bluuebunny/crossref_metadata_2025 huggingface dataset:
Endotracheal application of ultraviolet A light in critically ill severe acute respiratory syndrome coronavirus-2 patients: A first-in-human study
Authors: Rezaie Ali , Melmed Gil Y. , Leite Gabriela , Mathur Ruchi , Takakura Will , Pedraza Isabel , Lewis Michael , Murthy Rekha , Chaux George , Pimentel Mark
Published: March 2021

Background

Promising preclinical experiments show that, under specific and monitored conditions, ultraviolet-A (UVA) exposure reduces certain bacteria, fungi, and viruses including coronavirus-229E without harming mammalian columnar epithelial cells. We aimed to evaluate the safety and effects of UVA therapy administered by a novel device via endotracheal tube in critically ill subjects with SARS-CoV-2 infection.

Methods

Five newly intubated mechanically ventilated adults with SARS-CoV-2 infection, with an endotracheal tube size 7.5mm or greater, were treated with UVA for 20 minutes daily for 5 days, and followed for 30 days.

Results

Five subjects were enrolled (mean age 56.6yrs, 3 male). At baseline, all subjects scored 9/10 on the WHO clinical severity scale (10=death) with predicted mortality ranging from 21 to 95%. Average log changes in endotracheal viral load from baseline to day 5 and day 6 were -2.41 (range -1.16 to -4.54; Friedman P=0.002) and -3.20 (range -1.20 to -6.77; Friedman P<0.001), respectively. There were no treatment-emergent adverse events. One subject died 17 days after enrollment due to intracranial hemorrhagic complications of anticoagulation while receiving extracorporeal membrane oxygenation. The remaining subjects clinically improved and scored 2, 4, 5, and 7 on the WHO scale at day 30. In these subjects, the slope of viral load reduction during UVA treatment correlated with the slope of improvement in clinical WHO severity score over time (Spearman rho=1, P<0.001).

Conclusion

In this first-in-human study, endotracheal UVA therapy under specific and monitored settings, was safe with a significant reduction in respiratory SARS-CoV-2 viral burden over the treatment period.

Trial Registration

ClinicalTrials.gov #NCT04572399.

Key Messages

What is the key question?

Can endotracheal narrow-band UVA therapy be a safe and effective treatment for severe SARS-CoV-2 infection?

What is the bottom line?

Under specific and monitored settings, endotracheal UVA light therapy may be an effective treatment for SARS-CoV-2 infection. Endotracheal UVA light therapy appears to be well tolerated in critically ill patients with SARS-CoV-2 infection.

Why read on?

This is the fist-in-human trial of internal UVA therapy using a alternative novel approach to combat COVID-19.
Long-Term Duration of Antibody Response to SARS CoV-2 in One of the Largest Slums of Buenos Aires
Authors: Pagotto Vanina , Luna Lorena , Salto Julieta , Manslau Magdalena Wagner , Figar Silvana , Mistchenko Alicia S. , Boyero Georgina Carciofi , Weinberger Natacha ,   COVIDAR Group, Gómez Saldaño Ana María , Alponte Carla Alpire , Alarcón Patricia Auza , Tarqui Ayelén Copa , Cortez Sheila , Gallardo Pamela , Pinaya Janeth Gemio , Navarro Ángeles Hernandez , Maccio Alejandro , Mosqueda Paula , Neme Nicole , Quispe Bania , Bernal Emilio Ramírez , Soria Thelma , Arce Angélica Fernández , Gamarnik Andrea , de Quirós Fernán González Bernaldo
Published: March 2021

The durability of the antibody response following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has not been fully elucidated. We have performed a cross-sectional study in one of the largest slums of Buenos Aires, Barrio Padre Mugica in June 2020, detecting a seroprevalence of 53.4%. To evaluate the persistence of the humoral response against SARS-CoV-2 in this area, we designed a second study assessing only the people that were IgG positive in the first survey. The IgG levels against the full spike (S) protein in 175 individuals that were seropositive, at least 6 months before, were evaluated in a second survey. The positivity rate was 92.0%, 161 from 175 individuals remained IgG positive. We observed a contraction in the overall IgG levels measured by ELISA. The median IgG dropped 62% from June to December 2020. Most of the individuals tested (87%) reported to be asymptomatic or oligo-symptomatic. No difference was found between men and women, but people aged less than 50 showed a lower IgG level in each period compared to older individuals. Our data indicate sustained humoral immunity for at least 6 months in a specific socio-economical setting in a population that was mainly asymptomatic for COVID-19.
Elevated mortality among people experiencing homelessness with COVID-19
Authors: Leifheit Kathryn M. , Chaisson Lelia H. , Medina Jesus Alejandro , Wahbi Rafik , Shover Chelsea L.
Published: March 2021

We reviewed publicly available data from major U.S. health jurisdictions to compare case fatality rates in people experiencing homelessness (PEH) to the general population. Case fatality among PEH was 1.3 times (95% CI 1.1, 1.5) that of the general population, suggesting that PEH should be prioritized for vaccination.
Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and increases cortical blood flow in an Alzheimer’s disease mouse model
Authors: Ali Muhammad , Falkenhain Kaja , Njiru Brendah N , Murtaza-Ali Muhammad , Ruiz-Uribe Nancy E , Haft-Javaherian Mohammad , Catchers Stall , Nishimura Nozomi , Schaffer Chris B. , Bracko Oliver
Published: March 2021

