bluuebunny/crossref_metadata_2025 huggingface dataset:
Occurrence of 4 Dengue Virus Serotypes and Chikungunya Virus in Kilombero Valley, Tanzania, During the Dengue Outbreak in 2018
Authors: Chipwaza Beatrice , Sumaye Robert David , Weisser Maja , Gingo Winfrid , Yeo Nicholas Kim-Wah , Amrun Siti Naqiah , Okumu Fredros O , Ng Lisa F P
Published: December 2020

Background

Dengue and Chikungunya viruses can cause large-scale epidemics, with attack rates of up to 80%. In Tanzania, there have been repeated outbreaks of dengue fever, the most recent in 2018 and 2019, mostly affecting the coastal areas. Despite the importance of these viruses, there is limited knowledge on the epidemiology of dengue (DENV) and Chikungunya (CHIKV) in Tanzania. This study was conducted to investigate the prevalence of DENV and CHIKV in Kilombero Valley, Tanzania.

Methods

A cross-sectional study was conducted at Kibaoni Health Center in Kilombero Valley, Southeastern Tanzania, in the rainy and dry seasons of 2018. Febrile patients of any age and gender were enrolled from the outpatient department. Blood samples were taken and screened for DENV and CHIKV viral RNA by real-time reverse transcription polymerase chain reaction assays.

Results

Overall, 294 patients were recruited. Most were females (65%), and one-third of patients were aged 14–25 years. DENV and CHIKV were detected in 29 (9.9%) and 3 (1.0%) patients, respectively. DENV was detected across all age groups during both the dry and rainy seasons. Although all 4 DENV serotypes were detected, serotypes 1 and 3 dominated and were present in 14 patients (42.4%) each. Additionally, the study showed DENV-1 and DENV-3 co-infections.

Conclusions

This study reveals the co-circulation of all 4 DENV serotypes and CHIKV in Kilombero. Importantly, we report the first occurrence of DENV-4 in Tanzania. Unlike previous DENV outbreaks caused by DENV-2, the 2018 outbreak was dominated by DENV-1 and DENV-3. The occurrence of all serotypes suggests the possibility of severe clinical outcomes in future DENV epidemics in Tanzania.
Risk of Clinical Severity by Age and Race/Ethnicity Among Adults Hospitalized for COVID-19—United States, March–September 2020
Authors: Pennington Audrey F , Kompaniyets Lyudmyla , Summers April D , Danielson Melissa L , Goodman Alyson B , Chevinsky Jennifer R , Preston Leigh Ellyn , Schieber Lyna Z , Namulanda Gonza , Courtney Joseph , Strosnider Heather M , Boehmer Tegan K , Mac Kenzie William R , Baggs James , Gundlapalli Adi V
Published: December 2020

Background

Older adults and people from certain racial and ethnic groups are disproportionately represented in coronavirus disease 2019 (COVID-19) hospitalizations and deaths.

Methods

Using data from the Premier Healthcare Database on 181 813 hospitalized adults diagnosed with COVID-19 during March–September 2020, we applied multivariable log-binomial regression to assess the associations between age and race/ethnicity and COVID-19 clinical severity (intensive care unit [ICU] admission, invasive mechanical ventilation [IMV], and death) and to determine whether the impact of age on clinical severity differs by race/ethnicity.

Results

Overall, 84 497 (47%) patients were admitted to the ICU, 29 078 (16%) received IMV, and 27 864 (15%) died in the hospital. Increased age was strongly associated with clinical severity when controlling for underlying medical conditions and other covariates; the strength of this association differed by race/ethnicity. Compared with non-Hispanic White patients, risk of death was lower among non-Hispanic Black patients (adjusted risk ratio, 0.96; 95% CI, 0.92–0.99) and higher among Hispanic/Latino patients (risk ratio [RR], 1.15; 95% CI, 1.09–1.20), non-Hispanic Asian patients (RR, 1.16; 95% CI, 1.09–1.23), and patients of other racial and ethnic groups (RR, 1.13; 95% CI, 1.06–1.21). Risk of ICU admission and risk of IMV were elevated among some racial and ethnic groups.

Conclusions

These results indicate that age is a driver of poor outcomes among hospitalized persons with COVID-19. Additionally, clinical severity may be elevated among patients of some racial and ethnic minority groups. Public health strategies to reduce severe acute respiratory syndrome coronavirus 2 infection rates among older adults and racial and ethnic minorities are essential to reduce poor outcomes.
North American Breeding Bird Survey status and trend estimates to inform a wide range of conservation needs, using a flexible Bayesian hierarchical generalized additive model
Authors: Smith Adam C , Edwards Brandon P M
Published: December 2020

