bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between continuous Positive end-expiratory pressure (PEEP) values and occurrence of Pneumothorax and Pneumomediastinum in SARS-CoV2 patients during non-invasive ventilation with Helmet
Authors: Gidaro Antonio , Samartin Federica , Brambilla Anna M. , Cogliati Chiara , Ingrassia Stella , Banfi Francesco , Cupiraggi Viola , Bonino Cecilia , Schiuma Marco , Giacomelli Andrea , Rusconi Stefano , Currà Jaqueline , Brucato Antonio Luca , Salvi Emanuele
Published: September 2020

Background

Acute Hypoxemic Respiratory Failure is a common complication of SARS-CoV2 related pneumonia, for which non-invasive ventilation (NIV) with Helmet Continuous Positive Airway Pressure (CPAP) is widely used. The frequency of pneumothorax in SARS-CoV2 was reported in 0.95% of hospitalized patients in 6% of mechanically ventilated patients, and in 1% of a post-mortem case series.

Objectives

Aim of our retrospective study was to investigate the incidence of pneumothorax and pneumomediastinum (PNX/PNM) in SARS-CoV2 pneumonia patients treated with Helmet CPAP. Moreover, we examined the correlation between PNX/PNM and Positive end-expiratory pressure (PEEP) values.

Methods

We collected data from patients admitted to “Luigi Sacco” University Hospital of Milan from 2 February to 5 May 2020 with SARS-CoV2 pneumonia requiring CPAP. Patients, who need NIV with bi-level pressure or endotracheal intubation (ETI) for any reason except those who needed ETI after PNX/PNM, were excluded. Population was divided in two groups according to PEEP level used (≤10 cmH2O and >10 cmH20).

Results

154 patients were enrolled. In the overall population, 42 patients (27%) were treated with High-PEEP (>10 cmH2O), and 112 with Low-PEEP (≤10 cmH2O). During hospitalization 3 PNX and 2 PNM occurred (3.2%). Out of these five patients, 2 needed invasive ventilation after PNX and died. All the PNX/PNM occurred in the High-PEEP group (5/37 vs 0/112, p<0,001).

Conclusion

The incidence of PNX appears to be lower in SARS-CoV2 than SARS and MERS. Considering the association of PNX/PNM with high PEEP we suggest using the lower PEEP as possible to prevent these complications.
Exploring the utility of social-ecological and entomological risk factors for dengue infection as surveillance indicators in the dengue hyper-endemic city of Machala, Ecuador
Authors: Lippi Catherine A. , Stewart-Ibarra Anna M. , Endy Timothy P. , Abbott Mark , Cueva Cinthya , Heras Froilán , Polhemus Mark , Beltrán-Ayala Efraín , Ryan Sadie J.
Published: September 2020

The management of mosquito-borne diseases is a challenge in southern coastal Ecuador, where dengue is hyper-endemic and co-circulates with other arboviral diseases. Prior work in the region has explored social-ecological factors, dengue case data, and entomological indices. In this study, we bring together entomological and epidemiological data to describe links between social-ecological factors associated with risk of dengue transmission at the household level in Machala, Ecuador. Households surveys were conducted from 2014–2016 to assess the presence of adult Aedes aegypti (collected via aspiration) and to enumerate housing conditions, demographics, and mosquito prevention behaviors. Household-level dengue infection status was determined by laboratory diagnostics in 2014–2015. Logistic models and multimodel selection were used to identify social-ecological variables associated with household presence of female Ae. aegypti and household dengue infection status, respectively. We identified significant risk factors for household-level dengue infection reflecting household condition, including bamboo cane construction material, shaded patios, and adjacency to abandoned properties, while housing structures in good condition were identified as protective against dengue infection. Aedes aegypti presence was associated with a greater than average number people per household and interrupted water supply, but was not associated with household level dengue infections. Models of Ae aegypti presence were unstable, and not well resolved in ranking of competing models, suggesting that highly localized entomological surveillance indicators may not be indicative of risk in communities with hyperendemic dengue fever. These findings add to our understanding of the systems of mosquito-borne disease transmission in Machala, and in the larger region of southern Ecuador, aiding in the development of improved vector surveillance efforts, and targeted interventions.
Arm choice post-stroke is habitual rather than optimal in right-, but not in left-paretic individuals
Authors: Kim Sujin , Han Cheol E. , Kim Bokkyu , Winstein Carolee J. , Schweighofer Nicolas
Published: September 2020

In non-disabled individuals, arm choice in pointing movements depends on expected biomechanical effort, expected success, and a handedness bias. Following a stroke, is arm choice re-optimized to account for the decreased motor performance, or does it follow a pre-injury habitual pattern? Because premorbidly right-handed individuals with left hemiparesis generally use their affected arm less than those with right hemiparesis, we hypothesized that arm choice follows a more habitual pattern in right-than in left-hemiparetic individuals. Participants with mild to moderate chronic stroke who were right-handed before stroke performed pointing movements in both free- and forced-choice blocks, both under a no-time constraint condition and under a fast-time constraint condition designed to promote habitual choice. Mixed-effects models of arm choice revealed that expected effort and side of stroke predicted choices overall. However, expected success predicted choice in left-, but not of right-hemiparetic individuals. Furthermore, while left-hemiparetic individuals tended to avoid unsuccessful movements in the fast condition by selecting their non-paretic arm, right-hemiparetic individuals persevered in choosing their more affected arm. In addition, reaction times decreased in left-hemiparetic individuals between the no-time and the fast condition but showed no changes in right-hemiparetic individuals. Finally, arm choice in the no-time condition correlated with a clinical measure of spontaneous arm use for right-, but not for left-hemiparetic individuals. Our results thus show that, in premorbidly right-handed individuals with mild to moderate chronic stroke, arm choice is habitual in right-hemiparetic individuals, but shows a greater degree of optimality by taking account expected success in left-hemiparetic individuals.

