Andreas , Mahnkopf Christian , Murray Benjamin , Ourselin Sebastien , Valdes Ana M. , Horcajada Juan P , Castells Xavier , Pascual Julio , Allegri Massimo , Primorac Dragan , Spector Tim D. , Barrios Clara , Lauc Gordan
Published: July 2020

Background

Most respiratory viruses show pronounced seasonality, but for SARS-CoV-2 this still needs to be documented.

Methods

We examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application.

Findings

Meta-analysis of the mortality risk in seven European hospitals estimated odds ratios per one day increase in the admission date to be 0.981 (0.973-0.988, p<0.001) and per increase in ambient temperature of one degree Celsius to be 0.854 (0.773-0.944, p=0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to Intensive Care Unit and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time.

Interpretation

Severity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.
Impact of COVID-19 Second Wave on Healthcare Networks in the United States
Authors: Hassan Emad M. , Mahmoud Hussam
Published: July 2020

The risk of overwhelming healthcare systems from a second wave of COVID-19 is yet to be quantified. Here, we investigate the impact of different reopening scenarios of states around the U.S. on COVID-19 hospitalized cases and the risk of overwhelming the healthcare system while considering resources at the county level. We show that the second wave might involve an unprecedented impact on the healthcare system if an increasing number of the population becomes susceptible and/or if the various protective measures are discontinued. Furthermore, we explore the ability of different mitigation strategies in providing considerable relief to the healthcare system. The results can aid healthcare planners, policymakers, and state officials in making decisions on additional resources required and on when to return to normalcy.

One Sentence Summary

A second wave of COVID-19 will have an unprecedented impact on the healthcare system.
Revisiting Role of Bilateral Ligation of Internal Iliac Arteries and Preperitoneal Pelvic Packing for Hemorrhage Control in Patients with Pelvic Injuries in Resource Constraint Settings
Authors: Bagaria Dinesh Kumar , Anwer Majid , Choudhary Narendra , kumar Abhinav , Priyadarshini Pratyusha , Banerjee Niladri , Alam Junaid , Gupta Amit , Mishra Biplab , Sagar Sushma , Kumar Subodh
Published: July 2020

Background

Since the description of bilateral ligation of internal iliac arteries (BLIIA) and preperitoneal pelvic packing (PPP) for haemorrhage control in pelvic injury patients, multiple reports have been published advocating its use with acceptable outcomes. We analyzed our experience with this technique in a setting where the facility of hybrid Operating room for simultaneous angioembolisation is not available.

Material and Methods

We prospectively analysed data of sixty-six patients who presented in a state of unresponsive shock with pelvic fracture between January 2014 and September 2019. After initial resuscitation, they all underwent BLIIA with PPP as part of damage control surgery.

Results

Out of 66 patients, 55 were male. The mean age was 36.12 years. All patients sustained blunt trauma, with road traffic injuries being the most common mechanism involving 65 % of the patients followed by fall from height. The mean systolic blood pressure at the time of surgery was 77 ±34.46mm Hg. Median packed red blood cell transfusion in the first 24 hours was 8.5 units with IQR of 6-12. The hemorrhage related mortality was 48%.

Conclusion

BLIIA with PPP may be considered as a viable treatment option in hemodynamically unstable patients with pelvic injuries in resource constraint facilities.
Atomoxetine modulates the contribution of high- and low-level signals during free viewing of natural images in rhesus monkeys
Authors: Reynaud Amélie J. , Blini Elvio , Koun Eric , Macaluso Emiliano , Meunier Martine , Hadj-Bouziane Fadila
Published: July 2020