The status and trend estimates derived from the North American Breeding Bird Survey (BBS) are critical sources of information for bird conservation. However, the estimates are partly dependent on the statistical model used. Therefore, multiple models are useful because not all of the varied uses of these estimates (e.g., inferences about long-term change, annual fluctuations, population cycles, and recovery of once-declining populations) are supported equally well by a single statistical model. Here we describe Bayesian hierarchical generalized additive models (GAMs) for the BBS, which share information on the pattern of population change across a species’ range. We demonstrate the models and their benefits using data from a selection of species, and we run full cross-validation of the GAMs against 2 other models to compare the predictive fit. The GAMs have a better predictive fit than the standard model for all species studied here and comparable predictive fit to an alternative first difference model. In addition, one version of the GAM described here (GAMYE) estimates a population trajectory that can be decomposed into a smooth component and the annual fluctuations around that smooth component. This decomposition allows trend estimates based only on the smooth component, which are more stable between years and are therefore particularly useful for trend-based status assessments, such as those by the International Union for the Conservation of Nature. It also allows for the easy customization of the model to incorporate covariates that influence the smooth component separately from those that influence annual fluctuations (e.g., climate cycles vs. annual precipitation). For these reasons and more, this GAMYE model is a particularly useful model for the BBS-based status and trend estimates.
The Equivalence of Definitions of Algorithmic Randomness†
Authors: Porter Christopher
Published: December 2020

In this paper, I evaluate the claim that the equivalence of multiple intensionally distinct definitions of random sequence provides evidence for the claim that these definitions capture the intuitive conception of randomness, concluding that the former claim is false. I then develop an alternative account of the significance of randomness-theoretic equivalence results, arguing that they are instances of a phenomenon I refer to as schematic equivalence. On my account, this alternative approach has the virtue of providing the plurality of definitions of randomness with conceptual unity and a rationale for certain investigations that are carried out in the field.
Spatial patterns in planktonic cnidarian distribution in the western boundary current system of the tropical South Atlantic Ocean
Authors: Tosetto Everton Giachini , Bertrand Arnaud , Neumann-Leitão Sigrid , Costa da Silva Alex , Nogueira Júnior Miodeli
Published: December 2020

In marine western boundary systems, strong currents flowing coastward spread oceanic water masses over the continental shelves. Here we propose to test the hypothesis according to which oceanic cnidarian species may dominate western boundary system regions even in coastal waters. For that purpose we use a set of data collected above the shelf, slope and around oceanic seamounts and islands in the Western Tropical South Atlantic. Samples were acquired with a plankton net with 300 μm mesh size over 34 stations during an oceanographic cruise carried out in October 2015. Results reveal a diverse cnidarian assemblage in the area, extending the known distribution of many species. In addition, the Fernando de Noronha Chain and most of the narrow continental shelf presented a typical oceanic cnidarian community, dominated by holoplanktonic siphonophores. In this western boundary system, this condition was likely driven by the strong currents, which carry the oceanic tropical water and associated planktonic fauna toward the coast. A specific area with reduced influence of oceanic currents presented typical coastal species. The pattern we observed with the dominance of oceanic plankton communities up to coastal areas may be typical in western boundary systems characterized by a narrow continental shelf.
D5-brane on topological black holes
Authors: Nagasaki Koichi
Published: December 2020

Our interest is in finding the difference in behavior between black holes with three different topologies. These black holes have spherical, hyperbolic and toroidal structures. We study in this paper the behavior of probe D5-branes in this nontrivial black hole spacetime. We would like to find the solution that describes the embedding of a probe D5-brane. This system realizes an “interface” solution, a kind of non-local operators, on the boundary gauge theories. These operators are important to deepen understanding of AdS/CFT correspondence.
Portfolio Liquidity and Security Design with Private Information
Authors: DeMarzo Peter M , Frankel David M , Jin Yu
Published: December 2020

A privately informed seller seeks to liquidate a portfolio to raise cash. Each asset’s liquidity thus depends on the impact of its sale on the value of the entire portfolio. We demonstrate the importance of cross-signaling and derive sufficient conditions for a liquidity “pecking order” that determines the order of sale. For assets backed by a common pool, liquidity naturally aligns with seniority. Finally, we extend the portfolio liquidation game to consider security design and demonstrate the optimality of pooling securities and selling senior tranches or debt secured by the pool, with retention increasing in asset quality or informational asymmetry.
Comparison of a Point-of-Care Testing with Enzyme-Multiplied Immunoassay Technique and Liquid Chromatography Combined With Tandem Mass Spectrometry Methods for Therapeutic Drug Monitoring of Mycophenolic Acid: A Preliminary Study
Authors: Zhou Hong , Xiang Hongping , Cai Jie , Wang Yirong , Zhang Min , Han Yong , Zhang Yu
Published: December 2020

Background:

For mycophenolic acid (MPA), therapeutic drug monitoring is an essential tool for dosage optimization in transplant recipients and autoimmune diseases. In China, a new commercial kit using an immunochromatographic assay (FICA) with a point-of-care testing system was approved for therapeutic drug monitoring of MPA. However, corroboration between FICA and clinically used assays remains unknown. The authors evaluated MPA concentrations in heart transplant recipients obtained by FICA, high-performance liquid chromatography combined with tandem mass spectrometry (LC-MS/MS), and enzyme-multiplied immunoassay technique (EMIT).

Methods:

Nine heart transplant recipients administered a single mycophenolate mofetil (MMF) dose, and 4 administered multiple MMF doses were enrolled. MPA samples were collected before administration, and after 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours, and assessed by 2 immunoassays (EMIT and FICA) and LC-MS/MS. Consistency between methods was evaluated using Passing–Bablok regression and Bland–Altman analysis.

