bluuebunny/crossref_metadata_2025 huggingface dataset:
KLF5 is involved in Ang II‐induced VSMC proliferation through trans‐activating cyclin D1 expression
Authors: Liu Yu , Wen Jin‐kun , Zheng Bin , Meng Fang , Wang Chao , He Ming , Han Mei
Published: June 2021

Kr̈¹ ppel‐like transcription factor 5 (KLF5) plays key roles in regulating cell proliferation and differentiation. In this work, we reported that Ang II stimulated KLF5 expression with concurrent acceleration of the cell cycle progression in vascular smooth muscle cells (VSMCs). The overexpression of KLF5 also increased the expression of cyclin D1 and proliferation in VSMCs. Conversely, silencing KLF5 expression abrogated the inducing effects of Ang II on KLF5 and cyclin D1 expression, and neutralized the Ang II‐induced VSMC proliferation. KLF5 plays a crucial role in Ang II‐induced cyclin D1 expression and proliferation of VSMCs. Furthermore, we also showed that the Ang II stimulated the activity of KLF5 by inducing its phosphorylation mediated by the ERK 1/2 and p38 MAPK pathways. A specific interaction was found between KLF5 and c‐Jun, which enhances binding activity of the both proteins in cyclin D1 promoter, and consequently leads to a synergistic increase in the transcription of cyclin D1 gene that is important for cell cycle progression and cell proliferation. Cotransfection of KLF5 and c‐Jun expression vectors significantly increased the cyclin D1 promoter activity by over 5‐fold. These results indicate that KLF5 plays a positive regulatory effect on cell cycle progression and proliferation through trans‐activating cyclin D1 expression via synergistic interaction with c‐Jun in Ang II‐induced VSMCs.
Characterization of Plasmepsin 10 from the Malaria Parasite P. falciparum
Authors: Machhar Raj P. , Marzahn Melissa R. , Johnson Zachary L. , Beyer Carl A. , Soni Ashik
Published: June 2021

Malaria infection is caused by the protozoan parasite Plasmodium. Of the four forms of Plasmodium that infect humans, P. falciparum is the most deadly. Furthermore, chloroquine, the most popular anti‐malarial drug, is slowly becoming ineffective because of P. falciparum's growing resistance to it. This means that new anti‐malarial drugs need to be developed immediately to continue combating malaria across the globe and curb the perpetuation of P. falciparum.

P. falciparum genome encodes for ten aspartic proteases known as plasmepsins. The primary objective of my research project is to obtain active and purified plasmepsin 10 that can be used in kinetic assays and x‐ray crystallographic studies.

The protein was expressed in a recombinant bacterial system. Once the protein is purified, folded and active, kinetic assays can be performed to determine the kinetic parameters Km, Ki and Kcat. Next, optimal conditions for x‐ray crystallography are determined, and x‐ray crystallography is carried out to observe and analyze the enzyme‐inhibitor complex. This allows us to learn about the interactions between plasmepsin 10 and relevant inhibitors, along with the structural stability of the protein. This data will hopefully lead to a new anti‐malarial drug that could save the lives of millions of people every year.
Nitric Oxide Synthase: Catalytic Model for Reductase Function
Authors: Assan‐Mensah Issac B , Couser Laura M. , Dinsmore Natalie E. , Vogelien Dale L. , Lester Army , Smith Susan M.E. , Salerno John C.
Published: June 2021

The NOS reductase unit, comprising three C terminal domains, is closely related to homologs studied intensively for many years. Several groups proposed ping‐pong and two state ping‐pong models for NADPH P450 reductase (e.g., Sem and Kasper, 1994). These proposals were adapted to NOS (Wolthers and Schimerlik, 2002) and shown to describe the kinetics of NADPH cytochrome c reductase activity at low substrate concentrations.

We previously constructed a King‐Altman 'Ligand Restricted Conformational Shuttle' (LRCS) model based on an FMN domain shuttle in which cytochrome c interacts with FMN when the FMN binding domain is dissociated from the reductase complex. Here we show that this model explains details of NADPH cytochrome c reductase activity at high and low substrate concentrations without extra inhibitory weak binding sites. This includes potent substrate inhibition at high concentrations of cytochrome c as well as pseudo ping‐pong behavior at low substrate concentrations. The major effect of calmodulin binding on nNOS and eNOS reductase activities is to increase dissociation of the FMN binding domain, making it accessible to cytochrome c for electron transfer. Because of its size and specific interaction with the FMN binding domain, cytochrome c is a good model for NOS catalytic electron transfer. DCIP and ferricyanide reduction do not require similar large scale conformational change.
Outcomes of Various Antibiotic Cement–Coated Intramedullary Implants on the Treatment of Long Bone Septic Nonunion
Authors: Lopas Luke A. , Albertson Spencer , Solomon Eric , Watson David T. , Shah Anjan R. , Maxson Benjamin J. , Infante Anthony F. , Donohue David , Downes Katheryne L. , Sanders Roy W. , Mir Hassan R.
Published: June 2021

Objective:

To determine the effectiveness of various types of antibiotic-coated intramedullary implants in the treatment of septic long bone nonunion.

Design:

Retrospective chart review.

Setting:

Level 1 trauma center.

Participants:

Forty-one patients with septic long bone nonunion treated with an antibiotic cement–coated intramedullary implant.

Intervention:

Surgical debridement and placement of a type of antibiotic-coated intramedullary implant.