New & Noteworthy

Although we are seldom aware of it, we constantly make decisions to use one arm or the other in our daily activities. Here, we study whether these decisions change following a chronic mild to moderate stroke that affects motor control. Our results show that chronic stroke survivors with a right hemiparesis make arm choice using a habitual strategy, while those with left hemiparesis re-optimize their choices to account for their impaired motor performance.
Increased amygdala volume and functional connectivity with cognitive control networks in chronic migraine
Authors: DeSouza Danielle D. , Krimmel Samuel R. , Sanjanwala Bharati M. , Peretz Addie , Menon Vinod , Seminowicz David A. , Cowan Robert P.
Published: September 2020

Objective

To characterize the role of the amygdala in episodic (EM) and chronic (CM) migraine, we evaluated amygdala volumes, functional connectivity (FC), and associations with clinical and affective measures.

Methods

Eighty-eight patients (44 with EM and 44 age- and sex-matched patients with CM) completed anatomical and resting-state functional MRI scans. Amygdala volumes and resting-state FC to three core large-scale cognitive control networks (default mode (DMN), salience (SN), central executive (CEN)) were compared between groups. Associations between amygdala volume and FC, measures of headache severity (frequency and intensity), and cognitive-affective measures (depression, anxiety, pain catastrophizing) were evaluated.

Results

Compared to EM, patients with CM had larger amygdala volume bilaterally. Headache frequency and intensity were associated with increased left and right amygdala volume, and depression was associated with increased right amygdala volume. Patients with CM also demonstrated increased left amygdala FC with the DMN, which across patients was related to headache frequency. Left amygdala FC to the SN was correlated with headache intensity while right amygdala FC to the CEN was correlated with pain catastrophizing.

Conclusion

Our findings reveal increased amygdala volume and FC with large-scale neurocognitive networks in patients with CM compared to EM. Aberrant amygdala volume and FC measures were associated with increased migraine severity, depression, and pain catastrophizing, pointing to a link between emotion and pain in migraine. Our findings provide novel insights into amygdala involvement in chronic migraine and may inform future interventions aimed at preventing the progression of both headache and its negative cognitive-affective symptoms.
Predicting Depression from Hearing Loss Using Machine Learning
Authors: Crowson Matthew G. , Franck Kevin H , Rosella Laura C. , Chan Timothy C. Y.
Published: September 2020

Background

Hearing loss is the most common sensory loss in humans and carries an enhanced risk of depression. No prior studies have attempted a contemporary machine learning approach to predict depression using subjective and objective hearing loss predictors.

Objective

To deploy supervised machine learning to predict scores on a validated depression scale using subjective and objective audiometric variables and other health determinant predictors.

Design

We used a large predictor set of health determinants to forecast individuals’ scores on a validated instrument to screen for the presence and severity of depression (PHQ-9). After model training, the relative influence of individual predictors on depression scores was stratified and analyzed.

Setting

National Health and Nutrition Examination Survey (NHANES) 2015-2016 database.

Patients

Adult survey participants.

Measurements

Model prediction error performance.

Results

The test-set mean absolute error was 3.03 (CI 95%: 2.91-3.14) and 2.55 (CI 95%: 2.48-2.62) on datasets with audiology-only predictors and all predictors, respectively, on the PHQ-9’s 27-point scale. Participants’ self-reported frustration when talking to members of family or friends due to hearing loss was the fifth-most influential of all predictors. Of the top ten most influential audiometric predictors, five were related to social contexts, two for significant noise exposure, two objective audiometric parameters, and one presence of bothersome tinnitus.

Conclusions

Machine learning algorithms can accurately predict PHQ-9 depression scale scores from NHANES data. The most influential audiometric predictors of higher scores on a validated depression scale were social dynamics of hearing loss and not objective Such models could be useful in predicting depression scale scores at the point-of-care in conjunction with a standard audiologic assessment.
SARS-CoV-2 Viral RNA Load Dynamics in the Nasopharynx of Infected Children
Authors: Kam Kai-qian , Thoon Koh Cheng , Maiwald Matthias , Chong Chia Yin , Soong Han Yang , Loo Liat Hui , Tan Natalie Woon Hui , Li Jiahui , Nadua Karen Donceras , Yung Chee Fu
Published: September 2020