Results:

For Passing–Bablok regression between FICA and LC-MS/MS, FICA = 0.784 LC-MS/MS + 0.360 (95% CI slope: 0.739 to 0.829, 95% CI intercept: 0.174–0.545). Regardless of a significant observed correlation coefficient (R2 = 0.9126), statistical analyses revealed a significant difference between FICA and the reference LC-MS/MS method. The mean absolute bias was 0.69 mcg/mL between FICA and LC-MS/MS. Bland–Altman plots showed a mean bias of −0.23 mcg/mL (±1.96 SD, −2.19 to 1.72 mcg/mL) and average relative bias of 14.73% (±1.96 SD, −67.91% to 97.37%) between FICA and LC-MS/MS. Unsatisfactory consistency was observed between EMIT and LC-MS/MS, and FICA and EMIT. Differences between pharmacokinetic parameters after a single or 7 days of MMF administration, by LC-MS/MS and FICA, were not statistically significant.

Conclusions:

The consistency of the new FICA using a point-of-care testing device with LC-MS/MS and EMIT was inadequate, and the accuracy of EMIT and LC-MS/MS was inappropriate. Clinicians should be informed when switching MPA detection methods to avoid misleading results.
Identification of potential core genes in hepatoblastoma via bioinformatics analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya , Kotturshetti Iranna
Published: December 2020

Hepatoblastoma is the childhood liver cancer. Profound efforts have been made to illuminate the pathology, but the molecular mechanisms of hepatoblastoma are still not well understood. To identify the candidate genes in the carcinogenesis and progression of hepatoblastoma, microarray dataset GSE131329 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and pathway and Gene Ontology (GO) enrichment analysis were performed. The protein-protein interaction network (PPI), module analysis, target gene - miRNA regulatory network and target gene - TF regulatory network were constructed and analyzed. A total of 996 DEGs were identified, consisting of 499 up regulated genes and 497 down regulated genes. The pathway and Gene Ontology (GO) enrichment analysis of the DEGs include proline biosynthesis, superpathway of tryptophan utilization, chromosome organization and organic acid metabolic process. Twenty-four hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell cycle, chromosome organization, lipid metabolic process and oxidation-reduction process. Validation of hub genes showed that TP53, PLK1, AURKA, CDK1, ANLN, ESR1, FGB, ACAT1, GOT1 and ALAS1 may be involved in the carcinogenesis, invasion or recurrence of hepatoblastoma. In conclusion, DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the carcinogenesis and progression of hepatoblastoma, and provide candidate targets for diagnosis and treatment of hepatoblastoma.
Characteristics of SARS-CoV-2 Testing for Rapid Diagnosis of COVID-19 during the Initial Stages of a Global Pandemic
Authors: Guthrie Jennifer L. , Chen Allison J. , Budhram Dalton R. , Cronin Kirby , Peci Adriana , Nelson Paul , Mallo Gustavo V. , Broukhanski George , Murti Michelle , Majury Anna , Mazzulli Tony , Allen Vanessa G. , Patel Samir N. , Kus Julianne V. , Tran Vanessa , Gubbay Jonathan B.
Published: December 2020

Accurate SARS-CoV-2 diagnosis is essential to guide prevention and control of COVID-19. From January 11 – April 22, 2020, Public Health Ontario conducted SARS-CoV-2 testing of 86,942 specimens collected from 80,354 individuals, primarily using real-time reverse-transcription polymerase chain reaction (rRT-PCR) methods. We analyzed test results across specimen types and for individuals with multiple same-day and multi-day collected specimens. Nasopharyngeal compared to throat swabs had a higher positivity (8.8% vs. 4.8%) and an adjusted estimate 2.9 Ctlower (SE=0.5,p<0.001). Same-day specimens showed high concordance (98.8%), and the median Ctof multi-day specimens increased over time. Symptomatic cases had rRT-PCR results with an adjusted estimate 3.0 Ct(SE=0.5,p<0.001) lower than asymptomatic/pre-symptomatic cases. Overall test sensitivity was 84.6%, with a negative predictive value of 95.5%. Molecular testing is the mainstay of SARS-CoV-2 diagnosis and testing protocols will continue to be dynamic and iteratively modified as more is learned about this emerging pathogen.
Clinical practices underlie COVID-19 patient respiratory microbiome composition and its interactions with the host
Authors: Lloréns-Rico Verónica , Gregory Ann C. , Van Weyenbergh Johan , Jansen Sander , Van Buyten Tina , Qian Junbin , Braz Marcos , Menezes Soraya Maria , Van Mol Pierre , Vanderbeke Lore , Dooms Christophe , Gunst Jan , Hermans Greet , Meersseman Philippe ,   CONTAGIOUS collaborators, Wauters Els , Neyts Johan , Lambrechts Diether , Wauters Joost , Raes Jeroen
Published: December 2020

Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the respiratory microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 respiratory microbiome studies by analyzing the upper (n=58) and lower (n=35) respiratory tract microbiome in well-phenotyped COVID-19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling. We found that time in the intensive care unit and the type of oxygen support, both of which are associated to additional treatments such as antibiotic usage, explained the most variation within the upper respiratory tract microbiome, while SARS-CoV-2 viral load had a reduced impact. Specifically, mechanical ventilation was linked to altered community structure, lower species- and higher strain-level diversity, and significant shifts in oral taxa previously associated with COVID-19. Single-cell transcriptomic analysis of the lower respiratory tract of mechanically ventilated COVID-19 patients identified specific oral bacteria, different to those observed in controls. These oral taxa were found physically associated with proinflammatory immune cells, which showed higher levels of inflammatory markers. Overall, our findings suggest confounders are driving contradictory results in current COVID-19 microbiome studies and careful attention needs to be paid to ICU stay and type of oxygen support, as bacteria favored in these conditions may contribute to the inflammatory phenotypes observed in severe COVID-19 patients.
Association between Use of Qingfei Paidu Tang and Mortality in Hospitalized Patients with COVID-19: A national retrospective registry study
Authors: Zhang Lihua , Zheng Xin , Bai Xueke , Wang Qing , Chen Bowang , Wang Haibo , Lu Jiapeng , Hu Shuang , Zhang Xiaoyan , Zhang Haibo , Liu Jiamin , Shi Ying , Zhou Zhiye , Gan Lanxia , Li Xi , Li Jing
Published: December 2020

Background

Qingfei Paidu Tang (QPT), a formula of traditional Chinese medicine, which was suggested to be able to ease symptoms in patients with Coronavirus Disease 2019 (COVID-19), has been recommended by clinical guidelines and widely used to treat COVID-19 in China. However, whether it decreases mortality remains unknown.

Purpose

We aimed to explore the association between QPT use and in-hospital mortality among patients hospitalized for COVID-19.

Study design

A retrospective study based on a real-world database was conducted.

Methods

We identified patients consecutively hospitalized with COVID-19 in 15 hospitals from a national retrospective registry in China, from January through May 2020. Data on patients’ characteristics, treatments, and outcomes were extracted from the electronic medical records. The association of QPT use with mortality was evaluated using Cox proportional hazards models based on propensity score analysis.

Results

Of the 8939 patients included, 28.7% received QPT. The crude mortality was 1.2% (95% confidence interval [CI] 0.8% to 1.7%) among the patients receiving QPT and 4.8% (95% CI 4.3% to 5.3%) among those not receiving QPT. After adjustment for patient characteristics and concomitant treatments, QPT use was associated with a relative reduction of 50% in in-hospital mortality (hazard ratio, 0.50; 95% CI, 0.37 to 0.66 P <0.001). This association was consistent across subgroups by sex and age. Meanwhile, the incidence of acute liver injury (8.9% [95% CI, 7.8% to 10.1%]vs. 9.9% [95% CI, 9.2% to 10.7%]; odds ratio, 0.96 [95% CI, 0.81% to 1.14%], P =0.658) and acute kidney injury (1.6% [95% CI, 1.2% to 2.2%] vs. 3.0% [95% CI, 2.6% to 3.5%]; odds ratio, 0.85 [95% CI, 0.62 to 1.17], P =0.318) was comparable between patients receiving QPT and those not receiving QPT. The major study limitations included that the study was an observational study based on real-world data rather than a randomized control trial, and the quality of data could be affected by the accuracy and completeness of medical records.

Conclusions

QPT was associated with a substantially lower risk of in-hospital mortality, without extra risk of acute liver injury or acute kidney injury among patients hospitalized with COVID-19.
Motion prediction using electromyography and sonomyography for an individual with transhumeral limb loss
Authors: Engdahl Susannah , Dhawan Ananya , Lévay György , Bashatah Ahmed , Kaliki Rahul , Sikdar Siddhartha
Published: December 2020

Controlling multi-articulated prosthetic hands with surface electromyography can be challenging for users. Sonomyography, or ultrasound-based sensing of muscle deformation, avoids some of the problems of electromyography and enables classification of multiple motion patterns in individuals with upper limb loss. Because sonomyography has been previously studied only in individuals with transradial limb loss, the purpose of this study was to assess the feasibility of an individual with transhumeral limb loss using this modality for motion classification. A secondary aim was to compare motion classification performance between electromyography and sonomyography. A single individual with transhumeral limb loss created two datasets containing 11 motions each (individual flexion of each finger, thumb abduction, power grasp, key grasp, tripod, point, pinch, wrist pronation). Electromyography or sonomyography signals associated with every motion were acquired and cross-validation accuracy was computed for each dataset. While all motions were usually predicted successfully with both electromyography and sonomyography, the cross-validation accuracies were typically higher for sonomyography. Although this was an exploratory study, the results suggest that controlling an upper limb prosthesis using sonomyography may be feasible for individuals with transhumeral limb loss.
Association of MRI-measured cerebral ventricular volume with APOE ε4 genotype, cerebrospinal fluid biomarkers (Aβ42 and Tau) and neuropsychological measures in Alzheimer’s disease: A Systematic Review
Authors: Piersson Albert Dayor , Mohamad Mazlyfarina , Rajab Fadilah , Suppiah Subapriya
Published: December 2020

Rationale and Objectives

Although neuroimaging studies suggest that the cerebral ventricle is independently associated with APOE ε4, cerebrospinal fluid (CSF) biomarkers, and neuropsychological scores in aging and Alzheimer’s disease (AD), there is no formal synthesis of these findings. We summarized the association of ventricular changes with APOE ε4, CSF biomarkers, and neuropsychological measures.

Materials and Methods

The Preferred Reporting Items for Systematic reviews and Meta-Analyses guideline was used. PubMed, Scopus, Ovid, Cochrane, and grey literature were searched, and assessment of eligible articles was conducted using the Newcastle-Ottawa Scale.