Main Outcome Measurements:

Union and need for reoperation.

Results:

At an average 27-month follow-up (6–104), 27 patients (66%) had a modified radiographic union score of the tibia of 11.5 or greater, 12 patients (29%) a score lower than 11.5, and 2 patients (5%) underwent subsequent amputation. Six patients underwent no further surgical procedures after the index operation. Patients treated with a rigid, locked antibiotic nail achieved earlier weight-bearing (P = 0.001), less frequently required autograft (P = 0.005), and underwent fewer subsequent procedures (average 0.38 vs. 3.60, P = 0.004) than those treated with flexible core antibiotic rods.

Conclusions:

Antibiotic-coated intramedullary implants are successful in the treatment of septic nonunions in long bones. In our cohort, rigid, statically locked nails allowed faster rehabilitation, decreased the need for autograft, and decreased the number of additional surgical procedures. Further study is needed to confirm these findings.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Efficacy of Percutaneous Retrograde Transphyseal Guided Growth Screw in Distal Femoral Angular Deformity Correction: A New Technique
Authors: Abdelaziz Ahmed , ElAshry Sameeh M. , Awadh Mohammad M. , Khaja Aliaa , Alsaifi Saleh
Published: June 2021

Background:

We modified the original technique for percutaneous transphyseal screw which was described in 1998 by Metaizeau and colleagues for distal femoral coronal angular deformity correction; the modification is related to the screw direction, whereas the screw is administered in a retrograde pattern, starting from the epiphysis and directed toward the metaphysis. This technique opposes the original technique that was started with a metaphyseal entry point which aimed toward the epiphysis. This study evaluates the efficacy of the newly suggested surgical technique regarding the rate of correction and growth resumption after screw removal.

Methods:

This prospective study looked at 40 patients (65 distal femoral physes), who underwent a percutaneous retrograde transphyseal guided growth screw procedure, from October 2017 to September 2019. All the patients included had distal femoral coronal angular deformities; 52 in valgus and 13 in varus deformities. The study included 17 females with an average age of 11.75 (range: 8.4 to 14.5 y) for 29 femurs and 23 males with an average age of 13.75 (range: 11.75 to 15.6 y) for 36 femurs. The mechanical lateral distal femoral angle was measured initially, and then again was measured after reaching the desired corrected orientation. The patients were then followed up after the screw removal and followed up to maturity, if the physis had continued to grow postcorrection. The degree of correction per month was calculated, and the consequence of screw removal was detected. Follow-up average time was 12.6 months (range: 30 to 6 mo).

Results:

The average correction in the distal femur was 1.3 degrees per month (range: 0.5 to 1.857 degrees/mo). In all of the 65 segments (61 femurs had significant growth remaining and 4 femurs had reached skeletal maturity with suboptimal mechanical lateral distal femoral angle correction), the screws were removed at the time of angular correction. Rebound growth was observed in 15 physes with an average of 1.8 degrees (range: 2 to 3 degrees); they were stable in 42 physes and progressed in 4 physes with an average of 1.6 degrees (range: 1 to 2 degrees). Complications were minor and related to entrapment of soft tissue under the screw washer.

Conclusion:

Percutaneous retrograde transphyseal guided growth screw for distal femur coronal angular deformity is a minimally invasive procedure, with a statistically significant correction rate when compared with the original transphyseal screw technique. The new technique has proven to have growth resumption after screw removal with minimal complication risk.

Level of Evidence:

Level III—prospective observational study.
Comparison between capnodynamic and thermodilution method for cardiac output monitoring during major abdominal surgery
Authors: Sigmundsson Thorir S. , Öhman Tomas , Hallbäck Magnus , Suarez-Sipmann Fernando , Wallin Mats , Oldner Anders , Hällsjö-Sander Caroline , Björne Håkan
Published: June 2021

BACKGROUND

Cardiac output (CO) monitoring is the basis of goal-directed treatment for major abdominal surgery. A capnodynamic method estimating cardiac output (CO

EPBF
) by continuously calculating nonshunted pulmonary blood flow has previously shown good agreement and trending ability when evaluated in mechanically ventilated pigs.

OBJECTIVES

To compare the performance of the capnodynamic method of CO monitoring with transpulmonary thermodilution (CO
TPTD) in patients undergoing major abdominal surgery.

DESIGN

Prospective, observational, method comparison study. Simultaneous measurements of CO

EPBF
and CO
TPTD were performed before incision at baseline and before and after increased (+10 cmH2O) positive end-expiratory pressure (PEEP), activation of epidural anaesthesia and intra-operative events of hypovolemia and low CO. The first 25 patients were ventilated with PEEP 5 cmH2O (PEEP5), while in the last 10 patients, lung recruitment followed by individual PEEP adjustment (PEEPadj) was performed before protocol start.

SETTING

Karolinska University Hospital, Stockholm, Sweden.

PATIENTS

In total, 35 patients (>18 years) scheduled for major abdominal surgery with advanced hemodynamic monitoring were included in the study.

MAIN OUTCOME MEASURES AND ANALYSIS

Agreement and trending ability between CO

EPBF
and CO
TPTD at different clinical moments were analysed with Bland--Altman and four quadrant plots.