Increased incidence of stalled capillary blood flow caused by adhesion of leucocytes to the brain microvascular endothelium leads to a 17% reduction of cerebral blood flow (CBF) and exacerbates short-term memory loss in multiple mouse models of Alzheimer’s disease (AD). Here, we report that Vascular Endothelial Growth Factor (VEGF) signaling at the luminal side of the brain microvasculature plays an integral role in the capillary stalling phenomenon of the APP/PS1 mouse model. Administration of the anti-mouse VEGF-A164 antibody, an isoform that inhibits blood brain barrier (BBB) hyperpermeability, reduced the number of stalled capillaries within an hour of injection, leading to an immediate increase in average capillary blood flow but not capillary diameter. VEGF-A inhibition also reduced the overall eNOS protein concentrations, increased occludin levels, and decreased the penetration of circulating Evans Blue dye across the BBB into the brain parenchyma, suggesting increased BBB integrity. Capillaries prone to neutrophil adhesion after anti-VEGF-A treatment also had lower occludin concentrations than flowing capillaries. Taken together, our findings demonstrate that VEGF-A signaling in APP/PS1 mice contributes to aberrant eNOS/occludin- associated BBB permeability, increases the incidence of capillary stalls, and leads to reductions in CBF. Reducing leucocyte adhesion by inhibiting luminal VEGF signaling may provide a novel and well-tolerated strategy for improving brain microvascular blood flow in AD patients.
Detection of HIV and Mycobacterium tuberculosis among University Students in Port Harcourt, Nigeria
Authors: Okonko IO , Cookey TI , Okoli EM
Published: March 2021

Assessment of HIV and Mycobacterium tuberculosis infection is crucial to detect HIV and/or Mycobacterium tuberculosis coinfection and the strategy for infection management and treatment. This study assessed the proportion of students with HIV, Mycobacterium tuberculosis, and HIV/Mycobacterium tuberculosis coinfection. Two hundred and thirty-five university students in Port Harcourt, Nigeria were recruited, ages 16 – 39 years. Samples of blood were collected and processed using standard laboratory procedures. All the students were screened for antibodies to HIV using 2 rapid screening strips and a commercially available enzyme-linked immunosorbent assay (ELISA)-based kit for determination of HIV-1/2/P24/O. The presence of Mycobacterium tuberculosis was done using TB rapid kits and a commercially available ELISA-based kit. The results showed that 3.4% of the students were positive for HIV, 2.1% for Mycobacterium tuberculosis and none for HIV/Mycobacterium tuberculosis coinfection. The age-specific infection rate showed a higher HIV infection rate in the age group 16-24 years (4.7%) than ≥25 years (2.8%). While higher Mycobacterium tuberculosis infection rate occurred in the age group ≥25 years (2.8%) than in <25 years (2.3%). The gender-specific infection rate showed that females had a higher infection rate (HIV, 4.7% and Mycobacterium tuberculosis, 2.3%) than males (HIV, 2.6% and Mycobacterium tuberculosis, 1.7%). Age and sex were the main correlates (P<0.05) of HIV and Mycobacterium tuberculosis. This study further confirmed the presence of HIV and Mycobacterium tuberculosis infections among University students. These findings suggest the need for regular screening of University students for HIV and Mycobacterium tuberculosis.
Limb apparent motion perception: modification by tDCS, and clinically or experimentally altered bodily states
Authors: Saetta Gianluca , Ho Jasmine T. , Bekrater-Bodmann Robin , Brugger Peter , Dijkerman H. Chris , Lenggenhager Bigna
Published: March 2021

Limb apparent motion perception (LAMP) refers to the illusory visual perception of a moving limb upon observing two rapidly alternating photographs depicting the same limb in two different postures. Fast stimulus onset asynchronies (SOAs) induce the more visually guided perception of physically impossible movements. Slow SOAs induce the perception of physically possible movements. According to the motor theory of LAMP, the latter perception depends upon the observers’ sensorimotor representations. Here, we tested this theory in two independent studies by performing a central (study 1) and peripheral (study 2) manipulation of the body’s sensorimotor states during two LAMP tasks. In the first sham-controlled transcranial direct current stimulation between-subject designed study, we observed that the dampening of left sensorimotor cortex activity through cathodal stimulation biased LAMP towards the more visually guided perception of physically impossible movements for stimulus pairs at slow SOAs. In the second, online within-subject designed study, we tested three participant groups twice: (1) individuals with an acquired lower limb amputation, either while wearing or not wearing their prosthesis; (2) individuals with body integrity dysphoria (i.e., with a desire for amputation of a healthy leg) while sitting in a regular position or binding up the undesired leg (to simulate the desired amputation); (3) able-bodied individuals while sitting in a normal position or sitting on one of their legs. We found that the momentary sensorimotor state crucially impacted LAMP in individuals with an amputation and able-bodied participants, but not in BID individuals. Taken together, the results of these two studies substantiate the motor theory of LAMP.
Latency structure of BOLD signals within white matter in resting-state fMRI
Authors: Guo Bin , Zhou Fugen , Li Muwei , Gore John C.
Published: March 2021

Purpose

Previous studies have demonstrated that BOLD signals in gray matter in resting-state functional MRI (RSfMRI) have variable time lags, representing apparent propagations of fMRI BOLD signals in gray matter. We complemented existing findings and explored the corresponding variations of signal latencies in white matter.