Results

24 studies met the inclusion criteria. Progressive ventricular volume is increased in AD patients at an average volume of 4.4 – 4.7 cm3/ year compared to average volumes of 2.7 – 2.9 cm3/ year and 1.1 – 1.4 cm3/year for patients with MCI and healthy controls (HCs) respectively. The ventricular volume is estimated to increase by 1.7 cm3/year for progression from MCI to AD. APOE ε4 is an independent risk factor for ventricular enlargement in aging and dementia, with AD patients most affected. The combination of CSF Aβ42 with ventricular volume compared to tau is more robust, for tracking the progression of the AD continuum. Further, the combination of ventricular volume with mini-mental state examination (MMSE) scores is the most robust for differentiating AD and MCI from HCs and tracking the progression of the disease.

Conclusion

The combination of ventricular volume with APOE ε4, CSF Aβ42, and MMSE scores independently may be potentially useful biomarkers for differentiating and tracking the progression of AD.
The importance of continued non-pharmaceutical interventions during the upcoming SARS-COV-2 vaccination campaign
Authors: Galanti Marta , Pei Sen , Yamana Teresa K. , Angulo Frederick J. , Charos Apostolos , Swerdlow David L. , Shaman Jeffrey
Published: December 2020

In this communication we assess the potential benefit of SARS-COV-2 pandemic vaccination in the US and show how continued use of non-pharmaceutical interventions (NPIs) will be crucial during implementation.
Support and follow-up needs of patients discharged from Intensive Care after severe COVID-19: a mixed-methods study of the views of UK general practitioners and intensive care staff during the pandemic’s first wave
Authors: Castro-Avila Ana , Jefferson Laura , Dale Veronica , Bloor Karen
Published: December 2020

Background

After discharge from an intensive care unit(ICU), over 50% of patients face significant physical, mental and cognitive problems. The COVID-19 pandemic has resulted in a large cohort of these patients who will need follow-up services that can address their support needs.

Objectives

To identify follow-up services planned for COVID-19 patients discharged from ICU, and to explore the views of ICU staff and General Practitioners(GPs) regarding these patients’ future needs and care coordination.

Design

Sequential mixed-methods UK study. We explored usual follow-up practice after ICU discharge and changes in follow-up during the pandemic through a survey of ICU staff, and GP awareness of follow-up and support needs of patients discharged from ICU through a survey of GPs. Through these surveys, we identified participants for semi-structured interviews with both groups.

Results

We obtained 170 survey responses and conducted 23 interviews. Over 60% of GPs were unaware of the follow-up services generally provided by their local hospitals, and whether or not these were functioning during the pandemic. Eighty percent of ICUs reported some form of follow-up services, with 25% of these suspending provision during the peak of the pandemic, and over half modifying their provision (usually to provide the service remotely). Complex funding streams, poor communication between primary and secondary care, and lack of clarity about who was responsible for referrals and follow-up were the most common problems identified. Discharge documentation was described as poor and lacking key information. Both groups mentioned difficulties accessing services in the community.

Conclusions

The pandemic has highlighted long-standing issues of continuity of care and complex funding streams for post-ICU follow-up care. The large cohort of ICU patients admitted due to COVID-19 highlights the need for improved follow-up services and communication between specialists and GPs, not only for COVID-19 patients, but for all those discharged from ICU.

Article Summary

Strengths and limitations of this study

This is the first study exploring NHS staff views of post-ICU follow-up services to support patients recovering from severe COVID-19.

Responses to our survey had good geographic spread but were limited in number and relied on volunteers.

GP interviews were small in number, but our findings align with those of larger studies conducted before the pandemic.
Pseudomonas putidagroup species serve as reservoirs of conjugative plasmids disseminating Tn402-like class 1 integrons carryingblaVIM-2metallo-β-lactamase genes
Authors: Brovedan Marco A. , Marchiaro Patricia M. , Díaz María S. , Faccone Diego , Corso Alejandra , Pasteran Fernando , Viale Alejandro M. , Limansky Adriana S.
Published: December 2020

ThePseudomonas putidagroup (P. putidaG) is composed of at least 21 species associated to a wide range of environments, including the clinical setting. Here, we characterized 13 carbapenem-resistantP. putidaG clinical isolates carryingblaVIM-2from different hospitals of Argentina. Multilocus sequencing (MLSA) and phylogenetic analyses based on the 16S rDNA,gyrBandrpoDsequences comparison allowed us to assign them to 7 well-differentiated species. Sequencing analysis revealed thatblaVIM-2genes were carried in these isolates by three different class 1 integrons (In41, In899and In528) embedded into Tn402-like transposons. Those harboring In41and In899were designated Tn6335and Tn6336, respectively, with the former found among 10 isolates. Both encompassed complete transposition modules and inverted repeats boundaries characteristic of the Tn5053/Tn402family, whereas the third, bearing In528, exhibited a defectivetnimodule. Tn6335and Tn6336were located in conjugative pLD209-type plasmids inP. asiatica, P. juntendi, P. putidaG/II, andP. putidaG/V isolates, and could be mobilized toEscherichia coliandP. aeruginosaindicating a relevant mechanism ofblaVIM-2dissemination. In otherP. asiaticaandP. putidaG/II isolates, Tn6335was found inserted into the Tn21subgroup transposons-resregion, indicating capability for intragenomic mobilization and further dissemination associated to Tn3family transposons. The Tn402-like defective element was also found inserted into theresregion of another Tn3family transposon in aP. monteiliiisolate, but in an atypical orientation. Overall findings shed light on the mechanisms by which resistance genes move through environmental and opportunistPseudomonasspecies.
Single point mutations can potentially enhance infectivity of SARS-CoV-2 revealed by in silico affinity maturation and SPR assay
Authors: Xue Ting , Wu Weikun , Guo Ning , Wu Chengyong , Huang Jian , Lai Lipeng , Liu Hong , Li Yalun , Wang Tianyuan , Wang Yuxi
Published: December 2020