It is important to understand the temporal trend of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load to estimate the transmission potential of children in schools and communities. We determined differences in SARS-CoV-2 viral load dynamics between nasopharyngeal samples of infected asymptomatic and symptomatic children. The daily cycle threshold values of SARS-CoV-2 in the nasopharynx of a cohort of infected children were collected for analysis. Among 17 infected children, 10 (58.8%) were symptomatic. Symptomatic children, when compared to asymptomatic children, had higher viral load (mean cycle threshold on day 7 of illness 28.6 versus 36.7, p = 0.02). Peak SARS-CoV-2 viral loads occured around days 2-3 of illness/days of diagnosis in infected children. After adjusting for the estimated date of infection, the higher SARS-CoV-2 viral loads in symptomatic children remained. We postulate that symptomatic SARS-CoV-2-infected children may have higher transmissibility than asymptomatic children. As peak viral load in infected children occurred in the early stage of illness, viral shedding and transmission in the pre-symptomatic phase probable. Our study highlights the importance of screening for SARS-CoV-2 in children with epidemiological risk factors, even when they are asymptomatic in order to improve containment of the virus in the community, including educational settings.

Key points

Symptomatic children had higher SARS-CoV-2 viral loads in the nasopharynx than asymptomatic children, which may indicate that symptomatic children have higher transmissibility.

Peak SARS-CoV-2 viral loads occurred early around 2-3 days post symptom onset iin children and therefore, pre-symptomatic transmission of the virus is probable.

Symptom based screening for SARS-CoV-2 may not be effective in diagnosing coronavirus disease 2019 (COVID-19) in children as a proportion of children may be asymptomatic or pauci-symptomatic.

Children with high epidemiological risk factors should be screened or isolated as they may be carriers of the virus and contribute to transmission.
Flagellar energetics from high-resolution imaging of beating patterns in tethered mouse sperm
Authors: Nandagiri Ashwin , Gaikwad Avinash S. , Potter David L. , Nosrati Reza , Soria Julio , O’Bryan Moira K. , Jadhav Sameer , Prabhakar Ranganathan
Published: September 2020

While much is known about the microstructure of sperm flagella, the mechanisms behind the generation of flagellar beating patterns by the axoneme are still not fully understood. We demonstrate a technique for investigating the energetics of flagella or cilia. We record the planar beating of tethered wildtype andCrisp2-knockout mouse sperm at high-speed and high-resolution and extract centerlines using digital image processing techniques. We accurately reconstruct beating waveforms using a Chebyshev-polynomial based Proper Orthogonal Decomposition of the centerline tangent-angle profiles. External hydrodynamic forces and the internal resistance from the passive flagellar material are calculated from the observed kinematics of the beating patterns using a Soft, Internally-Driven Kirchhoff-Rod (SIDKR) model. Energy conservation is employed to further compute the flagellar energetics. We thus obtain the distribution of mechanical power exerted by the dynein motors without any further assumptions about mechanisms regulating axonemal function. We find that, in both the mouse genotypes studied, a large proportion of the mechanical power exerted by the dynein motors is dissipated internally, within the passive structures of the flagellum and by the motors themselves. This internal dissipation is considerably greater than the hydrodynamic dissipation in the aqueous medium outside. The net power input from the dynein motors in sperm fromCrisp2-knockout mice is significantly smaller than in corresponding wildtype samples. The reduced power is correlated with slower beating and smaller amplitudes. These measurements of flagellar energetics indicate that the ion-channel regulating cysteine-rich secretory proteins (CRISPs) may also be involved in regulating mammalian sperm motility.
Identification of Lysine Isobutyrylation as A New Histone Modification Mark
Authors: Zhu Zhesi , Han Zhen , Halabelian Levon , Yang Xiangkun , Ding Jun , Zhang Nawei , Ngo Liza , Song Jiabao , Zeng Hong , He Maomao , Zhao Yingming , Arrowsmith Cheryl H. , Luo Minkui , Bartlett Michael G. , Zheng Y. George
Published: September 2020

Short-chain acylation of lysine residues in eukaryotic proteins are recognized as essential posttranslational chemical modifications (PTMs) that regulate cellular processes from transcription, cell cycle, metabolism, to signal transduction. Lysine butyrylation was initially discovered as a normal straight chain butyrylation (Knbu). Here we report its structural isomer, branched chain butyrylation, i.e. lysine isobutyrylation (Kibu), existing as a new PTM on nuclear histones. Uniquely, isobutyryl-CoA is derived from valine catabolism and branched chain fatty acid oxidation which is distinct from the metabolism of n-butyryl-CoA. Several histone acetyltransferases were found to possess lysine isobutyryltransferase activity, especially p300 and HAT1. We resolved the X-ray crystal structures of HAT1 in complex with isobutyryl-CoA that gleaned an atomic level insight into HAT-catalyzed isobutyrylation. RNA-Seq profiling revealed that isobutyrate greatly affected the expression of genes associated with many pivotal biological pathways. Our findings identify Kibu as a novel chemical modification mark in histones and suggest its extensive role in regulating epigenetics and cellular physiology.
Neither the availability of D2 nor CP43 limits the biogenesis of PSII in tobacco
Authors: Fu Han-Yi , Ghandour Rabea , Ruf Stephanie , Zoschke Reimo , Bock Ralph , Schöttler Mark Aurel
Published: September 2020