Methods

We used data from the Brain Genomics Superstruct Project, consisting of 1412 subjects (both sexes included) and divided the dataset into ten equal groups to study both the patterns and reproducibility of latency estimates within white matter. We constructed latency matrices by computing cross-correlations between voxel pairs. We also applied a clustering analysis to identify functional networks within white matter, based on which latency analysis was also performed to investigate lead/lag relationship at network level. A dataset consisting of various sensory states (eyes closed, eyes open and eyes open with fixation) was also included to examine the relationship between latency structure and different states.

Results

Projections of voxel latencies from the latency matrices were highly correlated (average Pearson correlation coefficient = 0.89) across the subgroups, confirming the reproducibility and structure of signal lags in white matter. Analysis of latencies within and between networks revealed a similar pattern of inter- and intra-network communication to that reported for gray matter. Moreover, a dominant direction, from inferior to superior regions, of BOLD signal propagation was revealed by higher resolution clustering. The variations of lag structure within white matter are associated with different sensory states.

Conclusions

These findings provide additional insight into the character and roles of white matter BOLD signals in brain functions.
Structural variants are a major source of gene expression differences in humans and often affect multiple nearby genes
Authors: Scott Alexandra J , Chiang Colby , Hall Ira M
Published: March 2021

Structural variants (SVs) are an important source of human genome diversity but their functional effects are not well understood. We mapped 61,668 SVs in 613 individuals with deep genome sequencing data from the GTEx project and measured their effects on gene expression. We estimate that common SVs are causal at 2.66% of eQTLs, which is a 10.5-fold enrichment relative to their abundance in the genome and consistent with prior work using smaller sample sizes. Duplications and deletions were the most impactful variant types, whereas the contribution of mobile element insertions was surprisingly small (0.12% of eQTLs, 1.9-fold enriched). Multi-tissue analysis of expression effects revealed that gene-altering SVs show significantly more constitutive effects than other variant types, with 62.09% of coding SV-eQTLs active in all tissues with known eQTL activity compared to 23.08% of coding SNV- and indel-eQTLs, whereas noncoding SVs, SNVs and indels show broadly similar patterns. We also identified 539 rare SVs associated with nearby gene expression outliers. Of these, 62.34% are noncoding SVs that show strong effects on gene expression yet modest enrichment at known regulatory elements, demonstrating that rare noncoding SVs are a major source of gene expression differences but remain difficult to predict from current annotations. Remarkably, both common and rare noncoding SVs often show strong regional effects on the expression of multiple genes: SV-eQTLs affect an average of 1.82 nearby genes compared to 1.09 genes affected by SNV- and indel-eQTLs, and 21.34% of rare expression-altering SVs show strong effects on 2-9 different genes. We also observe significant effects on gene expression extending 1 Mb from the SV. This provides a mechanism by which individual noncoding SVs may have strong and/or pleiotropic effects on phenotypic variation and disease.
Persistence of symptoms up to 10 months following acute COVID-19 illness
Authors: Perlis Roy H. , Green Jon , Santillana Mauricio , Lazer David , Ognyanova Katherine , Simonson Matthew , Baum Matthew A. , Quintana Alexi , Chwe Hanyu , Druckman James , Volpe John Della , Lin Jennifer
Published: March 2021

Importance

COVID-19 symptoms are increasingly recognized to persist among a subset of individual following acute infection, but features associated with this persistence are not well-understood.

Objective

We aimed to identify individual features that predicted persistence of symptoms over at least 2 months at the time of survey completion.

Design: Non-probability internet survey. Participants were asked to identify features of acute illness as well as persistence of symptoms at time of study completion. We used logistic regression models to examine association between sociodemographic and clinical features and persistence of symptoms at or beyond 2 months.

Setting

Ten waves of a fifty-state survey between June 13, 2020 and January 13, 2021.

Participants

6,211 individuals who reported symptomatic COVID-19 illness confirmed by positive test or clinician diagnosis.

Exposure

symptomatic COVID-19 illness

Results

Among 6,211 survey respondents reporting COVID-19 illness, with a mean age of 37.8 (SD 12.2) years and 45.1% female, 73.9% white, 10.0% Black, 9.9% Hispanic, and 3.1% Asian, a total of 4946 (79.6%) had recovered within less than 2 months, while 491 (7.9%) experienced symptoms for 2 months or more. Of the full cohort, 3.4% were symptomatic for 4 months or more and 2.2% for 6 months or more. In univariate analyses, individuals with persistent symptoms on average reported greater initial severity. In logistic regression models, older age was associated with greater risk of persistence (OR 1.10, 95% CI 1.01-1.19 for each decade beyond 40); otherwise, no significant associations with persistence were identified for gender, race/ethnicity, or income. Presence of headache was significantly associated with greater likelihood of persistence (OR 1.44, 95% CI 1.11-1.86), while fever was associated with diminished likelihood of persistence (OR 0.66, 95% CI 0.53-0.83).

Conclusion and Relevance

A subset of individuals experience persistent symptoms from 2 to more than 10 months after acute COVID-19 illness, particularly those who recall headache and absence of fever. In light of this prevalence, strategies for predicting and managing such sequelae are needed.

Trial Registration

NA

Key Points

Question

Which individuals are at greatest risk for post-acute sequelae of COVID-19?