Visuo-spatial attentional orienting is fundamental to selectively process behaviorally relevant information, depending on both low-level visual attributes of stimuli in the environment and higher-level factors, such as goals, expectations and prior knowledge. Growing evidence suggests an impact of the locus-coeruleus-norepinephrine (LC-NE) system in attentional orienting that depends on task-context. Nonetheless, most of previous studies used visual displays encompassing a target and various distractors, often preceded by cues to orient the attentional focus. This emphasizes the contribution of goal-driven processes, at the expense of other factors related to the stimulus content. Here, we aimed to determine the impact of NE on attentional orienting in more naturalistic conditions, using complex images and without any explicit task manipulation. We tested the effects of atomoxetine (ATX) injections, a NE reuptake inhibitor, on four monkeys during free viewing of images belonging to three categories: landscapes, monkey faces and scrambled images. Analyses of the gaze exploration patterns revealed, first, that the monkeys spent more time on each fixation under ATX compared to the control condition, regardless of the image content. Second, we found that, depending on the image content, ATX modulated the impact of low-level visual salience on attentional orienting. This effect correlated with the effect of ATX on the number and duration of fixations. Taken together, our results demonstrate that ATX adjusts the contribution of salience on attentional orienting depending on the image content, indicative of its role in balancing the role of stimulus-driven and top-down control during free viewing of complex stimuli.
miR6236, a microRNA suppressed by the anisotropic surface topography, regulates neuronal development and regeneration
Authors: Chen Yi-Ju , Huang Yung-An , Ho Chris T. , Yang Jinn-Moon , Chao Jui-I , Li Ming-Chia , Hwang Eric
Published: July 2020

It has been well studied that the surface topography affects the growth and development of neurons. However, the precise mechanism that the surface topography leads to cellular changes remains unknown. In this study, we created an anisotropic surface using nanodiamonds and discovered this surface topography accelerates the development of primary neurons from both the central and peripheral nervous systems. Using RNA sequencing technology, a previously uncharacterized microRNA (miR6236) was found to exhibit significant and the most substantial decrease when neurons are cultured on this nanodiamond surface. Gain- and loss-of-function assays confirm that miR6236 is the predominant molecule responsible for converting the surface topography into biological responses. We further demonstrate that the depletion of miR6236 can enhance neuroregeneration on inhibitory substrate, uncovering its therapeutic potential for promoting central nervous system regeneration.
Global Geographic and Temporal Analysis of SARS-CoV-2 Haplotypes Normalized by COVID-19 Cases during the Pandemic
Authors: Justo Arevalo Santiago , Zapata Sifuentes Daniela , Huallpa Robles Cesar , Landa Bianchi Gianfranco , Castillo Chavez Adriana , Garavito-Salini Casas Romina , Uceda-Campos Guillermo , Pineda Chavarria Roberto
Published: July 2020

Since the identification of SARS-CoV-2, a large number of genomes have been sequenced with unprecedented speed around the world. This marks a unique opportunity to analyze virus spreading and evolution in a worldwide context. Currently, there is not a useful haplotype description to help to track important and globally scattered mutations. Also, differences in the number of sequenced genomes between countries and/or months make it difficult to identify the emergence of haplotypes in regions where few genomes are sequenced but a large number of cases are reported. We propose an approach based on the normalization by COVID-19 cases of relative frequencies of mutations using all the available data to identify major haplotypes. Furthermore, we can use a similar normalization approach to tracking the temporal and geographic distribution of haplotypes in the world. Using 171 461 genomes, we identify five major haplotypes (OTUs) based on nine high-frequency mutations. OTU_3 characterized by mutations R203K and G204R is currently the most frequent haplotype circulating in four of the six continents analyzed. On the other hand, during almost all months analyzed, OTU_5 characterized by the mutation T85I in nsp2 is the most frequent in North America. Recently (since September), OTU_2 has been established as the most frequent in Europe. OTU_1, the ancestor haplotype is near to extinction showed by its low number of isolations since May. Also, we analyzed whether age, gender, or patient status is more related to a specific OTU. We did not find OTU’s preference for any age group, gender, or patient status. Finally, we discuss structural and functional hypotheses in the most frequently identified mutations, none of those mutations show a clear effect on the transmissibility or pathogenicity.
PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2
Authors: Theise Neil D. , Arment Anthony R. , Chakravarty Dimple , Gregg John M. H. , Jacobson Ira M. , Jung Kie Hoon , Nair Sujit S. , Tewari Ashutosh , Thurston Archie W. , Van Drie John , Westover Jonna B.
Published: July 2020

