bluuebunny/crossref_metadata_2025 huggingface dataset:
Vent-Lock: A 3D Printed Ventilator Multiplexer to Enhance the Capacity of Treating Patients with COVID-19
Authors: Xun Helen , Shallal Christopher , Unger Justin , Tao Runhan , Torres Alberto , Vladimirov Michael , Frye Jenna , Singhala Mohit , Horne Brockett , Yesantharao Pooja , Kim Bo Soo , Burke Broc , Montana Michael , Talcott Michael , Winters Bradford , Frisella Margaret , Kushner Bradley , Sacks Justin M. , Guest James K. , Kang Sung Hoon , Caffrey Julie
Published: September 2020

Mechanical ventilators are essential to patients who become critically ill from acute respiratory distress syndrome (ARDS), and shortages have been reported due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We utilized cost-effective, on-demand 3D printing (3DP) technology to produce critical components for a novel ventilator multiplexer system, Vent-Lock, to split one ventilator or anesthesia gas machine between two patients. FloRest, a novel 3DP flow restrictor, provides clinicians control of tidal volumes and positive end expiratory pressure (PEEP), using the 3DP manometer adaptor to monitor pressures. We tested the ventilator splitter circuit in simulation centers between artificial lungs and used an anesthesia gas machine to successfully ventilate two swines. As one of the first studies to demonstrate splitting one anesthesia gas machine between two swines, we present proof-of-concept of a de novo, closed, multiplexing system, with flow restriction for individualized patient therapy. Our studies underscore that while possible, ventilator multiplexing is a complicated synergy between machine settings, circuit modification, and patient monitoring. Consequently, ventilator multiplexing is reserved only as a last emergency resource, by trained clinicians and respiratory therapists with ventilator operative experience.
Nasopharyngeal SARS-CoV2 viral loads in young children do not differ significantly from those in older children and adults
Authors: Madera Sharline , Crawford Emily , Langelier Charles , Tran Nam K , Thornborrow Ed , Miller Steve , DeRisi Joseph L
Published: September 2020

The role of children in the spread of the SARS-CoV2 coronavirus has become a matter of urgent debate as societies in the US and abroad consider how to safely reopen schools. Small studies have suggested higher viral loads in young children. Here we present a multicenter investigation on over five thousand SARS-CoV-2 cases confirmed by real-time reverse transcription (RT) PCR assay. Notably, we found no discernable difference in amount of viral nucleic acid among young children and adults.
DNA methylation patterns and disease activity in a longitudinal cohort of lupus patients
Authors: Coit Patrick , Ortiz-Fernandez Lourdes , Lewis Emily E. , McCune W. Joseph , Maksimowicz-McKinnon Kathleen , Sawalha Amr H.
Published: September 2020

Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in lupus granulocytes over 4 years of follow up and across disease activity levels using 229 patient samples. We demonstrate that DNA methylation profiles in lupus are influenced by ancestry-specific genetic variants and are highly stable over time. DNA methylation levels in two CpG sites correlated significantly with changes in lupus disease activity. Progressive demethylation inSNX18was observed with increasing disease activity in African-American patients. Importantly, demethylation of a CpG site located withinGALNT18was associated with the development of active lupus nephritis. Differentially methylated genes between African-American and European-American lupus patients include type I interferon-response genes such asIRF7andIFI44, and genes related to the NFkB pathway.TREML4, which plays a vital role in toll-like receptor signaling, was hypomethylated in African-American patients and demonstrated a strongcis-meQTL association.
Improved symptoms following bumetanide treatment in children aged 3 to 6 years with autism spectrum disorder via GABAergic mechanisms: a randomized, double-blind, placebo-controlled trial
Authors: Dai Yuan , Zhang Lingli , Yu Juehua , Zhou Xin , Ji Yiting , Wang Kai , Du Xiujuan , Liu Xin , Tang Yun , Deng Shining , Langley Christelle , Li Weiguang , Zhang Jun , Feng Jianfeng , Sahakian Barbara J , Luo Qiang , Li Fei
Published: September 2020