RESULTS

In total, 322 paired values, 227 in PEEP5 and 95 in PEEPadj were analysed. Respectively, the mean CO

EPBF
and CO

TPTD
were 4.5 ± 1.0 and 4.8 ± 1.1 in the PEEP5 group and 4.9 ± 1.2 and 5.0 ± 1.0 l min−1 in the PEEPadj group. Mean bias (levels of agreement) and percentage error (PE) were −0.2 (−2.2 to 1.7) l min−1 and 41% for the PEEP5 group and −0.1 (−1.7 to 1.5) l min−1 and 31% in the PEEPadj group. Concordance rates during changes in CO

EPBF
and CO
TPTD were 92% in the PEEP5 group and 90% in the PEEPadj group.

CONCLUSION

CO

EPBF
provides continuous noninvasive CO estimation with acceptable performance, which improved after lung recruitment and PEEP adjustment, although not interchangeable with COTPTD. This method may become a tool for continuous intra-operative CO monitoring during general anaesthesia in the future.

TRIAL REGISTRATION

Clinicaltrials.gov identifier: NCT03444545.
State of the art: the role of citrulline as biomarker in patients with chemotherapy- or graft-versus-host-disease-induced mucositis
Authors: Dekker Ingeborg M. , Bruggink Hanneke , van der Meij Barbara S. , Wierdsma Nicolette J.
Published: June 2021

Purpose of review

Serum or plasma citrulline levels are used as biomarker for a broad spectrum of intestinal functions. During high-dose chemotherapy, citrulline levels are decreased due to mucositis, a common side effect of chemotherapy. This may decrease intestinal function and result in diarrhea. In this review, most recent studies investigating citrulline as biomarker for intestinal function are discussed, with focus on patients with oncological diseases, specifically hematological malignancies with chemotherapy- or Graft-versus-Host-disease (GVHD)-induced mucositis.

Recent findings

Citrulline has recently been widely studied in relation to intestinal function and various clinical conditions. It seems therefore a promising noninvasive biomarker in clinical practice for more than intestinal function alone. The association between citrulline levels and intestinal function in patients with hematological malignancies, with or without mucositis remains unclear, as no other parameters of intestinal function for this purpose were assessed.

In conclusion, citrulline seems to be a promising noninvasive biomarker for various intestinal conditions in general, and potentially for intestinal function in patients with chemotherapy- or GVHD-induced mucositis. It is unclear from recent literature whether high fecal volume or diarrhea as side effect, results in impaired intestinal function and severe malabsorption and if citrulline biomarkers can be useful to detect this.
Cognitive impairment and functional change in COVID-19 patients undergoing inpatient rehabilitation
Authors: Patel Ruchi , Savrides Irene , Cahalan Christine , Doulatani Gargi , O’Dell Michael W. , Toglia Joan , Jaywant Abhishek
Published: June 2021

Cognitive impairment is increasingly recognized as a sequela of COVID-19. It is unknown how cognition changes and relates to functional gain during inpatient rehabilitation. We administered the Montreal Cognitive Assessment (MoCA) at admission to 77 patients undergoing inpatient rehabilitation for COVID-19 in a large US academic medical center. Forty-five patients were administered the MoCA at discharge. Functional gain was assessed by change in the quality indicator for self-care (QI-SC). In the full sample, 80.5% of patients exhibited cognitive impairment on admission, which was associated with prior delirium. Among 45 patients with retest data, there were significant improvements in MoCA and QI-SC. QI-SC score gain was higher in patients who made clinically meaningful changes on the MoCA, an association that persisted after accounting for age and delirium history. Cognitive impairment is frequent among COVID-19 patients, but improves over time and is associated with functional gain during inpatient rehabilitation.
Gut microbiota and microbiome in schizophrenia
Authors: Samochowiec Jerzy , Misiak Błażej
Published: June 2021

Purpose of review

Accumulating evidence indicates that there are bidirectional interactions between the gut microbiota and functioning of the central nervous system. Consequently, it has been proposed that gut microbiota alterations might play an important role in the pathophysiology of schizophrenia. Therefore, in this article, we aimed to perform a narrative review of studies addressing gut microbiota alterations in patients with schizophrenia that were published in the years 2019–2020.

Recent findings

Several studies have shown a number of gut microbiota alterations at various stages of schizophrenia. Some of them can be associated with neurostructural abnormalities, psychopathological symptoms, subclinical inflammation and cardiovascular risk. Experimental studies clearly show that transplantation of gut microbiota from unmedicated patients with schizophrenia to germ-free mice results in a number of behavioural impairments accompanied by altered neurotransmission. However, findings from clinical trials do not support the use of probiotics as add-on treatments in schizophrenia.

Gut microbiota alterations are widely observed in patients with schizophrenia and might account for various biological alterations involved in the cause of psychosis. However, longitudinal studies are still needed to conclude regarding causal associations. Well designed clinical trials are needed to investigate safety and efficacy of probiotics and prebiotics in schizophrenia.
Data-Driven Patterns in Protective Effects of Ibuprofen and Ketorolac on Hospitalized Covid-19 Patients
Authors: Lengerich Benjamin J. , Caruana Rich , Aphinayanaphongs Yin
Published: June 2021

The impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on patients with Covid-19 has been unclear. A major reason for this uncertainty is the confounding between treatments, patient comorbidities, and illness severity. Here, we perform an observational analysis of over 3000 patients hospitalized for Covid-19 in a New York hospital system to identify the relationship between in-patient treatment with Ibuprofen or Ketorolac and mortality. Our analysis finds evidence consitent with a protective effect for Ibuprofen and Ketorolac, with evidence stronger for a protective effect of Ketorolac than for a protective effect of Ibuprofen.
Data Driven Monitoring in Community Based Management of SAM children using Psychometric Techniques: An Operational Framework
Authors: Joshi Ankur , Pakhare Abhijit P , Nair Sivaja K , Revadi G , Chouhan Manoj , Pandey Deepak , Kokane Arun M
Published: June 2021