PT150 is a clinical stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an anti-depressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 μM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) binding molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.
Cold sensitivity of the SARS-CoV-2 spike ectodomain
Authors: Edwards Robert J , Mansouri Katayoun , Stalls Victoria , Manne Kartik , Watts Brian , Parks Rob , Janowska Katarzyna , Gobeil Sophie M. C. , Kopp Megan , Li Dapeng , Lu Xiaozhi , Mu Zekun , Deyton Margaret , Oguin Thomas H , Sprenz Jordan , Williams Wilton , Saunders Kevin , Montefiori David , Sempowski Gregory D. , Henderson Rory , Alam Munir , Haynes Barton F. , Acharya Priyamvada
Published: July 2020

The SARS-CoV-2 spike (S) protein, a primary target for COVID-19 vaccine development, presents its Receptor Binding Domain in two conformations: receptor-accessible “up” or receptor-inaccessible “down” conformations. Here, we report that the commonly used stabilized S ectodomain construct “2P” is sensitive to cold temperature, and that this cold sensitivity is resolved in a “down” state stabilized spike. Our results will impact structural, functional and vaccine studies that use the SARS-CoV-2 S ectodomain.
Reductions in 2020 US life expectancy due to COVID-19 and the disproportionate impact on the Black and Latino populations
Authors: Andrasfay Theresa , Goldman Noreen
Published: July 2020

COVID-19 has resulted in a staggering death toll in the US: over 180,000 by the end of August 2020, according to the National Center for Health Statistics. Black and Latino Americans have experienced a disproportionate burden of COVID-19 morbidity and mortality, reflecting persistent structural inequalities that increase risk of exposure to COVID-19 and mortality risk for those infected. We estimate life expectancy at birth and at age 65 for 2020, for the total US population and by race and ethnicity, using four scenarios of deaths – one in which the COVID-19 pandemic had not occurred and three including COVID-19 mortality projections produced by the Institute for Health Metrics and Evaluation. Our most likely estimate indicates a reduction in US life expectancy at birth of 1.41 years. This decline results in a life expectancy of 77.2 years, a value last observed in 2003. We also project a 1.08-year reduction in life expectancy at age 65. The Black and Latino populations are estimated to experience declines in life expectancy at birth of 2.69 and 3.66 years, respectively, both of which are several times the 0.84-year reduction for whites. These projections imply an increase of over 50% in the Black-white life expectancy gap, from 3.6 to 5.5 years, thereby eliminating twenty years of progress made in reducing this differential. Latinos, who have consistently experienced lower mortality than whites (a phenomenon known as the Latino or Hispanic paradox), would see their more than three-year survival advantage almost eliminated.
Efficacy of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-Analysis
Authors: Kashour Zakariya , Riaz Muhammad , Garbati Musa A. , AlDosary Oweida , Tlayjeh Haytham , Gerberi Dana , Murad M. Hassan , Sohail M. Rizwan , Kashour Tarek , Tleyjeh Imad M.
Published: July 2020

Background

Chloroquine (CQ) and hydroxychloroquine (HCQ) show anti-SARS-CoV-2 activity in vitro; however, clinical studies have reported conflicting results. We sought to systematically evaluate the effect of CQ and HCQ with or without azithromycin (AZ) on outcomes of COVID-19 patients.

Methods

We searched Medline, Embase, EBM Reviews, Scopus, Web of Science, preprints and grey literature up to July 7, 2020. We included studies that assessed COVID-19 patients treated with CQ or HCQ, with or without AZ. We pooled only adjusted effect estimates of mortality using a random effect model. We summarized the effect of CQ or HCQ on viral clearance and ICU admission/ mechanical ventilation.

Results

Out of 1463 citations screened for eligibility, five RCTs and 14 cohort studies were included (20,263 hospitalized patients). Thirteen studies (1 RCT and 12 cohorts) with 15,938 patients examined the effect of HCQ on short term mortality. The pooled adjusted OR was 1.05 (95% CI 0.96-1.15, I2=0 %, p=0.647). Six cohort studies examined the effect of HCQ and AZ combination among 14,016 patients. The pooled adjusted OR was 0.93 (95% CI 0.79-1.11, I2=59.3%, p=0.003). Two cohort studies and three RCTs found no significant effect of HCQ on viral clearance. One RCT with 48 patients demonstrated improved viral clearance in patients treated with CQ and HCQ. Three cohort studies found that HCQ with or without AZ had no significant effect on mechanical ventilation/ ICU admission.