Findings

In this non-probability internet survey, among 6,211 individuals with symptomatic COVID-19 illness, 7.9% experienced persistence of symptoms lasting 2 months or longer. Older age, but not other sociodemographic features, was associated with risk for persistence, as was headache.

Meaning

Identifying individuals at greater risk for symptomatic persistence may facilitate development of targeted interventions.
U5 snRNA interactions with exons ensure splicing precision
Authors: Artemyeva-Isman Olga V. , Porter Andrew C.G.
Published: March 2021

Imperfect conservation of human pre-mRNA splice sites is necessary to produce alternative isoforms. This flexibility is combined with precision of the message reading frame. Apart from intron-termini GU_AG and the branchpoint A, the most conserved are the exon-end guanine and +5G of the intron-start. Association between these guanines cannot be explained solely by base-pairing with U1snRNA in the early spliceosome complex. U6 succeeds U1 and pairs +5G in the pre-catalytic spliceosome, while U5 binds the exon-end. Current U5snRNA reconstructions by CryoEM cannot explain the conservation of the exon-end G. Conversely, human mutation analyses show that guanines of both exon-termini can suppress splicing mutations. Our U5 hypothesis explains the mechanism of splicing precision and the role of these conserved guanines in the pre-catalytic spliceosome. We propose: 1) Optimal binding register for human exons and U5 - the exon junction positioned at U5Loop1 C39|C38. 2) Common mechanism of base pairing of human U5snRNA with diverse exons and bacterialLl.LtrB intron with new loci in retrotransposition - guided by base pair geometry. 3) U5 plays a significant role in specific exon recognition in the pre-catalytic spliceosome. Our statistical analyses show increased U5 Watson-Crick pairs with the 5’exon in the absence of +5G at the intron-start. In 5’exon positions -3 and -5 this effect is specific to U5snRNA rather than U1snRNA of the early spliceosome. Increased U5 Watson-Crick pairs with 3’exon position +1 coincide with substitutions of the conserved -3C at the intron 3’end. Based on mutation and X-ray evidence we propose that -3C pairs with U2 G31juxtaposing the branchpoint and the 3’intron-end. The intron-termini pair, formed in the pre-catalytic spliceosome to be ready for transition after branching, and the early involvement of the 3’intron-end ensure that the 3’exon contacts U5 in the pre-catalytic complex. We suggest that splicing precision is safeguarded cooperatively by U5, U6 and U2snRNAs that stabilise the pre-catalytic complex by Watson-Crick base pairing. In addition, our new U5 model explains the splicing effect of exon-start +1G mutations: U5 Watson-Crick pairs with exon +2C/+3G strongly promote exon inclusion. We discuss potential applications for snRNA-therapeutics and gene repair by reverse splicing.
Simultaneous equations modelling of communities with interacting species networks
Authors: Porto Miguel , Beja Pedro
Published: March 2021

To understand community assembly, ecologists have long sought to extract the signal of biotic interactions from species co-occurrence patterns. These efforts face multiple difficulties such as confounding environmental effects, confounding indirect interactions between multiple species and asymmetry of interactions. To address these problems, we propose Simultaneous Community Equations Modelling (SCEM) as a framework to explicitly account for asymmetric interaction networks in community models. SCEM uses a system of equations to model the occurrence of each species as a function of measured and unmeasured (latent) environmental predictors, and the occurrence of potentially all the other species in the community. Biotic interactions most supported by the data are identified using heuristic optimization of a parsimony criterion, implemented as a Genetic Algorithm. Extensive simulations show that SCEM can recover interaction network topologies in virtual communities. We present a software to implement SCEM and illustrate its application with a case study.
Nitric oxide synthases from photosynthetic organisms improve growth and confer nitrosative stress tolerance inE. coli. Insights on the pterin cofactor
Authors: Correa-Aragunde Natalia , Nejamkin Andrés , Del Castello Fiorella , Foresi Noelia , Lamattina Lorenzo
Published: March 2021

Nitric oxide synthase (NOS) synthesizes NO from the substrate L-arginine (Arg). NOS with distinct biochemical properties were characterized from two photosynthetic microorganisms, the unicellular algaeOstreococcus tauri(OtNOS) and the cyanobacteriaSynechococcusPCC 7335 (SyNOS). In this work we studied OtNOS and SyNOS recombinantly expressed inE. coliand analyzed bacterial growth and tolerance to nitrosative stress. Results show that the expression of OtNOS and SyNOS promotes bacterial growth and allows metabolizing Arg as N source. In accordance to a high NO producing activity, OtNOS expression induces thehmpflavohemoglobin inE. coli, suggesting that this strain is sensing nitrosative stress. The addition of 1 mM of the NO donor sodium nitroprusside (SNP) is toxic and generates a strong nitrosative stress. The expression of OtNOS or SyNOS reduced SNP toxicity restoring bacterial growth. Finally, using bioinformatic tools and ligand docking analyses, we propose tetrahydromonapterin (MH4), an endogenous pterin found inE. coli, as potential cofactor required for NOS catalytic activity. Our findings could be useful for the development of biotechnological applications using NOS expression to improve growth in bacteria.

Key points

- The NO synthase (NOS) from photosynthetic microorganisms were expressed inE. coli

- Expression of NOS increases bacterial growth and tolerance to nitrosative stress.