Background

The success of the Community Based Management of Severe Malnutrition (CSAM)programme, largely depends on the knowledge and skills of Front-Line Workers (FLWs).A robust supportive supervision system in CSAM should be tailored to individualistic learning needs by distinguishing the FLWs as per their ability and simultaneously identifying the task domains to be emphasized more in supervisory visits.This paper details the ability assessment strategy developed and employed in the selected geographical locations in state of Madhya Pradesh (Central India) among the 197 Anganwadi workers (FLWs involved in CSAM implementation)

Methodology

A 25 items tool was developed based on an analytical construct for ability estimation through Rasch Analysis (RA). RA models the probability of right/wrong answer as a function of person(participants) and item (questions) parameters and calculates the item difficulty in relation with person ability on same unidimensional linear scale. The fitting of the data to Rasch model (Rasch diagnostic) was tested by both numeric (Anderson LR and Wald test) and graphical method. Suitable visualization like Item Characteristic Curve (ICC) and Person Item Map (PIM) were plotted in RA.

Further a quadratic allocation of all AWWs into 4 quadrants were done as per the ability estimation (Rasch score) and adjusted numbers of SAM/MAM children in her center.

Results

The item easiness parameter (β) value related to Diarrhoeal assessment was lowest (−2.32, -2.91 to -1.73) and related to peer assessment consequential action (2.009, 1.669-2.348)) was highest (most difficult). Anderson LR test (LR=31.32, df=24, p=0.079) showed the absence of global outliers. Quadrant analysis using the permutations of ability score and adjusted burden of malnutrition further mapped 41/197 (20.8%) FLWs to low ability -high burden quadrant and 44/197(25%) as low ability low burden quadrant.

Conclusion

RASCH assessment may address the innate challenges to maintain homogeneity, discrimination capacity and linearity in a raw score-based measurement construct. The monitoring strategy developed on this thus may offer a judicious, pragmatic and thematic approach to supportive supervision in CSAM program.
Stable IgG-antibody levels in patients with mild SARS-CoV-2 infection
Authors: Åkerlund Thomas , Zakikhany Katherina , Löfström Charlotta , Lindmark Evelina , Källberg Henrik , Elofsson Ulla , Cederbrant Karin , Nygren Erik , Kallin Anders , Lagerqvist Nina , Nilsson Peter , Hober Sophia , Wollberg Anna Ridderstad , Björndal Åsa Szekely
Published: June 2021

More knowledge regarding persistence of antibody response to SARS-CoV-2 infections in the general population with mild symptoms is needed. We measured and compared levels of SARS-CoV-2 spike- and nucleocapsid-specific IgG-antibodies in serum samples from 145 laboratory-confirmed COVID-19 cases and 324 non-cases. The IgG-antibody levels against the spike protein in cases were stable over the time-period studied (14 to 256 days), while antibody levels against the nucleocapsid protein decreased over time.
Prevalence of different sleep problems in patients with respiratory diseases presented to a respiratory outdoor clinic: A Descriptive analysis
Authors: Haldar Arup Kumar , Chatterjee Arpita Halder
Published: June 2021

Introduction

A patient with compromised respiratory system due to some diseases, may have disturbed sleep to a great extent. It has been proved in various community based epidemiologic studies. Though most of such studies available had concentrated on single respiratory disease like COPD or Asthma in the community. But such studies are hardly available for patients attending a respiratory clinic, where all respiratory ailments were evaluated with concurrent sleep problems. The present study is one such.

Methods

Total 163 patients were screened and among them 100 were selected as the study group. The patients were enquired with a standard questionnaire provided to them. In addition, they were given seperate questionnaire as STOP BANG, Insomnia Severity Index Score, RLS questionnaire. Those persons with STOP BANG > 5, were also advised for a Polysomnography (PSG), if not already done. Descriptive statistical analysis has been carried out in the present study.

Results

The present study is a cross-sectional depiction of relationships between various respiratory diseases and sleep problems. As per this study, most patients were asthmatic and commonest sleep problem was OSA. A subgroup analysis was done to determine the significance of difference of various parameters between the three groups of asthmatic patients, patients having COPD and the ‘Other’ group.

Discussion

Subjective sleep problems were significantly more in Asthma group than COPD group (p<0.0362). The mean STOP BANG was more in COPD group than the Asthma group (p<0.0301). Though OSA was the commonest sleep problem between the three groups, but the prevalence was not statistically significant between them. More patients in the COPD group had insomnia, but it was not statistically significantly more than in Asthma group. Sleeping pill use was significantly more in COPD group than the Asthma group (p<0.0039).