Conclusion

Moderate certainty evidence suggests that HCQ, with or without AZ, lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19.

This systematic review and meta-analysis showed that in-hospital treatment of COVID-19 patients with antimalarials medications failed to reduce short-term mortality and morbidity with potential harm if used in combination with azithromycin.
Novel surrogate virus neutralization test reveals low serum neutralizing anti-SARS-CoV-2-S antibodies levels in mildly affected COVID-19 convalescents
Authors: Bošnjak Berislav , Stein Saskia Catherina , Willenzon Stefanie , Cordes Anne Katrin , Puppe Wolfram , Bernhardt Günter , Ravens Inga , Ritter Christiane , Schultze-Florey Christian R. , Gödecke Nina , Martens Jörg , Kleine-Weber Hannah , Hoffmann Markus , Cossmann Anne , Yilmaz Mustafa , Pink Isabelle , Hoeper Marius M. , Behrens Georg M.N. , Pöhlmann Stefan , Blasczyk Rainer , Schulz Thomas F. , Förster Reinhold
Published: July 2020

Neutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells using surface-expressed angiotensin-converting enzyme 2 (ACE2). We developed a surrogate neutralization test (sVNT) to assess at what degree serum antibodies interfere with the binding of SARS-CoV-2-S-RBD to ACE2. The sVNT revealed neutralizing anti-SARS-CoV-2-S antibodies in the sera of 90% of mildly and 100% of severely affected coronavirus-disease-2019 (COVID-19) convalescent patients. Importantly, sVNT results correlated strongly to the results from pseudotyped-vesicular stomatitis virus-vector-based neutralization assay and to levels of anti-SARS-CoV-2-S1 IgG and IgA antibodies. Moreover, levels of neutralizing antibodies also correlated to duration and severity of clinical symptoms, but not patient age or gender. These findings together with the sVNT will not only be important for evaluating the prevalence of neutralizing antibodies in a population but also for identifying promising plasma donors for successful passive antibody therapy.
Model-based reasoning methods for diagnosis in integrative medicine based on electronic medical records and natural language processing
Authors: Geng Wenye , Qin Xuanfeng , Wang Zhuo , Kong Qing , Tang Zihui , Jiang Lin
Published: July 2020

Background

This study aimed to investigate model-based reasoning (MBR) algorithms for the diagnosis of integrative medicine based on electronic medical records (EMRs) and natural language processing.

Methods

A total of 14,075 medical records of clinical cases were extracted from the EMRs as the development dataset, and an external test dataset consisting of 1,000 medical records of clinical cases was extracted from independent EMRs. MBR methods based on word embedding, machine learning, and deep learning algorithms were developed for the automatic diagnosis of syndrome pattern in integrative medicine. MBR algorithms combining rule-based reasoning (RBR) were also developed. A standard evaluation metrics consisting of accuracy, precision, recall, and F1 score were used for the performance estimation of the methods. The association analyses were conducted on the sample size, number of syndrome pattern type, and diagnosis of lung diseases with the best algorithms.

Results

The Word2Vec CNN MBR algorithms showed high performance (accuracy of 0.9586 in the test dataset) in the syndrome pattern diagnosis. The Word2Vec CNN MBR combined with RBR also showed high performance (accuracy of 0.9229 in the test dataset). The diagnosis of lung diseases could enhance the performance of the Word2Vec CNN MBR algorithms. Each group sample size and syndrome pattern type affected the performance of these algorithms.

Conclusion

The MBR methods based on Word2Vec and CNN showed high performance in the syndrome pattern diagnosis in integrative medicine in lung diseases. The parameters of each group sample size, syndrome pattern type, and diagnosis of lung diseases were associated with the performance of the methods.