The pathway of photosystem II assembly is well understood and multiple auxiliary proteins supporting it have been identified. By contrast, little is known about rate-limiting steps controlling PSII biogenesis. In the green algaChlamydomonas reinhardtii, biosynthesis of the chloroplast-encoded D2 reaction center subunit (PsbD) limits PSII accumulation. To determine the importance of D2 synthesis for PSII accumulation in vascular plants and elucidate the contributions of transcriptional and translational regulation, the 5’-untranslated region ofpsbDwas modified via chloroplast transformation in tobacco. A drastic reduction inpsbDmRNA abundance resulted in a strong decrease of PSII content, impaired photosynthetic electron transport, and retarded growth under autotrophic conditions. Overexpression of thepsbDmRNA also increased transcript abundance ofpsbC(the CP43 inner antenna protein), which is co-transcribed withpsbD. Because translation efficiency remained unaltered, translation output ofpbsDandpsbCincreased with mRNA abundance. However, this did not result in increased PSII accumulation. The introduction of point mutations into the Shine-Dalgarno-like sequence or start codon ofpsbDdecreased translation efficiency without causing pronounced effects on PSII accumulation and function. These data show that neither transcription nor translation ofpsbDandpsbCare rate-limiting for PSII biogenesis in vascular plants, and that PSII assembly and accumulation in tobacco are controlled by different mechanisms than inChlamydomonas.

One sentence summary

PSII biogenesis in tobacco is neither limited by transcript accumulation nor translation ofpsbDandpsbC.
Engineered Trimeric ACE2 Binds and Locks “Three-up” Spike Protein to Potently Inhibit SARS-CoVs and Mutants
Authors: Guo Liang , Bi Wenwen , Wang Xinling , Xu Wei , Yan Renhong , Zhang Yuanyuan , Zhao Kai , Li Yaning , Zhang Mingfeng , Bao Xingyue , Cai Xia , Li Yutang , Qu Di , Jiang Shibo , Xie Youhua , Zhou Qiang , Lu Lu , Dang Bobo
Published: September 2020

SARS-CoV-2 enters cells via ACE-2, which binds the spike protein with moderate affinity. Despite a constant background mutational rate, the virus must retain binding with ACE2 for infectivity, providing a conserved constraint for SARS-CoV-2 inhibitors. To prevent mutational escape of SARS-CoV-2 and to prepare for future related coronavirus outbreaks, we engineered ade novotrimeric ACE2 (T-ACE2) protein scaffold that binds the trimeric spike protein with extremely high affinity (KD< 1 pM), while retaining ACE2 native sequence. T-ACE2 potently inhibits all tested pseudotyped viruses including SARS-CoV-2, SARS-CoV, eight naturally occurring SARS-CoV-2 mutants, two SARSr-CoVs as well as authentic SARS-CoV-2. The cryo-EM structure reveals that T-ACE2 can induce the transit of spike protein to “three-up” RBD conformation upon binding. T-ACE2 thus represents a promising class of broadly neutralizing proteins against SARS-CoVs and mutants.
Disrupting the ArcA regulatory network increases tetracycline susceptibility of TetREscherichia coli
Authors: Arrieta-Ortiz Mario L. , Pan Min , Kaur Amardeep , Srinivas Vivek , Dash Ananya , Immanuel Selva Rupa Christinal , Baliga Nitin S.
Published: September 2020

There is an urgent need for strategies to discover secondary drugs to prevent or disrupt antimicrobial resistance (AMR), which is causing >700,000 deaths annually. Here, we demonstrate that tetracycline resistant (TetR)Escherichia coliundergoes global transcriptional and metabolic remodeling, including down-regulation of tricarboxylic acid cycle and disruption of redox homeostasis, to support consumption of the proton motive force for tetracycline efflux. Targeted knockout of ArcA, identified by network analysis as a master regulator among 25 transcription factors of this new compensatory physiological state, significantly increased the susceptibility of TetRE. colito tetracycline treatment. A drug, sertraline, which generated a similar metabolome profile as thearcAknockout strain also synergistically re-sensitized TetRE. colito tetracycline. The potentiating effect of sertraline was eliminated upon knocking outarcA, demonstrating that the mechanism of synergy was through action of sertraline on the tetracycline-induced ArcA network in the TetRstrain. Our findings demonstrate that targeting mechanistic drivers of compensatory physiological states could be a generalizable strategy to re-sensitize AMR pathogens to lost antibiotics.
Immunogenicity studies of various experimental vaccines in chickens
Authors: Vaillant Angel Justiz , Akpaka Patrick E.
Published: September 2020

In this paper, the main objective was to raise chickens’ antibodies against three crucial public health microorganisms: the human immunodeficiency virus-1,Salmonellaspp, andStaphylococcus aureus. Immunogens were prepared from the said microorganisms. Chickens were vaccinated either orally or intramuscularly. After a booster immunization, mostly eggs were collected and assess for the presence of specific antibodies. The most important results were the production of a large amount of anti-HIV antibodies in chicken’s eggs, and also the synthesis of anti-protein A antibodies with the ability to inhibit the growth ofS. aureus in vitroand to serve as anti-anti-idiotypic antibodies with the capacity of neutralizing the original antigen. Enzyme-linked immune absorbent assays detected the presence of these antibodies as anti-Salmonella antibodies that were critical in reducing the bacterial load in the stomach and caeca compared with a control group. The vaccines were effective and safe, but more laboratory work, and economics have to be carried out to start a human trial.
PyClone-VI: Scalable inference of clonal population structures using whole genome data
Authors: Gillis Sierra , Roth Andrew
Published: September 2020