Conclusion

Sleep problems are common in patients with respiratory diseases and OSA is the most common problem according to the present study. Asthma patients had more subjective sleep problems. Sleeping pill use is more common in COPD patients instead of having less subjective sleep complaints than asthma patients.
An Extended Susceptible-Exposed-Infected-Recovered (SEIR) Model with Vaccination for Predicting the COVID-19 Pandemic in Sri Lanka
Authors: Rajapaksha R. M. Nayani Umesha , Wijesinghe Millawage Supun Dilara , Thomas Toms K. , Jayasooriya Sujith P. , Gunawardana B. M. W. Indika , Weerasinghe W. M. Prasad Chathuranga , Bhakta Shalini , Assefa Yibeltal
Published: June 2021

The role of modelling in predicting the spread of an epidemic is important for health planning and policies. This study aimed to apply a compartmental model for predicting the variations of epidemiological parameters in Sri Lanka. We used a dynamic Susceptible-Exposed-Infected-Recovered-Vaccinated (SEIRV) model and simulated potential vaccine strategies under a range of epidemic conditions. The predictions were based on different vaccination coverages (5% to 90%), vaccination-rates (1%, 2%, 5%) and vaccine-efficacies (40%, 60%, 80%) under different R0 (2,4,6). We estimated the duration, exposed, and infected populations. When the R0 was increased, the days of reduction of susceptibility and the days to reach the peak of the infection were reduced gradually. At least 45% vaccine coverage is required for reducing the infected population to mitigate a disastrous situation in Sri Lanka. The results revealed that when R0 is increased in the SEIRV model along with the increase of vaccination efficacy and vaccination rate, the population to be vaccinated is reducing. Thus, the vaccination offers greater benefits to the local population by reducing the time to reach the peak, exposed and infected population through flattening the curves.
COVID-19 Vaccine Coverage Index: Identifying barriers to COVID-19 vaccine uptake across U.S. counties
Authors: Mishra Anubhuti , Sutermaster Staci , Smittenaar Peter , Stewart Nicholas , Sgaier Sema K.
Published: June 2021

Importance

The United States is in a race against time to vaccinate its population to contain the COVID-19 pandemic. With limited resources, a proactive, targeted effort is needed to reach widespread community immunity.

Objective

Identify county-level barriers to achieving rapid COVID-19 vaccine coverage and validate the index against vaccine rollout data.

Design

Ecological study

Setting

Population-based

Participants

Longitudinal COVID-19 vaccination coverage data for 50 states and the District of Columbia and 3118 counties from January 12 through May 25, 2021.

Exposure(s)

The COVID-19 Vaccine Coverage index (CVAC) ranks states and counties on barriers to coverage through 28 indicators across 5 themes: historic undervaccination, sociodemographic barriers, resource-constrained health system, healthcare accessibility barriers, and irregular care-seeking behaviors. A score of 0 indicates the lowest level of concern, whereas a score of 1 indicates the highest level of concern.

Main Outcome(s) and Measure(s)

State-level vaccine administrations from January 12 through May 25, 2021, provided by the Centers for Disease Control and Prevention (CDC) and Our World In Data. County-level vaccine coverage as of May 25, 2021, provided by the CDC.

Results

As of May 25, 2021, the CVAC strongly correlated with the percentage of population fully vaccinated against COVID-19 by county (r = -0.39, p=2.2×10−16) and state (r=-0.77, p=4.9×10−11). Low-concern states and counties have fully vaccinated 26.5% [t=6.8, p=1.7×10−7] and 26% (t=22.0, p=2.2×10−16) more people, respectively, compared to their high-concern counterparts. This vaccination gap is at its highest point since the start of vaccination and continues to grow. Higher concern on each of the five themes predicts a lower rate of vaccination at the county level (all p<.001). We identify five types of counties with distinct barrier profiles.

Conclusions and Relevance

The CVAC measures underlying barriers to vaccination and is strongly associated with the speed of rollout. As the coverage gap between high- and low-concern regions continues to grow, the CVAC can inform a precision public health response targeted to underlying barriers.

Key Points

Question

Which U.S. counties face barriers to COVID-19 vaccine rollout, and are these communities vaccinating fewer individuals?

Findings

The COVID-19 Vaccine Coverage Index (CVAC) comprises five themes reflecting county-level concern for low coverage. We report rural, regional, and racial divides in exposure to these vaccination barriers. The top third of states and counties of highest concern have vaccinated 19% and 20% fewer people, respectively, compared to regions of least concern.

Meaning

The CVAC can help contextualize progress to widespread COVID-19 vaccine coverage, identifying underlying community-level factors that could be driving suboptimal rollout to inform precision solutions.
No evidence of SARS-CoV-2 infection in Neotropical Primates sampled during COVID-19 pandemic in Minas Gerais and Rio Grande do Sul, Brazil
Authors: Abreu Filipe Vieira Santos de , Macedo Mariana Viana , Silva Alex Junio Jardim da , Oliveira Cirilo Henrique de , Ottone Vinícius de Oliveira , Almeida Marco Antônio Barreto de , Santos Edmilson dos , Cardoso Jader da Cruz , Campos Aline Scarpellini , Silva Claudia Maria Dornelles da , Silva Amanda Gonzales da , Andrade Miguel de Souza , Bernis Valéria Magro Octaviano , Bernis Filho Walter Octaviano , Trindade Giliane de Souza , Albuquerque George Rego , Sevá Anaiá da Paixão , Ribeiro Bergmann Morais , Teixeira Danilo Simonini , Campos Fabrício Souza , Franco Ana Cláudia , Roehe Paulo Michel , Oliveira Danilo Bretas de
Published: June 2021