The RBD (receptor binding domain) of the SARS-CoV-2 virus S (spike) protein mediates the viral cell attachment and serves as a promising target for therapeutics development. Mutations on the S-RBD may alter its affinity to cell receptor and affect the potency of vaccines and antibodies. Here we used an in-silico approach to predict how mutations on RBD affect its binding affinity to hACE2 (human angiotensin-converting enzyme2). The effect of all single point mutations on the interface was predicted. SPR assay result shows that 6 out of 9 selected mutations can strengthen binding affinity. Our prediction has reasonable agreement with the previous deep mutational scan results and recently reported mutants. Our work demonstrated in silico method as a powerful tool to forecast more powerful virus mutants, which will significantly benefit for the development of broadly neutralizing vaccine and antibody.
TCR meta-clonotypes for biomarker discovery with tcrdist3: identification of public, HLA-restricted SARS-CoV-2 associated TCR features
Authors: Mayer-Blackwell Koshlan , Schattgen Stefan , Cohen-Lavi Liel , Crawford Jeremy Chase , Souquette Aisha , Gaevert Jessica A. , Hertz Tomer , Thomas Paul G. , Bradley Philip , Fiore-Gartland Andrew
Published: December 2020

As the mechanistic basis of adaptive cellular antigen recognition, T cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages antigen-enriched repertoires to form meta-clonotypes – groups of biochemically similar TCRs – that can be used to robustly identify and quantify functionally similar TCRs in bulk repertoires. We apply the framework to TCR data from COVID-19 patients, generating 1831 public TCR meta-clonotypes from the 17 SARS-CoV-2 antigen-enriched repertoires with the strongest evidence of HLA-restriction. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 patients that expressed the putative restricting HLA allele (FDR < 0.01), demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates flexible workflows for distance-based TCR repertoire analysis.
Influence of HLA class II polymorphism on predicted cellular immunity against SARS-CoV-2 at the population and individual level
Authors: Copley Hannah C , Gragert Loren , Leach Andrew R , Kosmoliaptsis Vasilis
Published: December 2020

Development of effective adaptive immune responses after coronavirus disease 2019 (COVID-19) and after vaccination against SARS-CoV-2 is predicated on recognition of viral peptides, presented in the context of HLA class II molecules, by CD4+T-cells. We capitalised on extensive high resolution HLA data deposited in the National Marrow Donor Program registry to obtain detailed information on human HLA haplotype frequencies of twenty five human populations and used a bioinformatics approach to investigate the role of HLA polymorphism on SARS-CoV-2 immunogenicity at the population and at the individual level. Within populations, we identify wide inter-individual variability in predicted CD4+T-cell reactivity against structural, non-structural and accessory SARS-CoV-2 proteins, according to expressed HLA genotype. However, we find similar potential for anti-SARS-CoV-2 cellular immunity at the population level, across all ethnic groups examined, suggesting that HLA polymorphism is unlikely to account for observed disparities in clinical outcomes after COVID-19 among different race and ethnic groups. We predict robust immune reactivity against SARS-CoV-2 Spike protein, the basis for the majority of current vaccination efforts, both at the population and individual level, despite significant variation in Spike-derived peptide presentation by individual HLA genotypes. Finally, we provide comprehensive maps of SARS-CoV-2 proteome immunogenicity accounting for population coverage in major ethnic groups. Our findings provide important insight on the potential role of HLA polymorphism on development of protective immunity after SARS-CoV-2 infection and after vaccination and a firm basis for further experimental studies in this field.
Differential Dynamic Behavior of Prefusion Spike Proteins of SARS Coronaviruses 1 and 2
Authors: Kumar Vivek Govind , Ogden Dylan S , Isu Ugochi H , Polasa Adithya , Losey James , Moradi Mahmoud
Published: December 2020

The coronavirus spike protein, which binds to the same human receptor in both SARS-CoV-1 and 2, has been implied to be a potential source of their differential transmissibility. However, the mechanistic details of spike protein binding to its human receptor remain elusive at the molecular level. Here, we have used an extensive set of unbiased and biased microsecond-level all-atom molecular dynamics (MD) simulations of SARS-CoV-1 and 2 spike proteins to determine the differential dynamic behavior of prefusion spike protein structure in the two viruses. Our results indicate that the active form of the SARS-CoV-2 spike protein is more stable than that of SARS-CoV-1 and the energy barrier associated with the activation is higher in SARS-CoV-2. Our results also suggest that not only the receptor binding domain (RBD) but also other domains such as the N-terminal domain (NTD) could play a role in the differential binding behavior of SARS-CoV-1 and 2 spike proteins.
The root of the transmissible cancer: first description of a widespreadMytilus trossulus-derived cancer lineage inM. trossulus
Authors: Skazina Maria , Odintsova Nelly , Maiorova Maria , Ivanova Angelina , Väinölä Risto , Strelkov Petr
Published: December 2020