We describe PyClone-VI, a computationally efficient Bayesian statistical method for inferring the clonal population structure of cancers. Our proposed method is 10-100x times faster than existing methods, while providing results which are as accurate. We demonstrate the utility of the method by analyzing data from 1717 patients from PCAWG study and 100 patients from the TRACERx study. Software implementing our method is freely availablehttps://github.com/Roth-Lab/pyclone-vi.
PhosR enables processing and functional analysis of phosphoproteomic data
Authors: Kim Hani Jieun , Kim Taiyun , Hoffman Nolan J , Xiao Di , James David E , Humphrey Sean J , Yang Pengyi
Published: September 2020

Mass spectrometry (MS)-based phosphoproteomics has revolutionised our ability to profile phosphorylation-based signalling in cells and tissues on a global scale. To infer the action of kinases and signalling pathways in phosphoproteomic experiments, we present PhosR, a set of tools and methodologies implemented in a suite of R packages facilitating comprehensive analysis of phosphoproteomic data. By applying PhosR to both published and new phosphoproteomic datasets, we demonstrate capabilities in data imputation and normalisation using a novel set of ‘stably phosphorylated sites’, and in functional analysis for inferring active kinases and signalling pathways. In particular, we introduce a ‘signalome’ construction method for identifying a collection of signalling modules to summarise and visualise the interaction of kinases and their collective actions on signal transduction. Together, our data and findings demonstrate the utility of PhosR in processing and generating novel biological knowledge from MS-based phosphoproteomic data.
Adaptation of codon and amino acid use for translational functions in highly expressed cricket genes
Authors: Whittle Carrie A. , Kulkarni Arpita , Chung Nina , Extavour Cassandra G.
Published: September 2020

Background

For multicellular organisms, much remains unknown about the dynamics of synonymous codon and amino acid use in highly expressed genes, including whether their use varies with expression in different tissue types and sexes. Moreover, specific codons and amino acids may have translational functions in highly transcribed genes, that largely depend on their relationships to tRNA gene copies in the genome. However, these relationships and putative functions are poorly understood, particularly in multicellular systems.

Results

Here, we rigorously studied codon and amino acid use in highly expressed genes from reproductive and nervous system tissues (male and female gonad, somatic reproductive system, brain, ventral nerve cord, and male accessory glands) in the cricket Gryllus bimaculatus. We report an optimal codon, defined as the codon preferentially used in highly expressed genes, for each of the 18 amino acids with synonymous codons in this organism. The optimal codons were largely shaped by selection, and their identities were mostly shared among tissue types and both sexes. However, the frequency of optimal codons was highest in gonadal genes. Concordant with translational selection, a majority of the optimal codons had abundant matching tRNA gene copies in the genome, but sometimes obligately required wobble tRNAs. We suggest the latter may comprise a mechanism for slowing translation of abundant transcripts, particularly for cell-cycle genes. Non-optimal codons, defined as those least commonly used in highly transcribed genes, intriguingly often had abundant tRNAs, and had elevated use in a subset of genes with specialized functions (gametic and apoptosis genes), suggesting their use promotes the upregulation of particular mRNAs. In terms of amino acids, we found evidence suggesting that amino acid frequency, tRNA gene copy number, and amino acid biosynthetic costs (size/complexity) had all interdependently evolved in this insect model, potentially for translational optimization.

Conclusions

Collectively, the results strongly suggest that codon use in highly expressed genes, including optimal, wobble, and non-optimal codons, and their tRNAs abundances, as well as amino acid use, have been adapted for various functional roles in translation within this cricket. The effects of expression in different tissue types and the two sexes are discussed.
Comparative metagenomics evidence distinct trends of genome evolution between sponge-dwelling bacteria and their pelagic counterparts
Authors: Kelly Joseph B. , Carlson David , Low Jun Siong , Thacker Robert W.
Published: September 2020

Prokaryotic associations with sponges are among the oldest host-microbiome relationships on Earth. In this study, we investigated how bacteria from several phyla have independently adapted to the sponge interior by comparing metagenome-assembled genomes of sponge-dwelling and pelagic bacteria sourced from broad phylogenetic and geographic samplings. We discovered that sponge-dwelling bacteria have more energetically expensive genomes and share patterns of depletion and enrichment for functional categories of genes that evidence evolution towards lower pathogenicity. We also identified a new defining genomic characteristic of sponge-dwelling bacteria that is virtually absent from pelagic bacteria, the presence of cassettes that contain eukaryotic steroid biosynthesis genes. Collectively, these results illuminate the trends in genome evolution that are associated with a sponge-dwelling life history strategy and have implications for furthering our understanding of how sponge-microbial symbioses have persisted through deep evolutionary time.