With the drug therapy for the core symptoms of autism spectrum disorder (ASD) currently limited, here we reported a randomised, double-blind, placebo-controlled trial to investigate the efficacy, safety, and potential neural mechanism of bumetanide in children with ASD aged 3 to 6 years old. In this trial, 120 children with ASD were 1:1 randomly assigned to receive 0.5 mg bumetanide or placebo orally twice daily for 3 months. The primary outcome was the score reduction of Childhood Autism Rating Scale (CARS) and the secondary outcomes were the score of Clinical Global Impressions (CGI) Improvement scale (CGI-I) at 3 months and the change from baseline to 3-month in Autism Diagnostic Observation Schedule (ADOS). Magnetic resonance spectroscopy (MRS) was used to measure γ-aminobutyric acid (GABA) and glutamate neurotransmitter concentrations in the insular cortex (IC) before and after the treatment. As compared with the placebo, bumetanide treatment was significantly better in reducing severity. No patient withdrew from the trial due to adverse events. The superiority of bumetanide to placebo in reducing insular GABA, measured using MRS, was demonstrated. The clinical improvement was associated with the decrease in insular GABA in the bumetanide group. In children with predominantly moderate and severe ASD, the treatment of bumetanide at a dose of 0.5 mg twice daily attenuated the core symptoms, as compared with placebo, with few adverse events. The neuroimaging data demonstrated that bumetanide decreased GABA levels in insular cortex, which was associated with symptom reduction.
I had to leave. I had to leave my clinic, my city, leave everything behind in Syria. Qualitative accounts from Syrian health care workers migrating from the war-torn country
Authors: Kallström Agneta , Orwa Al Abdulla , Jan Parkki , Häkkinen Mikko , Juusola Hannu , Jussi Kauhanen
Published: September 2020

Objectives

To explore the experiences of Syrian health care workers of violence since 2011 and reasons behind migration from the conflict-affected country

Design

A qualitative study using semi-structured interviews and inductive content analysis. Interviews were conducted in Turkey and Europe in 2016 - 2017.

Setting

Interviewees were Syrian health care workers who had been working in the country after the conflict started in 2011, but at some point, migrated from Syria to Turkey or Europe.

Participants

We studied data from 20 semi-structured in-depth interviews collected with a snowball sampling method.

Results

Our findings show that health care workers migrated from Syria only because of security concerns. In most cases, the decision to leave was a result of the generalised violence by different warring parties. Targeted attacks against health care was one of the main reasons for leaving. Some participants had a specific notable trigger event before they left; such as a colleague being detained or killed. Many just grew tired of living under constant threat and fear, with their families also at risk.

Conclusions

This research adds to the body of literature on violence in Syria. It helps to understand the reasons why health care workers, even though realising that it will leave their population without proper health care provision, nevertheless decide to flee the country. Understanding the motives of the health care workers will help to find new ways to protect them.
Health Impact Assessment of PM2.5attributable mortality from the September 2020 Washington State Wildfire Smoke Episode
Authors: Liu Yisi , Austin Elena , Xiang Jianbang , Gould Tim , Larson Tim , Seto Edmund
Published: September 2020

The historic wildfires of August and September 2020, up and down the west coast have made Western cities in the U.S. rank among the highest in the world for dirtiest air. Washington State was impacted by active wildfire smoke in the state as well as transported aged wood smoke from Oregon and California. Particulate matter smaller than 2.5 μm in aerodynamic diameter (PM2.5) is the primary pollutant from wildfire smoke of health concern for the public. This study aims to assess the potential population health impact of increased PM2.5concentrations attributable to the wildfire smoke. Daily PM2.5concentrations for each county before and during the 2020 Washington state wildfire smoke episode was obtained from the WA Department of Ecology. Utilizing previously established associations of short-term mortality and PM2.5concentrations we estimated increases in all-cause, respiratory, and cardiovascular mortality for Washington state attributable to the increased PM2.5levels during the wildfire episode. During the episode, PM2.5concentrations increased 99.4 μg/m3on average in Washington. Each week of wildfire smoke exposures are estimated to cause 91.0 (95% CI: 73.8, 107.1) cases of increased all-cause mortality, 19.9 (95% CI: 10.4, 29.3) increased cardiovascular disease deaths, and 9.7 (95% CI: 5.4, 14.0) increased respiratory disease deaths. This is without considering the coincidence with the COVID-19 pandemic, since wildfire smoke exposure may exacerbate the effects of SARS-CoV-2 infection based on some early evidence. Because wildfire smoke episodes are likely to continue impacting the Pacific Northwest in years to come, continued preparedness and mitigations to reduce exposures to wildfire smoke are necessary to avoid this excess health burden.
A comparison of five epidemiological models for transmission of SARS-CoV-2 in India
Authors: Purkayastha Soumik , Bhattacharyya Rupam , Bhaduri Ritwik , Kundu Ritoban , Gu Xuelin , Salvatore Maxwell , Mishra Swapnil , Mukherjee Bhramar
Published: September 2020