In 2019, a new coronavirus disease (COVID-19) was detected in China. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was capable to infect domestic and captive mammals like cats, tigers and minks. Due to genetic similarities, concern about the infection of Non-Human Primates (NHPs) and the establishment of a sylvatic cycle has grown in the Americas. In this study, neotropical primates (NP) were sampled in different areas from Brazil to investigate whether they were infected by SARS-CoV-2. A total of 89 samples from 51 NP of four species were examined. No positive samples were detected via RT-qPCR, regardless of the NHP species, tissue or habitat tested. This work provides the first report on the lack of evidence of circulation of SARS-CoV-2 in NP. The expand of wild animals sampling is necessary to understand their role in the epidemiology of SARS-CoV-2.
Neural Regression, Representational Similarity, Model Zoology & Neural Taskonomy at Scale in Rodent Visual Cortex
Authors: Conwell Colin , Mayo David , Buice Michael A. , Katz Boris , Alvarez George A. , Barbu Andrei
Published: June 2021

How well do deep neural networks fare as models of mouse visual cortex? A majority of research to date suggests results far more mixed than those produced in the modeling of primate visual cortex. Here, we perform a large-scale benchmarking of dozens of deep neural network models in mouse visual cortex with both representational similarity analysis and neural regression. Using the Allen Brain Observatory’s 2-photon calcium-imaging dataset of activity in over 6,000 reliable rodent visual cortical neurons recorded in response to natural scenes, we replicate previous findings and resolve previous discrepancies, ultimately demonstrating that modern neural networks can in fact be used to explain activity in the mouse visual cortex to a more reasonable degree than previously suggested. Using our benchmark as an atlas, we offer preliminary answers to overarching questions about levels of analysis (e.g. do models that better predict the representations of individual neurons also predict representational similarity across neural populations?); questions about the properties of models that best predict the visual system overall (e.g. is convolution or category-supervision necessary to better predict neural activity?); and questions about the mapping between biological and artificial representations (e.g. does the information processing hierarchy in deep nets match the anatomical hierarchy of mouse visual cortex?). Along the way, we catalogue a number of models (including vision transformers, MLP-Mixers, normalization free networks, Taskonomy encoders and self-supervised models) outside the traditional circuit of convolutional object recognition. Taken together, our results provide a reference point for future ventures in the deep neural network modeling of mouse visual cortex, hinting at novel combinations of mapping method, architecture, and task to more fully characterize the computational motifs of visual representation in a species so central to neuroscience, but with a perceptual physiology and ecology markedly different from the ones we study in primates.
Single-molecule, full-length transcript isoform sequencing reveals disease mutation-associated RNA isoforms in cardiomyocytes
Authors: Zhu Chenchen , Wu Jingyan , Sun Han , Briganti Francesca , Meder Benjamin , Wei Wu , Steinmetz Lars M.
Published: June 2021

Alternative splicing generates differing RNA isoforms that govern phenotypic complexity of eukaryotes. Its malfunction underlies many diseases, including cancer and cardiovascular diseases. Comparative analysis of RNA isoforms at the genome-wide scale has been difficult. Here, we established an experimental and computational pipeline that performs de novo transcript annotation and accurately quantifies transcript isoforms from cDNA sequences with a full-length isoform detection accuracy of 97.6%. We generated a searchable, quantitative human transcriptome annotation with 31,025 known and 5,740 novel transcript isoforms (http://steinmetzlab.embl.de/iBrowser/). By analyzing the isoforms in the presence of RNA Binding Motif Protein 20 (RBM20) mutations associated with aggressive dilated cardiomyopathy (DCM), we identified 121 differentially expressed transcript isoforms in 107 cardiac genes. Our approach enables quantitative dissection of complex transcript architecture instead of mere identification of inclusion or exclusion of individual exons, as exemplified by novel IMMT isoforms. Thereby we achieve a path to direct differential expression testing independent of an existing annotation of transcript isoforms as the functional unit, instead of genes or exons, providing more immediate biological interpretation and higher resolution transcriptome comparisons.
Structure and computation-guided design of a mutation-integrated trimeric RBD candidate vaccine with broad neutralization against SARS-CoV-2
Authors: Liang Yu , Zhang Jing , Yuan Run Yu , Wang Mei Yu , He Peng , Su Ji Guo , Han Zi Bo , Jin Yu Qin , Hou Jun Wei , Zhang Hao , Zhang Xue Feng , Shao Shuai , Hou Ya Nan , Liu Zhao Ming , Du Li Fang , Shen Fu Jie , Zhou Wei Min , Tang Fang , Lei Ze Hua , Liu Shuo , Zhen Wei , Wu Jin Juan , Zheng Xiang , Liu Ning , Chen Shi , Ma Zhi Jing , Zheng Fan , Ren Si Yu , Hu Zhong Yu , Wu Gui Zhen , Huang Wei Jin , Ke Chang Wen , Li Qi Ming
Published: June 2021