Two lineages of bivalve transmissible neoplasia (BTN), BTN1 and BTN2, are known in blue musselsMytilus. Both lineages derive from the Pacific musselM. trossulusand are identified primarily by the unique genotypes of the nuclear gene EF1α. BTN1 is found in populations ofM. trossulusfrom the Northeast Pacific, while BTN2 has been detected in populations of otherMytilusspecies worldwide but not inM. trossulusitself. The aim of our study was to examine musselsM. trossulusfrom the Sea of Japan (Northwest Pacific) for the presence of BTN. Using hemocytology and flow cytometry of the hemolymph, we confirmed disseminated neoplasia in our specimens. Cancerous mussels possessed the unique BTN2 EF1α genotype and two mitochondrial haplotypes with different recombinant control regions, similar to that of common BTN2 lineages. This is the first report of BTN2 in its original host speciesM. trossuluspopulations in West Pacific may be the birthplace of BTN2 and a natural reservoir where it is maintained and whence it spreads worldwide. A comparison of all available BTN andM. trossulusCOI sequences suggests a common and recent, though presumably prehistoric origin of BTN2 diversity in populations ofM. trossulusoutside the Northeast Pacific.
Neural correlates of beauty retouching to enhance attractiveness of self-depictions in women
Authors: Ota Chisa , Nakano Tamami
Published: December 2020

Beauty filters, while often employed for retouching photos to appear more attractive on social media, when used in excess cause images to give a distorted impression. The neural mechanisms underlying this change in facial attractiveness according to beauty retouching level remain unknown. The present study used functional magnetic resonance imaging in women as they viewed photos of their own face or unknown faces that had been retouched at three levels: no, mild, and extreme. The activity in the nucleus accumbens (NA) exhibited a positive correlation with facial attractiveness, whereas amygdala activity showed a negative correlation with attractiveness. Even though the participants rated others’ faces as more attractive than their own, the NA showed increased activity only for their mildly retouched own face and the amygdala exhibited greater activation in the others’ faces condition than the own face condition. Moreover, amygdala activity was greater for extremely retouched faces than for unretouched or mildly retouched faces for both conditions. Frontotemporal and cortical midline areas showed greater activation for one’s own than others’ faces, but such self-related activation was absent when extremely retouched. These results suggest that neural activity dynamically switches between the NA and amygdala according to perceived attractiveness of one’s face.
Brain state-dependent cortico-hippocampal network dynamics are modulated by postnatal stimuli
Authors: Shinohara Yoshiaki , Koketsu Shinnosuke , Hirase Hajime , Ueki Takatoshi
Published: December 2020

Neurons in the cerebral cortex and hippocampus discharge synchronously in a brain state-dependent manner to transfer information. Published studies have highlighted the temporal coordination of neuronal activities between the hippocampus and a cortical area, however, how the spatial extent of cortex activity relates to hippocampal activity remains largely unknown. We imaged macroscopic cortical activity while recording hippocampal local field potentials in unanesthetized GCaMP-expressing transgenic mice. We found that cortical activity elevates before and after hippocampal sharp wave ripples (SWR). SWR-associated cortical activities occurred predominantly in vision-related regions including visual, retrosplenial and prefrontal cortex. While pre-SWR cortical activities were frequently observed in awake and sleep states, post-SWR cortical activity decreased significantly in sleep. During hippocampal theta oscillation states, phase-locked oscillations of calcium activity was observed throughout the entire cortex state. Environmental effects on cortico-hippocampal dynamics were also assessed by comparing mice reared in an enriched environment (ENR) or under isolated conditions (ISO). In both SWR and theta oscillations, mice reared in an isolated condition exhibited clearer brain state-dependent dynamics than those reared in an enriched environment. Our data demonstrate that the cortex and hippocampus exhibit heterogeneous activity patterns that characterize brain states, and postnatal experience plays a significant role in modulating these patterns.

Significant Statement

The hippocampus is a center for memory formation. However, the memory formed in the hippocampus is not stored forever, but gradually transferred into the cerebral cortex. As an underlying mechanism, phase-locked synchronized activities between the cortex and hippocampus has been hypothesized. However, spatio-temporal dynamics between hippocampus and whole cortical areas remained mostly unknown. We measured cortical calcium activities with hippocampal electroencephalogram (EEG) simultaneously, and found that the activities of widespread cortical areas are temporally associated with hippocampal EEG. The cortico-hippocampal dynamics is primarily regulated by animal awake/sleep state. Even if similar EEG patters were observed, temporal dynamics between the cortex and hippocampus exhibit distinct patterns between awake and sleep period. In addition, animals’ postnatal experience modulates the dynamics.
A quantitative model predicts how m6A reshapes the kinetic landscape of nucleic acid hybridization and conformational transitions
Authors: Liu Bei , Shi Honglue , Rangadurai Atul , Nussbaumer Felix , Chu Chia-Chieh , Erharter Kevin Andreas , Case David A. , Kreutz Christoph , Al-Hashimi Hashim M.
Published: December 2020