Many popular disease transmission models have helped nations respond to the COVID-19 pandemic by informing decisions about pandemic planning, resource allocation, implementation of social distancing measures and other non-pharmaceutical interventions. We study how five epidemiological models forecast and assess the course of the pandemic in India: a baseline model, an extended SIR (eSIR) model, two extended SEIR (SAPHIRE and SEIR-fansy) models, and a semi-mechanistic Bayesian hierarchical model (ICM). Using COVID-19 data for India from March 15 to June 18 to train the models, we generate predictions from each of the five models from June 19 to July 18. To compare prediction accuracy with respect to reported cumulative and active case counts and cumulative death counts, we compute the symmetric mean absolute prediction error (SMAPE) for each of the five models. For active case counts, SMAPE values are 0.72 (SEIR-fansy) and 33.83 (eSIR). For cumulative case counts, SMAPE values are 1.76 (baseline) 23.10 (eSIR), 2.07 (SAPHIRE) and 3.20 (SEIR-fansy). For cumulative death counts, the SMAPE values are 7.13 (SEIR-fansy) and 26.30 (eSIR). For cumulative cases and deaths, we compute Pearson’s and Lin’s correlation coefficients to investigate how well the projected and observed reported COVID-counts agree. Three models (SAPHIRE, SEIR-fansy and ICM) return total (sum of reported and unreported) counts as well. We compute underreporting factors as of June 30 and note that the SEIR-fansy model reports the highest underreporting factor for active cases (6.10) and cumulative deaths (3.62), while the SAPHIRE model reports the highest underreporting factor for cumulative cases (27.79).
An improved method to estimate the effective reproduction number of the COVID-19 pandemic: lessons from its application in Greece
Authors: Lytras Theodore , Sypsa Vana , Panagiotakos Demosthenes , Tsiodras Sotirios
Published: September 2020

Introduction

Monitoring the time-varying effective reproduction number Rt is crucial for assessing the evolution of the COVID-19 pandemic. We present an improved method to estimate Rt and its application to routine surveillance data from Greece.

Methods

Our method extends that of Cori et al (2013), adding Bayesian imputation of missing symptom onset dates, imputation of infection times using an external estimate of the incubation period, and an adjustment for reporting delay. To facilitate its use, we provide an R software package named “bayEStim”. We applied the method to COVID-19 surveillance data from Greece, and examined the resulting Rt estimates in relation to control measures applied, in order to assess their effectiveness. We also associated Rt, as a measure of transmissibility, to population mobility as recorded in Google data and to ambient temperature. We used a serial interval between 4 and 7.5 days, and a median incubation period of 5.1 days.

Results

In Greece Rt fell rapidly as the first control measures were introduced, dropping below 1 at least a week before a full lockdown came into effect. In mid-July Rt started increasing again, as increased mobility associated with tourism activity was observed. Each 10% of increase in relative mobility increased Rt by 8.1% (95% CrI 6.1–10.2%), whereas each unit celsius of temperature increase decreased Rt by 4.6% (95% CrI 5.4–13.7%).