The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 is an attractive target for COVID-19 vaccine developments, which naturally exists in a trimeric form. Here, guided by structural and computational analyses, we present a mutation-integrated trimeric form of RBD (mutI tri-RBD) as a broadly protective vaccine candidate, in which three RBDs were individually grafted from three different circulating SARS-CoV-2 strains including the prototype, Beta (B.1.351) and Kappa (B.1.617). The three RBDs were then connected end-to-end and co-assembled to possibly mimic the native trimeric arrangements in the natural S protein trimer. The recombinant expression of the mutI tri-RBD, as well as the homo-tri-RBD where the three RBDs were all truncated from the prototype strain, by mammalian cell exhibited correct folding, strong bio-activities, and high stability. The immunization of both the mutI tri-RBD and homo-tri-RBD plus aluminum adjuvant induced high levels of specific IgG and neutralizing antibodies against the SARS-CoV-2 prototype strain in mice. Notably, regarding to the “immune-escape” Beta (B.1.351) variant, mutI tri-RBD elicited significantly higher neutralizing antibody titers than homo-tri-RBD. Furthermore, due to harboring the immune-resistant mutations as well as the evolutionarily convergent hotspots, the designed mutI tri-RBD also induced strong broadly neutralizing activities against various SARS-CoV-2 variants, especially the variants partially resistant to homo-tri-RBD. Homo-tri-RBD has been approved by the China National Medical Products Administration to enter clinical trial (No. NCT04869592), and the superior broad neutralization performances against SARS-CoV-2 support the mutI tri-RBD as a more promising vaccine candidate for further clinical developments.
Higher order phosphatase-substrate contacts terminate the Integrated Stress Response
Authors: Yan Yahui , Harding Heather P. , Ron David
Published: June 2021

Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits are known to engage PP1c’s surface, locally affecting flexible phosphopeptides access to the active site. However, catalytic efficiency of holophosphatases towards their natively-folded phosphoprotein substrates is largely unexplained. Here we present a Cryo-EM structure of the tripartite PP1c/PPP1R15A/G-actin holophosphatase that terminates signalling in the Integrated Stress Response (ISR) in pre-dephosphorylation complex with its substrate, translation initiation factor 2α (eIF2α). G-actin’s role in eIF2α dephosphorylation is supported crystallographically by the structure of the binary PPP1R15A-G-actin complex, and by biochemical and genetic confirmation of the essential role of PPP1R15A-G-actin contacts to eIF2αP dephosphorylation. In the pre-dephosphorylation CryoEM complex, G-actin aligns the catalytic and regulatory subunits, creating a composite surface that engages eIF2α’s N-terminal domain to position the distant phosphoserine-51 at the active site. eIF2α residues specifying affinity for the holophosphatase are confirmed here to make critical contacts with the eIF2α kinase PERK. Thus, a convergent process of higher-order substrate recognition specifies functionally-antagonistic phosphorylation and dephosphorylation in the ISR.
Persistent DNA Repair Signaling and DNA Polymerase Theta Promote Broken Chromosome Segregation
Authors: Clay Delisa E. , Bretscher Heidi S. , Jezuit Erin A. , Bush Korie B. , Fox Donald T.
Published: June 2021

Cycling cells must respond to double-strand breaks (DSBs) to avoid genome instability. Mis-segregation of chromosomes with DSBs during mitosis results in micronuclei, aberrant structures linked to disease. How cells respond to DSBs during mitosis is incompletely understood. We previously showed that Drosophila papillar cells lack DSB checkpoints (as observed in many cancer cells). Here, we show that papillar cells still recruit early-acting repair machinery (Mre11 and RPA3) to DSBs. This machinery persists as foci on DSBs as cells enter mitosis. Repair foci are resolved in a step-wise manner during mitosis. Repair signaling kinetics at DSBs depends on both monoubiquitination of the Fanconi Anemia (FA) protein Fancd2 and the alternative end-joining protein DNA Polymerase Theta. Disruption of either or both of these factors causes micronuclei after DNA damage, which disrupts intestinal organogenesis. This study reveals a mechanism for how cells with inactive DSB checkpoints can respond to DNA damage that persists into mitosis.

Clay et. al. show that cells with DNA breaks that persist into mitosis activate sustained DNA repair signaling, regulated by Fanconi Anemia proteins and the alternative end-joining repair protein DNA Polymerase Theta. This signaling enables broken chromosome segregation and prevents micronuclei.
Stability of Polygenic Scores Across Discovery Genome-Wide Association Studies
Authors: Schultz Laura M. , Merikangas Alison K. , Ruparel Kosha , Jacquemont Sébastien , Glahn David C. , Gur Raquel E. , Barzilay Ran , Almasy Laura
Published: June 2021

Polygenic scores (PGS) are commonly evaluated in terms of their predictive accuracy at the population level by the proportion of phenotypic variance they explain. To be useful for precision medicine applications, they also need to be evaluated at the individual patient level when phenotypes are not necessarily already known. Hence, we investigated the stability of PGS in European-American (EUR)- and African-American (AFR)-ancestry individuals from the Philadelphia Neurodevelopmental Cohort (PNC) and the Adolescent Brain Cognitive Development (ABCD) cohort using different discovery GWAS for post-traumatic stress disorder (PTSD), type-2 diabetes (T2D), and height. We found that pairs of EUR-ancestry GWAS for the same trait had genetic correlations > 0.92. However, PGS calculated from pairs of sameancestry and different-ancestry GWAS had correlations that ranged from <0.01 to 0.74. PGS stability was higher for GWAS that explained more of the trait variance, with height PGS being more stable than PTSD or T2D PGS. Focusing on the upper end of the PGS distribution, different discovery GWAS do not consistently identify the same individuals in the upper quantiles, with the best case being 60% of individuals above the 80th percentile of PGS overlapping from one height GWAS to another. The degree of overlap decreases sharply as higher quantiles, less heritable traits, and different-ancestry GWAS are considered. PGS computed from different discovery GWAS have only modest correlation at the level of the individual patient, underscoring the need to proceed cautiously with integrating PGS into precision medicine applications.
Synergistic information in the frontal cortex-striatal pathway
Authors: Alsolami Ibrahim , Handa Takashi , Fukai Tomoki
Published: June 2021