- Ligand docking analyses indicate tetrahydromonapterin (MH4) as potential NOS cofactor inE. coli.
BioISO: an objective-oriented application for assisting the curation of genome-scale metabolic models
Authors: Cruz Fernando , Capela João , Ferreira Eugénio C. , Rocha Miguel , Dias Oscar
Published: March 2021

As the reconstruction of Genome-Scale Metabolic Models becomes standard practice in systems biology, the number of organisms having at least one metabolic model at the genome-scale is peaking at an unprecedented scale. The automation of several laborious tasks, such as gap-finding and gap-filling, allowed to develop GSMMs for poorly described organisms. However, such models’ quality can be compromised by the automation of several steps, which may lead to erroneous phenotype simulations.

The Biological networks constraint-basedIn SilicoOptimization (BioISO) is a computational tool aimed at accelerating the reconstruction of Genome-Scale Metabolic Models. This tool facilitates the manual curation steps by reducing the large search spaces often met when debuggingin silicobiological models.BioISOuses a recursive relation-like algorithm and Flux Balance Analysis to evaluate and guide debugging ofin silicophenotype simulations. The potential ofBioISOto guide the debugging of model reconstructions was showcased using GSMMs available in literature and compared with the results of two other state-of-the-art gap-filling tools (MenecoandfastGapFill). Furthermore,BioISOwas used asMeneco’s gap-finding algorithm to reduce the number of proposed solutions (reaction sets) for filling the gaps.

BioISOwas implemented as a webserver available athttps://bioiso.bio.di.uminho.pt; and integrated intomerlinas a plugin.BioISO’simplementation as a Python™ package can also be retrieved fromhttps://github.com/BioSystemsUM/BioISO.
Development and pre-clinical evaluation of Newcastle disease virus-vectored SARS-CoV-2 intranasal vaccine candidate
Authors: Díaz Manolo Fernandez , Calderon Katherine , Rojas-Neyra Aldo , Vakharia Vikram N. , Choque-Guevara Ricardo , Montalvan Angela , Poma-Acevedo Astrid , Rios-Matos Dora , Agurto-Arteaga Andres , Cauti-Mendoza María de Grecia , Perez-Martinez Norma , Isasi-Rivas Gisela , Tataje-Lavanda Luis , Palomino Miryam , Bailón Henri , Sernaque-Aguilar Yacory , Ygnacio-Aguirre Freddy , Criollo-Orozco Manuel , Huaccachi-Gonzalez Edison , Delgado-Ccancce Elmer , Villanueva-Pérez Doris , Montesinos-Millan Ricardo , Gutiérrez-Manchay Kristel , Pauyac-Antezana Katherine , Ramirez-Ortiz Ingrid , Quiñones-Garcia Stefany , Cauna-Orocollo Yudith , Vallejos-Sánchez Katherine , Rios-Angulo Angela A. , Núñez-Fernández Dennis , Salguedo-Bohorquez Mario I. , Ticona Julio , Sánchez Manolo Fernández , García Paquita , Icochea Eliana , Guevara Luis , Zimic Mirko ,   for the COVID-19 Working Group in Perú
Published: March 2021

The COVID-19 pandemic has claimed the lives of millions of people worldwide and threatens to become an endemic problem, therefore the need for as many types of vaccines as possible is of high importance.

Because of the millions of doses required, it is desirable that vaccines are not only safe and effective, but also easy to administer, store, and inexpensive to produce.

Newcastle Disease Virus (NDV) is responsible for a respiratory disease in chickens. It has no pathogenic homologue in humans. NDV is recognized as an oncolytic virus, and its use in humans for oncological treatment is being evaluated.

In the present work, we have developed two types of NDV-vectored candidate vaccines, which carry the surface-exposed RBD and S1 antigens of SARS-CoV-2, respectively. These vaccine candidates were produced in specific-pathogen-free embryonating chicken eggs, and purified from allantoic fluid before lyophilization. These vaccines were administered intranasally to three different animal models: mice, rats and hamsters, and evaluated for safety, toxicity, immunogenicity, stability and efficacy. Efficacy was evaluated in a challenge assay against active SARS-CoV-2 virus in the Golden Syrian hamster model.

The NDV-vectored vaccine based on the S1 antigen was shown to be safe and highly immunogenic, with the ability to neutralize SARS-CoV-2 in-vitro, even with an extreme dilution of 1/640. Our results reveal that this vaccine candidate protects the lungs of the animals, preventing cellular damage in this tissue. In addition, this vaccine reduces the viral load in the lungs, suggesting that it may significantly reduce the likelihood of transmission. Being lyophilized, this vaccine candidate is very stable and can be stored for several months at 4-8⁰C.

In conclusion, our NDV-based vaccine candidate has shown a very favorable performance in the pre-clinical study, serving as evidence for a future evaluation in a Phase-I human clinical trial. This candidate represents a promising tool in the fight against COVID-19.
Dissecting Transition Cells from Single-cell Transcriptome Data through Multiscale Stochastic Dynamics
Authors: Zhou Peijie , Wang Shuxiong , Li Tiejun , Nie Qing
Published: March 2021