Conclusions

Mobility patterns significantly affect Rt. Most of the reduction in COVID-19 transmissibility in Greece occurred already before the lockdown, likely as a result of decreased population mobility. Lower viral transmissibility in summer does not appear sufficient to counterbalance the increased mobility due to tourism. Monitoring Rt is an essential component of COVID-19 surveillance, and it is crucial for correctly assessing the effect of control measures.
Association of genetic variants in enamel-formation genes with dental caries: A meta- and gene-cluster analysis
Authors: Li Xueyan , Liu Di , Sun Yang , Yang Jingyun , Yu Youcheng
Published: September 2020

Previous studies have reported the association between multiple genetic variants in enamel formation-related genes and the risk of dental caries with inconsistent results. We performed a systematic literature search of the PubMed, Cochrane Library, HuGE and Google Scholar databases for studies published before March 21, 2020 and conducted meta-, gene-based and gene-cluster analysis on the association between genetic variants in enamel-formation-related genes and the risk of dental caries. Our systematic literature search identified 21 relevant publications including a total of 24 studies for analysis. The genetic variant rs17878486 in AMELX was significantly associated with dental caries risk (OR=1.40, 95% CI: 1.02-1.93, P=0.037). We found no significant association between the risk of dental caries with rs12640848 in ENAM (OR=1.15, 95% CI: 0.88-1.52, P=0.310), rs1784418 in MMP20 (OR=1.07, 95% CI: 0.76-1.49, P=0.702) and rs3796704 in ENAM (OR=1.06, 95% CI: 0.96-1.17, P=0.228). Gene-based analysis indicated that multiple genetic variants in AMELX showed joint association with the risk of dental caries (6 variants; P<10−5), so did genetic variants in MMP13 (3 variants; P=0.004), MMP2 (3 variants; P<10−5), MMP20 (2 variants; P<10−5) and MMP3 (2 variants; P<10−5). The gene-cluster analysis indicated a significant association between the genetic variants in this enamel-formation gene cluster and the risk of dental caries (P<10−5). The present meta-analysis revealed that genetic variant rs17878486 in AMELX were associated with dental caries, and multiple genetic variants in enamel-formation-related genes jointly contribute to the risk of dental caries, supporting the role of genetic variants in the enamel-formation genes in the etiology of dental caries.
COVID-19: Risks of Re-emergence, Re-infection, and Control Measures – A Long Term Modeling Study
Authors: Ghosh Subhas Kumar , Ghosh Sachchit
Published: September 2020

In this work we define a modified SEIR model that accounts for the spread of infection during the latent period, infections from asymptomatic or pauci-symptomatic infected individuals, potential loss of acquired immunity, people’s increasing awareness of social distancing and the use of vaccination as well as non-pharmaceutical interventions like social confinement. We estimate model parameters in three different scenarios - in Italy, where there is a growing number of cases and re-emergence of the epidemic, in India, where there are significant number of cases post confinement period and in Victoria, Australia where a re-emergence has been controlled with severe social confinement program. Our result shows the benefit of long term confinement of 50% or above population and extensive testing. With respect to loss of acquired immunity, our model suggests higher impact for Italy. We also show that a reasonably effective vaccine with mass vaccination program can be successful in significantly controlling the size of infected population. We show that for India, a reduction in contact rate by 50% compared to a reduction of 10% in the current stage can reduce death from 0.0268% to 0.0141% of population. Similarly, for Italy we show that reducing contact rate by half can reduce a potential peak infection of 15% population to less than 1.5% of population, and potential deaths from 0.48% to 0.04%. With respect to vaccination, we show that even a 75% efficient vaccine administered to 50% population can reduce the peak number of infected population by nearly 50% in Italy. Similarly, for India, a 0.056% of population would die without vaccination, while 93.75% efficient vaccine given to 30% population would bring this down to 0.036% of population, and 93.75% efficient vaccine given to 70% population would bring this down to 0.034%.
Determining the effects of preseasonal climate factors toward dengue early warning system in Bangladesh
Authors: Hossain M. Pear , Zhou Wen , Ren Chao , Marshall John , Yuan Hsiang-Yu
Published: September 2020

The incidence of dengue has increased rapidly in Bangladesh since 2010 with an outbreak in 2018 reaching a historically high number of cases, 10,148. Bangladesh is located to the northeast of India and spans both tropical and subtropical regions. A better understanding of the effects of preseasonal climate variability on the increasing incidence of dengue in Bangladesh may provide insight into whether dengue has been expanding from tropical to temperate regions through the subtropics in Southeast Asia and can enable early warning for preventative measures.