Strengths and limitations of this study

A novel application of artificial intelligence – natural language processing approaches on diagnosis of integrative medicine

A study of medical artificial intelligence based on real-world data of electronic medical records

Multiple approaches on artificial intelligence to include traditional machine learning algorithms, neural network, and deep learning algorithms

Rule-based combining model-based reasoning to be explored in this dataset
Assessing required SARS-CoV-2 blanket testing rates for possible control of the outbreak in the epicentre Lusaka province of Zambia with consideration for asymptomatic individuals: a simple mathematical modelling study
Authors: Sichone Joseph , Sinkala Musalula , Kikonko Mervis , Munsaka Sody M. , Simuunza Martin
Published: July 2020

Introduction

The novel Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2), in Africa is characterised by a more substantial proportion of asymptomatic (or mildly symptomatic) individuals thought to be playing a role in the spread of the infection. The exact proportion and degree of infectiousness of asymptomatic individuals remains unclear. Studies however indicate that their management is crucial for control of SARS-CoV-2 transmission.

Methodology

We developed a simplified deterministic susceptible-exposed-infectious-removed (SEIR) mathematical model to assess the effect of active isolation of SARS-CoV-2 infected but asymptomatic individuals through blanket testing for control of the outbreak in Lusaka Province of Zambia. Here we modelled two scenarios; (1) assuming asymptomatic individuals comprised 70% of all COVID-19 cases and (2) asymptomatic individuals comprised only 50% of the cases. For contrast, the model was assessed first under the assumption that asymptomatic individuals are equally as infectious as symptomatic individuals and then secondly, and more likely, assuming asymptomatic individuals are only half as infectious as symptomatic individuals.

Results

For the model assuming 70% asymptomatic cases, a minimum sustained blanket testing rate of ≥ 7911 tests/100000 population was sufficient to control the outbreak if asymptomatic individuals are only half as infectious while if equal infectiousness was assumed then a testing rate of ≥ 10028 tests/ 100000 population would be required. For 50% asymptomatic, minimum blanket testing rates of ≥ 4540 tests/ 100000 population was sufficient to control the outbreak at both assumed levels of infectiousness for asymptomatic individuals relative to symptomatic individuals.

Discussion and conclusion

Our model predicts that the current testing rates of ≈ 150/100,000 population are inadequate to control transmission of SARS-Cov-2 in Lusaka. Active isolation of COVID-19 cases including asymptomatic individuals through blanket testing can be used as a possible measure for control of the SARS-Cov-2 transmission in Lusaka, Zambia.
Integrating genetic dependencies and genomic alterations across pathways and cancer types
Authors: Park Tae Yoon , Leiserson Mark D.M. , Klau Gunnar W. , Raphael Benjamin J.
Published: July 2020

Recent genome-wide CRISPR-Cas9 loss-of-function screens have identified genetic dependencies across many cancer cell lines. Associations between these dependencies and genomic alterations in the same cell lines reveal phenomena such as oncogene addiction and synthetic lethality. However, comprehensive characterization of such associations is complicated by complex interactions between genes across genetically heterogeneous cancer types. We introduce SuperDendrix, an algorithm to identify differential dependencies across cell lines and to find associations between differential dependencies and combinations of genetic alterations and cell-type-specific markers. Application of SuperDendrix to CRISPR-Cas9 loss-of-function screens from 554 cancer cell lines reveals a landscape of associations between differential dependencies and genomic alterations across multiple cancer pathways in different combinations of cancer types. We find that these associations respect the position and type of interactions within pathways with increased dependencies on downstream activators of pathways, such asNFE2L2and decreased dependencies on upstream activators of pathways, such asCDK6. SuperDendrix also reveals dozens of dependencies on lineage-specific transcription factors, identifies cancer-type-specific correlations between dependencies, and enables annotation of individual mutated residues.
Understanding site choice and competition through the adaptive dynamics of microbial settling strategy in a chemostat
Authors: Cai Yuhua , Geritz Stefan A. H.
Published: July 2020