Advances of single-cell technologies allow scrutinizing of heterogeneous cell states, however, analyzing transitions from snap-shot single-cell transcriptome data remains challenging. To investigate cells with transient properties or mixed identities, we present MuTrans, a method based on multiscale reduction technique for the underlying stochastic dynamical systems that prescribes cell-fate transitions. By iteratively unifying transition dynamics across multiple scales, MuTrans constructs the cell-fate dynamical manifold that depicts progression of cell-state transition, and distinguishes meta-stable and transition cells. In addition, MuTrans quantifies the likelihood of all possible transition trajectories between cell states using the coarse-grained transition path theory. Downstream analysis identifies distinct genes that mark the transient states or drive the transitions. Mathematical analysis reveals consistency of the method with the well-established Langevin equation and transition rate theory. Applying MuTrans to datasets collected from five different single-cell experimental platforms and benchmarking with seven existing tools, we show its capability and scalability to robustly unravel complex cell fate dynamics induced by transition cells in systems such as tumor EMT, iPSC differentiation and blood cell differentiation. Overall, our method bridges data-driven and model-based approaches on cell-fate transitions at single-cell resolution.
A network regularized linear model to infer spatial expression pattern for single cells
Authors: Gu Chaohao , Liu Zhandong
Published: March 2021

Spatial gene-expression is a crucial determinant of cell fate and behavior. Recent imaging and sequencing-technology advancements have enabled scientists to develop new tools that use spatial information to measure gene-expression at close to single-cell levels. Yet, while Fluorescence In-situ Hybridization (FISH) can quantify transcript numbers at single-cell resolution, it is limited to a small number of genes. Similarly, slide-seq was designed to measure spatial-expression profiles at the single-cell level but has a relatively low gene-capture rate. And although single-cell RNA-seq enables deep cellular gene-expression profiling, it loses spatial information during sample-collection. These major limitations have stymied these methods’ broader application in the field. To overcome spatio-omics technology’s limitations and better understand spatial patterns at single-cell resolution, we designed a computation algorithm that uses glmSMA to predict cell locations by integrating scRNA-seq data with a spatialomics reference atlas. We treated cell-mapping as a convex optimization problem by minimizing the differences between cellular-expression profiles and location-expression profiles with a L1 regularization and graph Laplacian based L2 regularization to ensure a sparse and smooth mapping. We validated the mapping results by reconstructing spatial-expression patterns of well-known marker genes in complex tissues, like the mouse cerebellum and hippocampus. We used the biological literature to verify that the reconstructed patterns can recapitulate cell-type and anatomy structures. Our work thus far shows that, together, we can use glmSMA to accurately assign single cells to their original reference-atlas locations.
MicroRNA binding site variation is enriched in psychiatric disorders
Authors: Geaghan Michael P. , Reay William R. , Cairns Murray J.
Published: March 2021

Psychiatric disorders and other complex traits have a polygenic architecture, often associated with dozens or even hundreds of independent genomic loci. As each of these have a relatively small influence on the trait, the dissection of their biological components is a non-trivial task. For psychiatric disorders in particular, the majority of associated loci lie within non-coding regions of the genome, suggesting that most of the genetic risk for disease originates from the disruption of regulatory sequences. While previously exploration of the heritability of these sequences has focused on variants that modify DNA elements, those that altercis-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact in these disorders. MiRNA have already been shown to be dysregulated in these disorders through both genetic and environmental influence, so it is reasonable to suspect their target genes may also be affected by common variation. In this study, we investigated the distribution of miRNA binding site variants (MBSVs) predicted to alter miRNA binding affinity in psychiatric disorders and observed significant enrichment in schizophrenia, depression, bipolar disorder, and anorexia nervosa. We also observed significant enrichment of MBSVs in genes targeted by several miRNA families, including miR-335-5p, miR-21-5p/590-5p, miR-361-5p, and miR-557 in both schizophrenia and depression, and nominally significant enrichment of MBSV for miR-323b-3p in schizophrenia. We also identified a significant association between MBSVs in gene sets involved in regulation of the synapse and synaptic depression in schizophrenia. While these observations support the role of miRNA in the pathophysiology of psychiatric disorders, we also observed significant association of MBSVs in other complex traits suggesting that MBSVs are an important class of regulatory variants that have functional implications for many disorders.
Absent or insufficient anti-SARS-CoV-2 S antibodies at ICU admission are associated to higher viral loads in plasma, antigenemia and mortality in COVID-19 patients
Authors: Martin-Vicente María , Almansa Raquel , Martínez Isidoro , Tedim Ana P. , Bustamante Elena , Tamayo Luis , Aldecoa César , Gómez José Manuel , Renedo Gloria , Berezo Jose Ángel , Cedeño Jamil Antonio , Mamolar Nuria , Olivares Pablo García , Herrán Rubén , Cicuendez Ramón , Enríquez Pedro , Ortega Alicia , Jorge Noelia , de la Fuente Amanda , Bustamante-Munguira Juan , Muñoz-Gómez María José , González-Rivera Milagros , Puertas Carolina , Más Vicente , Vázquez Mónica , Pérez-García Felipe , Rico-Feijoo Jesús , Martín Silvia , Motos Anna , Fernandez-Barat Laia , Eiros Jose María , Dominguez-Gil Marta , Ferrer Ricard , Barbé Ferrán , Kelvin David J , Bermejo-Martin Jesús F , Resino Salvador , Torres Antoni
Published: March 2021

Purpose

to evaluate the association between anti-SARS-CoV-2 S IgM and IgG antibodies with viral RNA load in plasma, the frequency of antigenemia and with the risk of mortality in critically ill patients with COVID-19.