We developed a generalized linear model to predict the number of annual dengue cases based on monthly temperature, rainfall and sunshine prior to dengue season. Variable selection and leave-one-out cross-validation were performed to identify the best prediction model and to evaluate the model’s performance.

Our model successfully predicted the largest outbreak in 2018, with 10,077 cases (95% CI: [9,912–10,276]), in addition to smaller outbreaks in five different years (2003, 2006, 2010, 2012 and 2014) and successfully identified the increasing trend in cases between 2010 and 2018. We found that the temperature has an apparent dual effect on the annual incidence of dengue, with a positive effect seen prior to April and negative effect seen between April and June. Our results suggest that the optimal minimum temperature for mosquito population expansion is 21–23°C. This study has implications for understanding how climate variability has affected recent dengue expansion in northern India and Southeast Asia.

Author summary

Bangladesh has experienced an unprecedented outbreak of dengue in recent years. Climate factors are believed to have played a significant role in the increased mosquito population, the primary vector of dengue. We have observed an upward trend in the number of dengue cases since 2010, which has continued until recent years. However, in previous studies of dengue–climate association, this link was not investigated. Therefore, we developed a model that uses this information to assess the association of annual dengue incidence with climate factors such as temperature, rainfall and sunshine duration. Our findings suggest that warmer springs, with minimum monthly temperatures of 21–23°C, are more favorable for mosquito population expansion and subsequent dengue transmission. Shorter duration of sunshine increase the risk of dengue, whereas abundant rainfall reduces the incidence of dengue. This research will help increase understanding of the effect of climate variability on dengue expansion, not only in Bangladesh but also in northern India and Southeast Asia.
An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mproinhibitor
Authors: Zaidman Daniel , Gehrtz Paul , Filep Mihajlo , Fearon Daren , Prilusky Jaime , Duberstein Shirly , Cohen Galit , Owen David , Resnick Efrat , Strain-Damerell Claire , Lukacik Petra ,   Covid-Moonshot Consortium, Barr Haim , Walsh Martin A. , von Delft Frank , London Nir
Published: September 2020

Designing covalent inhibitors is a task of increasing importance in drug discovery. Efficiently designing irreversible inhibitors, though, remains challenging. Here, we presentcovalentizer, a computational pipeline for creating irreversible inhibitors based on complex structures of targets with known reversible binders. For each ligand, we create a custom-made focused library of covalent analogs. We use covalent docking, to dock these tailored covalent libraries and to find those that can bind covalently to a nearby cysteine while keeping some of the main interactions of the original molecule. We found ~11,000 cysteines in close proximity to a ligand across 8,386 protein-ligand complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In prospective evaluation against a panel of kinases, five out of nine predicted covalent inhibitors showed IC50between 155 nM - 4.2 μM. Application of the protocol to an existing SARS-CoV-1 Mproreversible inhibitor led to a new acrylamide inhibitor series with low micromolar IC50against SARS-CoV-2 Mpro. The docking prediction was validated by 11 co-crystal structures. This is a promising lead series for COVID-19 antivirals. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.
Rapid detection of inter-clade recombination in SARS-CoV-2 with Bolotie
Authors: Varabyou Ales , Pockrandt Christopher , Salzberg Steven L. , Pertea Mihaela
Published: September 2020

The ability to detect recombination in pathogen genomes is crucial to the accuracy of phylogenetic analysis and consequently to forecasting the spread of infectious diseases and to developing therapeutics and public health policies. However, previous methods for detecting recombination and reassortment events cannot handle the computational requirements of analyzing tens of thousands of genomes, a scenario that has now emerged in the effort to track the spread of the SARS-CoV-2 virus. Furthermore, the low divergence of near-identical genomes sequenced in short periods of time presents a statistical challenge not addressed by available methods. In this work we present Bolotie, an efficient method designed to detect recombination and reassortment events between clades of viral genomes. We applied our method to a large collection of SARS-CoV-2 genomes and discovered hundreds of isolates that are likely of a recombinant origin. In cases where raw sequencing data was available, we were able to rule out the possibility that these samples represented co-infections by analyzing the underlying sequence reads. Our findings further show that several recombinants appear to have persisted in the population.
Insertions of codons encoding basic amino acids in H7 hemagglutinins of influenza A viruses occur by recombination with RNA at hotspots near snoRNA binding sites
Authors: Gultyaev Alexander P. , Spronken Monique I. , Funk Mathis , Fouchier Ron A.M. , Richard Mathilde
Published: September 2020