Importance

Much attention has recently been devoted to investigating the evolution of microbes that live in symbiosis with sponge hosts using microbial metagenomic data. However, several biological questions regarding this symbiosis remain unanswered. Two questions that we address here are: 1) what are the long-term consequences of the symbiosis on the evolution of microbial symbiont genome size, protein content, and nucleotide content, and 2) how is the evolution of virulence in sponge-dwelling microbial symbionts, which generally undergo a mixed transmission modes (e.g. horizontal and vertical), related to long-term stability of the symbiosis? By employing the largest comparative metagenomic analysis to date in terms of host sponge species and geographic representation, we address these questions and provide further resolution into the evolutionary processes that are involved in mediating the crosstalk between sponge hosts and their microbial symbionts.
Characterization of neutralizing versus binding antibodies and memory B cells in COVID-19 recovered individuals from India
Authors: Nayak Kaustuv , Gottimukkala Kamalvishnu , Kumar Sanjeev , Reddy Elluri Seetharami , Edara Venkata Viswanadh , Kauffman Robert , Floyd Katharine , Mantus Grace , Savargaonkar Deepali , Goel Pawan Kumar , Arora Satyam , Rahi Manju , Davis Carl W , Linderman Susanne , Wrammert Jens , Suthar Mehul S , Ahmed Rafi , Sharma Amit , Murali-Krishna Kaja , Chandele Anmol
Published: September 2020

India is one of the countries most affected by the recent COVID-19 pandemic. Characterization of humoral responses to SARS-CoV-2 infection, including immunoglobulin isotype usage, neutralizing activity and memory B cell generation, is necessary to provide critical insights on the formation of immune memory in Indian subjects. In this study, we evaluated SARS-CoV-2 receptor-binding domain (RBD)-specific IgG, IgM, and IgA antibody responses, neutralization of live virus, and RBD-specific memory B cell responses in pre-pandemic healthy versus convalescent COVID-19 individuals from India. We observed substantial heterogeneity in the formation of humoral and B cell memory post COVID-19 recovery. While a vast majority (38/42, 90.47%) of COVID-19 recovered individuals developed SARS-CoV-2 RBD-specific IgG responses, only half of them had appreciable neutralizing antibody titers. RBD-specific IgG titers correlated with these neutralizing antibody titers as well as with RBD-specific memory B cell frequencies. In contrast, IgG titers measured against SARS-CoV-2 whole virus preparation, which includes responses to additional viral proteins besides RBD, did not show robust correlation. Our results suggest that assessing RBD-specific IgG titers can serve as a surrogate assay to determine the neutralizing antibody response. These observations have timely implications for identifying potential plasma therapy donors based on RBD-specific IgG in resource-limited settings where routine performance of neutralization assays remains a challenge.

Importance

Our study provides an understanding of SARS-CoV-2-specific neutralizing antibodies, binding antibodies and memory B cells in COVID-19 convalescent subjects from India. Our study highlights that PCR-confirmed convalescent COVID-19 individuals develop SARS-CoV-2 RBD-specific IgG antibodies, which correlate strongly with their neutralizing antibody titers. RBD-specific IgG titers, thus, can serve as a valuable surrogate measurement for neutralizing antibody responses. These finding have timely significance for selection of appropriate individuals as donors for plasma intervention strategies, as well as determining vaccine efficacy.
A versatile reporter system to monitor virus infected cells and its application to dengue virus and SARS-CoV-2
Authors: Pahmeier Felix , Neufeldt Christoper J , Cerikan Berati , Prasad Vibhu , Pape Costantin , Laketa Vibor , Ruggieri Alessia , Bartenschlager Ralf , Cortese Mirko
Published: September 2020

Positive-strand RNA viruses have been the etiological agents in several major disease outbreaks over the last few decades. Examples of that are flaviviruses, such as dengue virus and Zika virus that cause millions of yearly infections and spread around the globe, and coronaviruses, such as SARS-CoV-2, which is the cause of the current pandemic. The severity of outbreaks caused by these viruses stresses the importance of virology research in determining mechanisms to limit virus spread and to curb disease severity. Such studies require molecular tools to decipher virus-host interactions and to develop effective interventions. Here, we describe the generation and characterization of a reporter system to visualize dengue virus and SARS-CoV-2 replication in live cells. The system is based on viral protease activity causing cleavage and nuclear translocation of an engineered fluorescent protein that is expressed in the infected cells. We show the suitability of the system for live cell imaging and visualization of single infected cells as well as for screening and testing of antiviral compounds. Given the modular building blocks, the system is easy to manipulate and can be adapted to any virus encoding a protease, thus offering a high degree of flexibility.