Methods

anti-SARS-CoV-2 S antibodies levels, viral RNA load and antigenemia were profiled in plasma of 92 adult patients in the first 24 hours following ICU admission. The impact of these variables on 30-day mortality was assessed by using Kaplan-Meier curves and multivariate Cox regression analysis.

Results

non survivors showed more frequently absence of anti-SARS-CoV-2 S IgG and IgM antibodies than survivors (26.3% vs 5.6% for IgM and 18.4% vs 5.6% for IgG), and a higher frequency of antigenemia (47.4% vs 22.2%) (p <0.05). Non survivors showed lower concentrations of anti-S IgG and IgM and higher viral RNA loads in plasma, which were associated to increased 30-day mortality and decreased survival mean time. [Adjusted HR (CI95%), p]: [S IgM (AUC ≥60): 0.48 (0.24; 0.97), 0.040]; [S IgG (AUC ≥237): 0.47 (0.23; 0.97), 0.042]; [Antigenemia (+): 2.45 (1.27; 4.71), 0.007]; [N1 viral load (≥ 2.156 copies/mL): 2.21 (1.11; 4.39),0.024]; [N2 viral load (≥ 3.035 copies/mL): 2.32 (1.16; 4.63), 0.017]. Frequency of antigenemia was >2.5-fold higher in patients with absence of antibodies. Levels of anti-SARS-CoV-2 S antibodies correlated inversely with viral RNA load.

Conclusion

absence / insufficient levels of anti-SARS-CoV-2 S antibodies following ICU admission is associated to poor viral control, evidenced by increased viral RNA loads in plasma, higher frequency of antigenemia, and also to increased 30-day mortality.

Take-home message

absent or low levels of antibodies against the S protein of SARS-CoV- 2 at ICU admission is associated to an increased risk of mortality, higher frequency of antigenemia and higher viral RNA loads in plasma. Profiling anti-SARS-CoV-2 s antibodies at ICU admission could help to predict outcome and to better identify those patients potentially deserving replacement treatment with monoclonal or polyclonal antibodies.
Microfluidic Live-Imaging technology to perform research activities in 3D models
Authors: Martino Capuzzo Arnaud , Vigo Daniele
Published: March 2021

One of the most surprising differences observed when comparing cell cultures in 2D and 3D is morphological dissimilarity and their evolution over time. Cells grown in a monolayer tend to flatten in the lower part of the plate adhering to and spreading in the horizontal plane without expanding in the vertical dimension. The result is that cells grown in 2D have a forced apex-basal polarity. 3D cultures support co-cultivation and crosstalking between multiple cell types, which regulate development and formation in the in vivo counterpart. 3D models culture, with or without a scaffold matrix, can exhibit morein vivo-likemorphology and physiology. 3D cultures recapitulate relevant physiological cellular processes, transforming into unique platforms for drug screening. To support and guarantee the functional maintenance of a 3D structure, one must consider the structures and dynamics of regulatory networks, increasingly studied with live-imaging microscopy. However, commercially available technologies that can be used for current laboratory needs are limited, although there is a need to facilitate the acquisition of cellular kinetics with a high spatial and temporal resolution, to elevate visual performance and consequently that of experimentation. The CELLviewer is a newly conceived and developed multi-technology instrumentation, combining and synchronizing the work of different scientific disciplines. This work aims to test the system with two models: the first model is a singleJurkatcell while the second is anMCF-7spheroid. After having grown both models, the two models used are loaded into the microfluidic cartridge for each experiment and recorded in time-lapse for a total of 4 hours. After adaptive autofocus, when sliding inside the cartridge chamber, the samples used are tracked under the action of the optics and the 3D rotation was experimentally successfully obtained. A cell viability assessment was then used using the MitoGreen dye, a fluorescence marker selectively permeable to live cells. The ImageJ software was used to: calculate the model diameter, create fluorescence intensity graphs along a straight line passing through the cell, visualize the spatial fluorescence intensity distribution in 3D.
The developmental hourglass model is applicable to the spinal cord
Authors: Mukaigasa Katsuki , Sakuma Chie , Yaginuma Hiroyuki
Published: March 2021

The developmental hourglass model predicts that embryonic morphology is most conserved at the mid-embryonic stage and diverges at the early and late stages. This model is generally considered by whole embryonic level. Here, we demonstrate that the hourglass model is also applicable to a reduced element, the spinal cord. In the middle of spinal cord development, dorsoventrally arrayed neuronal progenitor domains are established, which are conserved among vertebrates. We found that, by comparing the single-cell transcriptomes between mice and zebrafish, V3 interneurons, a subpopulation of the post-mitotic spinal neurons, display divergent molecular profiles. We also found non-conservation ofcis-regulatory elements located around the progenitor fate determinants, indicating the rewiring of the upstream gene regulatory network. These results demonstrate that, despite the conservation of the progenitor domains, processes before and after the progenitor domain specification diverged. This study may help understand the molecular basis of the developmental hourglass model.
Co-culture of type I and type II pneumocytes as a model of alveolar epithelium
Authors: Brookes Oliver , Boland Sonja , Kuen René Lai , Baeza-Squiban Armelle
Published: March 2021

The epithelial tissues of the distal lung are continuously exposed to inhaled air, and are of research interest in studying respiratory exposure to both hazardous and therapeutic materials. Pharmaco-toxicological research depends on the development of sophisticated models of the alveolar epithelium, which better represent the different cell types present in the native lung and interactions between them.