To understand the choice and competition of sites in nature, we consider an ecological environment in a chemostat consisting of a polymorphic microbial population that can float in the fluid or settle down on the wall of the chemostat. For the transition of a microbe from its floating state to its settled state at a particular settling rate involving the choice and competition of sites on the wall, we consider three different mechanisms: (i)unimolecular-Bourgeois settling, i.e., floaters land freely on the wall, but in an occupied site, the owner keeps the site (Bourgeois behaviour); (ii)unimolecular-anti-Bourgeois settling, i.e., floaters land freely on the wall, but in an occupied site, the intruder gets the site (anti-Bourgeois behaviour); (iii)bimolecular settling, i.e., floaters land only on the vacant sites of the wall. Employing the framework of adaptive dynamics, we study the evolution of the settling rate with different settling mechanisms and investigate how physical operating conditions affect the evolutionary dynamics. Our results indicate that settling mechanisms and physical operating conditions have significant influences on the direction of evolution and the diversity of phenotypes. (1) For constant nutrient input, theoretical analysis shows that the population is always monomorphic during the long-term evolution. Notably, the direction of evolution depends on the settling mechanisms and physical operating conditions, which further determines the composition of the population. Moreover, we find two exciting transformations of types of Pairwise Invasibility Plots, which are thegradual transformationand thebang-bang transformation. (2) For periodic nutrient input, numerical analysis reveals that evolutionary coexistence is possible, and the population eventually maintains dimorphism. Remarkably, for all three settling mechanisms, the long-term evolution leads to one of the two coexisting species settle down totally on the wall if the input is low-frequency but float entirely in the fluid if the input becomes high-frequency.
Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses
Authors: Hoepel Willianne , Chen Hung-Jen , Allahverdiyeva Sona , Manz Xue , Aman Jurjan ,   Amsterdam UMC COVID-19 Biobank, Bonta Peter , Brouwer Philip , de Taeye Steven , Caniels Tom , van der Straten Karlijn , Golebski Korneliusz , Griffith Guillermo , Jonkers René , Larsen Mads , Linty Federica , Neele Annette , Nouta Jan , van Baarle Frank , van Drunen Cornelis , Vlaar Alexander , de Bree Godelieve , Sanders Rogier , Willemsen Lisa , Wuhrer Manfred , Bogaard Harm Jan , van Gils Marit , Vidarsson Gestur , de Winther Menno , den Dunnen Jeroen
Published: July 2020

For yet unknown reasons, severely ill COVID-19 patients often become critically ill around the time of activation of adaptive immunity. Here, we show that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyper-inflammatory response by human macrophages, which subsequently breaks pulmonary endothelial barrier integrity and induces microvascular thrombosis. The excessive inflammatory capacity of this anti-Spike IgG is related to glycosylation changes in the IgG Fc tail. Moreover, the hyper-inflammatory response induced by anti-Spike IgG can be specifically counteracted in vitro by use of the active component of fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk.

One sentence summary

Anti-Spike IgG promotes hyper-inflammation.
Unexpected diversity of CPR bacteria and nanoarchaea in the rare biosphere of rhizosphere-associated grassland soil
Authors: Nicolas Alexa M. , Jaffe Alexander L. , Nuccio Erin E. , Taga Michiko E. , Firestone Mary K. , Banfield Jillian F.
Published: July 2020

Candidate Phyla Radiation (CPR) bacteria and nanoarchaea populate most ecosystems, but are rarely detected in soil. We concentrated particles less than 0.2μm from grassland soil, enabling targeted metagenomic analysis of these organisms, which are almost totally unexplored in soil. We recovered a diversity of CPR bacteria and some nanoarchaea sequences, but no sequences from other cellular organisms. The sampled sequences include Doudnabacteria (SM2F11) and Pacearchaeota, organisms not previously reported in soil, as well as Saccharibacteria, Parcubacteria and Microgenomates. CPR and DPANN (an acronym of the names of the first included archaea phyla) enrichments of 100-1000-fold were achieved compared to bulk soil, in which we estimate these organisms comprise about 1 to 100 cells per gram of soil. Like most CPR and DPANN sequenced to date, we predict these microorganisms live symbiotic, anaerobic lifestyles. However, Saccharibacteria, Parcubacteria, and Doudnabacteria genomes sampled here also encode ubiquinol oxidase operons that may have been acquired from other bacteria, likely during adaptation to aerobic soil environments. We posit that although present at low abundance, CPR bacteria and DPANN archaea could impact overall soil microbial community function by modulating host organism abundances and activity.