N6-methyladenosine (m6A) is a post-transcriptional modification that controls gene expression by recruiting proteins to RNA sites. The modification also slows biochemical processes through mechanisms that are not understood. Using NMR relaxation dispersion, we show that m6A pairs with uridine with the methylamino group in theanticonformation to form a Watson-Crick base pair that transiently exchanges on the millisecond timescale with a singly hydrogen-bonded low-populated (1%) mismatch-like conformation in which the methylamino group issyn.This ability to rapidly interchange between Watson-Crick or mismatch-like forms, combined with differentsyn:antiisomer preferences when paired (~1:100) versus unpaired (~10:1), explains how m6A robustly slows duplex annealing without affecting melting via two pathways in which isomerization occurs before or after duplex annealing. Our model quantitatively predicts how m6A reshapes the kinetic landscape of nucleic acid hybridization and conformational transitions, and provides an explanation for why the modification robustly slows diverse cellular processes.
Engineered pH-Sensitive Protein G / IgG Interaction
Authors: Jha Ramesh K. , Yankey Allison , Shabazz Kalifa , Naranjo Leslie , Velappan Nileena , Bradbury Andrew , Strauss Charlie E. M.
Published: December 2020

While natural protein-protein interactions have evolved to be induced by complex stimuli, rational design of interactions that can be switched-on-demand still remain challenging in the protein design world. Here, we demonstrate a computationally redesigned natural interface for improved binding affinity could further be mutated to adopt a pH switchable interaction. The redesigned interface of Protein G-IgG Fc domain, when incorporated with histidine and glutamic acid on Protein G (PrG-EHHE), showed a switch in binding affinity by 50-fold when pH was altered from mild acidic to mild basic. The wild type (WT) interface only showed negligible switch. The overall binding affinity at mild acidic pH for PrG-EHHE outperformed the WT PrG interaction. The new reagent PrG-EHHE will be revolutionary in IgG purification since the traditional method of using an extreme acidic pH for elution can be circumvented.

Abstract Figure
Modeling brain reorganization after hemispherectomy
Authors: Seoane Luis F , Solé Ricard
Published: December 2020

Brain reorganization after hemispherectomy (i.e. after the removal of a whole hemisphere) is perhaps the most remarkable example of large-scale brain plasticity. Most often patients survive and recover their skills. Functional traits located in the lost side (e.g. language areas) can sometimes be completely reassembled in the remaining hemisphere, which seamlessly takes on the additional processing burden. This demands drastic rearrangements, perhaps involving the readaptation of functionally and structurally diverse neural structures. We lack mathematical models of how this happens. We introduce a very simple model, based on self-organized maps, that provides a rationale to the clinical aftermath of the intervention, putative windows for recovery, and the origins and nature of observed thresholds for irreversible function loss. The implications for brain symmetry and potential scenarios in simulated pathologies, including efficient suggested treatments, are outlined.
A small increase inCHEK1activity leads to the arrest of the first zygotic division in human
Authors: Chen Beili , Guo Jianying , Wang Ting , Lee Qianhui , Ming Jia , Ding Fangfang , Li Haitao , Zhang Zhiguo , Li Lin , Cao Yunxia , Na Jie
Published: December 2020

The first mitotic division in mammalian zygotes is unique. The fertilized egg reactivates its cell cycle, and the maternal and paternal genomes start to reprogram to become totipotent. The first division is very sensitive to a range of perturbations, particularly the DNA damage, leading to the embryo's failure to enter the first mitosis. We discovered that a point mutation in the humanCHEK1gene resulted in an Arginine 442 to Glutamine change at the C-terminus of the CHEK1 protein.CHEK1R442Q mutation caused the zygote to arrest just before the first division. Heterozygote individuals appeared to be healthy except that the female carriers are infertile. Expressing the corresponding mouse mutant Chk1 protein in zygotes also caused arrest before the first mitosis. Treating Chk1 R442Q mouse zygotes with low concentrations of CHEK1 inhibitor enabled the embryos to overcome the cell cycle arrest and resume normal development. Our results revealed an unexpected zygote mitotic checkpoint, which is extremely sensitive to the CHEK1 kinase activity. The fine-tuning of the DNA damage checkpoint permits the arrested one-cell embryos to overcome the first mitotic block and develop into healthy animals. These findings have important implications in assisted human reproduction.
Extensive High-Order Complexes within SARS-CoV-2 Proteome Revealed by Compartmentalization-Aided Interaction Screening
Authors: Xu Weifan , Pei Gaofeng , Liu Hongrui , Wang Jing , Li Pilong
Published: December 2020

Bearing the largest single-stranded RNA genome in nature, SARS-CoV-2 utilizes sophisticated replication/transcription complexes (RTCs), mainly composed of a network of nonstructural proteins and nucleocapsid protein, to establish efficient infection. Here, we developed an innovative interaction screening strategy based on phase separationin cellulo, namelycompartmentalization ofprotein-proteininteractions incells (CoPIC). Utilizing CoPIC screening, we mapped the interaction network among RTC-related viral proteins. We identified a total of 47 binary interactions among 14 proteins governing replication, discontinuous transcription, and translation of coronaviruses. Further exploration via CoPIC led to the discovery of extensive ternary complexes composed of these components, which infer potential higher-order complexes. Taken together, our results present an efficient, and robust interaction screening strategy, and indicate the existence of a complex interaction network among RTC-related factors, thus opening up new opportunities to understand SARS-CoV-2 biology and develop therapeutic interventions for COVID-19.