We developed an air-liquid interface (ALI) model of the alveolar epithelium which incorporates cell lines representative of both type I (NCI-H441) and type II (hAELVi) epithelial cells. We compared morphology of single cells and the structure of cell layers of the two lines using light and electron microscopy. Working both in monotypic cultures and cocultures, we measured barrier function by trans-epithelial electrical resistance (TEER), and demonstrated that barrier properties can be maintained for 30 days. We created a mathematical model of TEER development over time based on these data in order to make inferences about the interactions occurring in these culture systems. We assessed expression of a panel of relevant genes that play important roles in barrier function and differentiation.

The coculture model was observed to form a stable barrier akin to that seen in hAELVi, while expressing surfactant protein C, and having a profile of expression of claudins and aquaporins appropriate for the distal lung. We described cavities which arise within stratified cell layers in NCI-H441 and cocultured cells, and present evidence that these cavities represent an aberrant apical surface. In summary, our results support the coculture of these two cell lines to produce a model which better represents the breadth of functions seen in native alveolar epithelium.
Institutionalisation of weak conceptions of sustainability in the United Nations Clean Development Mechanism: empirical evidence from Malaysian organisations
Authors: Sidhu Ann Marie , Gibbon Jane
Published: March 2021

Purpose

The purpose of this study is to examine how accounting for sustainable development (SD) in Malaysian organisations decouples economic growth from ecological consequences. The research analyses the empirical evidence of organisational responses and actions that purport to support SD in a developing country.

Design/methodology/approach

This study uses a discursive model of institutional theory to examine the relationship between texts, discourse and action within Clean Development Mechanism (CDM) organisations. This study uses both qualitative content and interpretive textual analysis of Malaysian organisations project design documents (PDDs) and interview transcripts to interpret and determine the “conceptions” of SD.

Findings

Documentation and interviews with Malaysian CDM organisations show that SD conceptions range from “business as usual” to weak ecological modernisation. The key narratives are both economic and technocratic but have little to do with SD concerns about ecological limitations and social equity.

Originality/value

The empirical evidence provides insights into the motivations and challenges of a developing country's commitment to SD. We perform the study in an accountability space other than corporate financial reporting. Unlike external corporate reports, PDDs are closer to the underlying organisational reality as they are internal project documents made publicly accessible through the United Nations Framework Convention on Climate Change, allowing for a more transparent evaluation. The evidence shows how the organisational approach to SD is institutionalised through the mediating role of discourse and texts used by the actors within the CDM.
Accountability and governance in pursuit of Sustainable Development Goals: conceptualising how governments create value
Authors: Abhayawansa Subhash , Adams Carol A. , Neesham Cristina
Published: March 2021

Purpose

Drawing on Adams (2017a) conceptualisation of value creation by organisations published in the Accounting, Auditing and Accountability Journal, the purpose of this paper is to develop a conceptualisation of how national governments can create value for society and the economy through their approach to the UN Sustainable Development Goals (SDGs).

Design/methodology/approach

An initial conceptual framework was developed from literature situated at the intersection of accountability, public policy and sustainability/sustainable development. The authors' review of extant research on national policy development on value creation, sustainability and the SDGs identified gaps in (understanding of) approaches to national accountability and national governance (by state and civil society) processes. The subsequent thematic analysis of 164 written submissions made to the Australian Senate inquiry on the SDGs between December 2017 and March 2018, together with transcripts of five public hearings where 49 individuals and organisations appeared as witnesses during the second half of 2018, focussed on addressing these gaps.

Findings

Input to the Australian Senate Inquiry on the SDGs overwhelmingly emphasised the importance of transparency and stakeholder participation in accountability systems, commenting on data gathering, measuring and communicating. There was an emphasis on the need to involve all parts of society, including business, investors and civil society, and for strong central co-ordination by the Office of the Prime Minister and Cabinet. These data allowed the authors to refine the conceptualisation of how national governments can enhance social and economic value through a focus on the UN SDGs and their approach to accounting, accountability and governance.

Practical implications

The findings have implications: for national governments in developing approaches to achieve sustainable development; and, for supranational bodies such as the UN in developing agreements, frameworks and guidance for national governments.

Originality/value

Building on the extant literature about how global governance should be engaged to improve accountability in achieving the SDGs, the conceptual framework developed through the study shifts focus to national governance and accountability, and provides a blueprint for national governments to create value for the economy and society in the face of global sustainable development issues.
Effect of psychological capital on customer value cocreation behavior: the mediating role of employees' innovative behavior
Authors: Farrukh Muhammad , Ansari Nabeel Younus
Published: March 2021

Purpose

Customer value cocreation (VCC) behavior is gaining increased scholarly attention in the services marketing discipline and has become a top research priority in recent times. Despite the growing interest in studying VCC, less scholarly attention has been paid to study the crucial role of frontline service employees in activating customer participation in the VCC process. Hence, to bridge this research gap, the present research expanded VCC research streams by investigating the mediating effect of frontline service employees' innovative behavior in psychological capital and customer VCC behavior relationship.

Design/methodology/approach

Data collected from 255 hotel employee–customer dyads were analyzed through Smart PLS to measure the proposed relationships.

Findings

The results suggest the mediating effect of frontline service employees' innovative behavior in psychological capital and customer VCC behavior relationship.

Originality/value

The current research made a significant contribution to the VCC field by identifying driving forces that encourage customers to exhibit VCC behaviors.