Across the cortico-basal ganglia circuit, the medial frontal cortex (MFC) communicates with the dorsal striatum (DS) during learning and planning. How these two brain regions communicate with each other is, however, not fully understood. Here we report the presence of synergistic information during information transfer across the frontal cortex-striatal pathway. Synergistic information emerges from the positive interaction of DS and MFC neurons and provides the DS with additional cortical information. This information is held latent in neuronal signals. To reveal it, we simultaneously record neuronal activities from the MFC and DS of rats trained on an outcome-based decision-making task and determined whether past neuronal activities of the DS positively influence communication rates. We detect a neuronal synergy that enables the MFC to boost its communication rate to the DS. Our results suggest that past neuronal activities of the DS help decode MFC signals. This ability is not attributed to the inherent autocorrelation of DS spiking activities.
Infectiousness in omicron variant strain and bA.2 variant in Japan
Authors: Kurita Junko , Sugawara Tamie , Ohkusa Yasushi
Published: June 2021

Background

Omicron variant strain dominated since the beginning of 2022. Its infectivity was supposes to be higher than Delta variant strain or strains in past.

Object

We estimated prevalence of omicron variant strain, particularly bA.2 variant and COVID-19 vaccine effectiveness of the third dose in Japan as well as controlling for waning of second dose of vaccine, other mutated strains, the Olympic Games, and countermeasures.

Method

The effective reproduction number R(t) was regressed on shares of omicron variant strain and bA.2 and vaccine coverage of the third dose, as well as along with data of temperature, humidity, mobility, share of the other mutated strains, and an Olympic Games and countermeasures. The study period was February, 2020 through February 21, 2022, as of March 15, 2022.

Results

Estimation results indicated that waning of the second dose vaccine e with 150 days prior was the most appropriate specification. Moreover, bA.2 of omicron variant strain has higher infectively than other variant strain or traditional strain.

Discussion

Because of data limitation since emerging bA.2, the estimated its infectively will change over time.
Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns
Authors: Shahal Tamar , Segev Elad , Konstantinovsky Thomas , Marcus Yonit , Shefer Gabi , Pasmanik-Chor Metsada , Buch Assaf , Ebenstein Yuval , Zimmet Paul , Stern Naftali
Published: June 2021

Background

The epigenetic age can now be extrapolated from one of several epigenetic clocks, which are based on age-related changes in DNA methylation levels at specific multiple CpG sites. Accelerated aging, calculated from the discrepancy between the chronological age and the epigenetic age, has shown to predict morbidity and mortality rate. We assumed that deconvolution of epigenetic age to its components could shed light on the diversity of epigenetic, and by inference, on inter-individual variability in the causes of biological aging.

Results

Using the Horvath original epigenetic clock, we identified several CpG sites linked to distinct genes that quantitatively explain much of the interpersonal variability in epigenetic aging, with CpG sites related to secretagogin and malin being the most variable. We show that equal epigenetic age in different subjects can result from variable contribution size of the same CpG sites to the total epigenetic age. In a healthy cohort, the most variable CpG sites are responsible for accelerated and decelerated epigenetic aging, relative to chronological age.

Conclusions

Of the 353 CpG sites that form the basis for the Horvath epigenetic age, we have found the CpG sites that are responsible for accelerated and decelerated epigenetic aging in healthy subjects. However, the relative contribution of each site to aging varies between individuals, leading to variable personal aging patterns. Our findings pave the way to form personalized aging cards allowing the identification of specific genes related to CpG sites, as aging markers, and perhaps treatment of these targets in order to hinder undesirable age drifting.
The challenge of structural heterogeneity in the native mass spectrometry studies of the SARS-CoV-2 spike protein interactions with its host cell-surface receptor
Authors: Yang Yang , Ivanov Daniil G. , Kaltashov Igor A.
Published: June 2021

Native mass spectrometry (MS) enjoyed tremendous success in the past two decades in a wide range of studies aiming at understanding the molecular mechanisms of physiological processes underlying a variety of pathologies and accelerating the drug discovery process. However, the success record of native MS has been surprisingly modest with respect to the most recent challenge facing the biomedical community – the novel coronavirus infection (COVID-19). The major reason for the paucity of successful studies that use native MS to target various aspects of SARS-CoV-2 interaction with its host is the extreme degree of structural heterogeneity of the viral protein playing a key role in the host cell invasion. Indeed, the SARS-CoV-2 spike protein (S-protein) is extensively glycosylated, presenting a formidable challenge for native mass spectrometry (MS) as a means of characterizing its interactions with both the host cell-surface receptor ACE2 and the drug candidates capable of disrupting this interaction. In this work we evaluate the utility of native MS complemented with the experimental methods using gas-phase chemistry (limited charge reduction) to obtain meaningful information on the association of the S1 domain of the S-protein with the ACE2 ectodomain, and the influence of a small synthetic heparinoid on this interaction. Native MS reveals the presence of several different S1 oligomers in solution and allows the stoichiometry of the most prominent S1/ACE2 complexes to be determined. This enables meaningful interpretation of the changes in native MS that are observed upon addition of a small synthetic heparinoid (the pentasaccharide fondaparinux) to the S1/ACE2 solution, confirming that the small polyanion destabilizes the protein/receptor binding.