IMPORTANCE

Reporter systems are useful tools for fast and quantitative visualization of viral replication and spread within a host cell population. Here we describe a reporter system that takes advantage of virus-encoded proteases that are expressed in infected cells to cleave an ER-anchored fluorescent protein fused to a nuclear localization sequence. Upon cleavage, the fluorescent protein translocates to the nucleus, allowing for rapid detection of the infected cells. Using this system, we demonstrate reliable reporting activity for two major human pathogens from theFlaviviridaeand theCoronaviridaefamilies: dengue virus and SARS-CoV-2. We apply this reporter system to live cell imaging and use it for proof-of-concept to validate antiviral activity of a nucleoside analogue. This reporter system is not only an invaluable tool for the characterization of viral replication, but also for the discovery and development of antivirals that are urgently needed to halt the spread of these viruses.
SARS-CoV-2 causes severe alveolar inflammation and barrier dysfunction
Authors: Deinhardt-Emmer Stefanie , Böttcher Sarah , Häring Clio , Giebeler Liane , Henke Andreas , Zell Roland , Hornung Franziska , Brandt Christian , Marquet Mike , Mosig Alexander S. , Pletz Mathias W. , Schacke Michael , Rödel Jürgen , Heller Regine , Nietzsche Sandor , Löffler Bettina , Ehrhardt Christina
Published: September 2020

Infections with SARS-CoV-2 lead to mild to severe coronavirus disease-19 (COVID-19) with systemic symptoms. Although the viral infection originates in the respiratory system, it is unclear how the virus can overcome the alveolar barrier, which is observed in severe COVID-19 disease courses.

To elucidate the viral effects on the barrier integrity and immune reactions, we used mono-cell culture systems and a complex human alveolus-on-a-chip model composed of epithelial, endothelial, and mononuclear cells.

Our data show that SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including the interferon expression. By contrast, the adjacent endothelial layer was no infected and did neither show productive virus replication or interferon release. With prolonged infection, both cell types are damaged, and the barrier function is deteriorated, allowing the viral particles to overbear.

In our study, we demonstrate that although SARS-CoV-2 is dependent on the epithelium for efficient replication, the neighboring endothelial cells are affected, e.g., by the epithelial cytokine release, which results in the damage of the alveolar barrier function and viral dissemination.
Remote Vision Testing: Validation Of A Simple Home-Printable Vision Screening Test for Telemedicine
Authors: Crossland Michael D , Dekker Tessa M , Hancox Joanne , Lisi Matteo , Wemyss Thomas A , Thomas Peter BM
Published: September 2020

Importance

Hundreds of thousands of ophthalmology clinic appointments have been converted to telemedicine assessments. Here we validate a simple paper vision test (the Home Acuity Test) for ophthalmology telemedicine appointments, which can be used by people who are digitally excluded.

Objective

To determine the repeatability of vision measured on the Home Acuity Test, and the agreement between the Home Acuity Test and the last in-clinic visual acuity.

Design

Bland-Altman analysis of the Home Acuity Test chart, compared to the last measured visual acuity on a standard clinical test.

Setting

Routine outpatient ophthalmology telemedicine clinics in a large specialist eye hospital.

Participants

50 control subjects with no eye disease and 100 consecutive adult ophthalmology outpatients from strabismus and low vision telemedicine clinics. Participants were excluded if they reported subjective changes in their vision.

Main outcomes and measures

For control participants, test/retest variability of the HAT and agreement with standard logMAR visual acuity measurement. For ophthalmology outpatients, agreement with the last recorded clinic visual acuity and with ICD-11 visual impairment category.

Results

50 control subjects and 100 ophthalmology patients with a wide range of disease were recruited. For control participants, Home Acuity Test test/retest variability was -0.012 logMAR (95% CI: -0.25 to 0.11 logMAR). Agreement with standard vision charts was -0.14 logMAR, with a 95% confidence interval of -0.39 to +0.12 logMAR. For ophthalmology outpatients, agreement in visual acuity was -0.10 logMAR (one line on a conventional logMAR sight chart), with the Home Acuity Test indicating poorer vision than the previous in-clinic test. The 95% confidence interval for difference was –0.44 to +0.24 logMAR. Agreement in visual impairment category was good for patients (Cohen’s k test, k = 0.77 (95% CI, 0.74 to 0.81), and control participants (Cohen’s k test, k = 0.88 (95% CI, 0.88 to 0.88).

Conclusions and relevance

The Home Acuity Test can be used to measure vision by telephone for a wide range of ophthalmology outpatients with diverse conditions, including those who are severely visually impaired. Test/retest variability is low and agreement in visual impairment category is good.
A neutrophil activation signature predicts critical illness and mortality in COVID-19
Authors: Meizlish Matthew L. , Pine Alexander B. , Bishai Jason D. , Goshua George , Nadelmann Emily R. , Simonov Michael , Chang C-Hong , Zhang Hanming , Shallow Marcus , Bahel Parveen , Owusu Kent , Yamamoto Yu , Arora Tanima , Atri Deepak S. , Patel Amisha , Gbyli Rana , Kwan Jennifer , Won Christine H. , Cruz Charles Dela , Price Christina , Koff Jonathan , King Brett A. , Rinder Henry M. , Wilson F. Perry , Hwa John , Halene Stephanie , Damsky William , Dijk David van , Lee Alfred I. , Chun Hyung J.
Published: September 2020

Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of over 3,300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, HGF, IL-8, and G-CSF, as the strongest predictors of critical illness. Neutrophil activation was present on the first day of hospitalization in patients who would only later require transfer to the intensive care unit, thus preceding the onset of critical illness and predicting increased mortality. In the health system database, early elevations in developing and mature neutrophil counts also predicted higher mortality rates. Altogether, we define an essential role for neutrophil activation in the pathogenesis of severe COVID-19 and identify molecular neutrophil markers that distinguish patients at risk of future clinical decompensation.
Convalescent plasma as potential therapy for severe COVID-19 pneumonia
Authors: Valentini Ricardo , Fernández José , Riveros Dardo , Pálizas Fernando , Solimano Jorge , Saúl Pablo , Medina Juan , Falasco Viviana , Dupont María Laura , Laviano Julia , Fornillo Florencia , Maymó Daniela , Gotta Daniel , Martinez Alfredo , Bonvehí Pablo , Dupont Juan
Published: September 2020

At the beginning of the COVID-19 pandemic, there was high mortality and a lack of effective treatment for critically ill patients. Build on the experience in argentine hemorrhagic fever with convalescent plasma, we incorporated 90 patients into a multicenter study, and 87 were evaluable. We collected 397 donations from 278 convalescent donors. Patients received plasma with an IgG concentration of 0.7-0.8 (measured by Abbott chemiluminescence) for every 10 kg of body weight. Survival during the first 28 days was the primary objective. 77% were male, age 54 ± 15.6 y/o (range 27-85); body mass index 29.7 ± 4,4; hypertension 39% and diabetes 20%; 19.5% had an immunosuppression condition; 23% were healthcare workers. Plasma was administered to 55 patients (63%) on spontaneous breathing with oxygen supplementation (mainly oxygen mask with reservoir bag in 80%), and 32 patients (37%) were infused on mechanical ventilation. The 28-day survival rate was 80%, with 91% in patients infused on spontaneous breathing and 63% in those infused on mechanical ventilation (p = 0.0002). There was a significant improvement in the WHO pneumonia clinical scale at 7 and 14 days, and in PaO2 / FiO2, ferritin and LDH, in the week post-infusion. We observed an episode of circulatory volume overload and a febrile reaction, both mild. Convalescent plasma infusions are feasible, safe, and potentially effective, especially before requiring mechanical ventilation, and are an attractive clinical option for treating severe forms of COVID-19 until other effective therapies become available.
Rapid evaluation of neutralizing antibodies in COVID-19 patients
Authors: Zhang Pingping , Li Baisheng , Min Wei , Wang Xiaohui , Li Zhencui , Zhao Yong , Zhang Huan , Jiang Min , Zheng Huanying , Yang Chao , Zhang Wei , Zuo Le , Gao Qi , Yang Zhengrong , Li Yanzhao , Feng Tiejian , Lin Changqing , Hu Qinghua , Song Tie , Yang Ruifu
Published: September 2020

The ongoing coronavirus disease 2019 (COVID-19) pandemic calls for a method to rapidly and conveniently evaluate neutralizing antibody (NAb) activity in patients. Here, an up-conversion phosphor technology-based point-of-care testing (UPT-POCT) and a microneutralization assay were employed to detect total antibodies against the receptor-binding domain of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) spike protein and NAb activity in COVID-19 patients’ sera, respectively, in order to determine if UPT-POCT could be used as a surrogate method for rapid evaluation of serum NAb activity in COVID-19 patients. In total, 519 serum samples from 213 recovered and 99 polymerase chain reaction re-positive (RP) COVID-19 patients were used in this report. We found that UPT-POCT reporting values correlated highly with NAb titers from 1:4 to 1:1024, with a correlation coefficientr= 0.9654 (P< 0.001), as well as protection rate against RP (r = 0.9886, P < 0.0001). As a significant point for reducing re-positive rate, UPT-POCT values of 4.380 ± 2.677, corresponding to NAb titer of 1:64, may be appropriate as an indicator for evaluating high efficiency of protection. This study demonstrates that the quantitative lateral flow based UPT-POCT, could be used to rapidly evaluate NAb titer, which is of importance for assessing vaccine immunization efficacy, herd immunity, and screening patient plasma for high NAbs.
Tumour volume distribution can yield information on tumour growth and tumour control
Authors: Schneider Uwe , Besserer Jürgen
Published: September 2020

Background

It is shown that tumour volume distributions, can yield information on two aspects of cancer research: tumour induction and tumour control.

Materials and methods

From the hypothesis that the intrinsic distribution of breast cancer volumes follows an exponential distribution, firstly the probability density function of tumour growth time was deduced via a mathematical transformation of the probability density functions of tumour volumes. In a second step, the distribution of tumour volumes was used to model the variation of the clonogenic cell number between patients in order to determine tumour control probabilities for radiotherapy patients.

Results

Distribution of lag times, i.e. the time from the appearance of the first fully malignant cell until a clinicaly observable cancer, can be used to deduce the probability of tumour induction as a function of patient age. The integration of the volume variation with a Poisson-TCP model results in a logistic function which explains population-averaged survival data of radiotherapy patients.

Conclusions

The inclusion of tumour volume distributions into the TCP formalism enables a direct link to be deduced between a cohort TCP model (logistic) and a TCP model for individual patients (Poisson). The TCP model can be applied to non-uniform tumour dose distributions.