The presence of multiple basic amino acids in the protease cleavage site of the hemagglutinin (HA) protein is the main molecular determinant of virulence of highly pathogenic avian influenza (HPAI) viruses. Recombination of HA RNA with other RNA molecules of host or virus origin is a dominant mechanism of multi basic cleavage site (MBCS) acquisition for H7 subtype HA. Using alignments of HA RNA sequences from documented cases of MBCS insertion due to recombination, we show that such recombination with host RNAs is most likely to occur at particular hotspots in ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and viral RNAs. The locations of these hotspots in highly abundant RNAs indicate that RNA recombination is facilitated by the binding of small nucleolar RNA (snoRNA) near the recombination points.
Dissolved organic carbon (DOC) is essential to balance the metabolic demands of North-Atlantic deep-sea sponges
Authors: Bart Martijn C. , Mueller Benjamin , Rombouts Titus , van de Ven Clea , Tompkins Gabrielle J. , Osinga Ronald , Brussaard Corina P.D. , MacDonald Barry , Engel Anja , Rapp Hans Tore , de Goeij Jasper M.
Published: September 2020

Sponges are ubiquitous components of various deep-sea habitats, including cold water coral reefs and deep-sea sponge grounds. Despite being surrounded by oligotrophic waters, these ecosystems are known to be hotspots of biodiversity and carbon cycling. To assess the role of sponges in the carbon cycling of deep-sea ecosystems, we studied the energy budgets of six dominant deep-sea sponges (the hexactinellid speciesVazella pourtalesi, and demosponge speciesGeodia barretti, Geodia atlantica, Craniella zetlandica, Hymedesmia paupertasandAcantheurypon spinispinosum)in an ex situ aquarium setup. Additionally, we determined morphological metrics for all species (volume, dry weight (DW), wet weight (WW), carbon (C) content, and ash-free dry weight (AFDW)) and provide species-specific conversion factors. Oxygen (O2) removal rates averaged 3.3 ± 2.8µmol O2DWspongeh−1(all values mean ± SD), live particulate (bacterial and phytoplankton) organic carbon (LPOC) removal rates averaged 0.30 ± 0.39µmol C DWspongeh−1and dissolved organic carbon (DOC) removal rates averaged 18.70 ± 25.02µmol C DWspongeh−1. Carbon mass balances were calculated for four species (V. pourtalesi, G. barretti, G. atlanticaandH. paupertas) and revealed that the sponges acquired 1.3–6.6 times the amount of carbon needed to sustain their minimal respiratory demands. These results indicate that irrespective of taxonomic class, growth form, and abundance of microbial symbionts, DOC is responsible for over 90 % of the total net organic carbon removal of deep-sea sponges and allows them to sustain in otherwise food-limited environments on the ocean floor.
Distinct tooth regeneration systems deploy a conserved battery of genes
Authors: Square Tyler A. , Sundaram Shivani , Mackey Emma J. , Miller Craig T.
Published: September 2020

Background

Vertebrate teeth exhibit a wide range of regenerative systems. Many species, including most mammals, reptiles, and amphibians, form replacement teeth at a histologically distinct location called the successional dental lamina, while other species do not employ such a system. Notably, a ‘lamina-less’ tooth replacement condition is found in a paraphyletic array of ray-finned fishes, such as stickleback, trout, cod, medaka, and bichir. Furthermore, the position, renewal potential, and latency times appear to vary drastically across different vertebrate tooth regeneration systems. The progenitor cells underlying tooth regeneration thus present highly divergent arrangements and potentials. Given the spectrum of regeneration systems present in vertebrates, it is unclear if morphologically divergent tooth regeneration systems deploy an overlapping battery of genes in their naïve dental tissues.

Results

In the present work, we aimed to determine whether or not tooth progenitor epithelia could be composed of a conserved cell type between vertebrate dentitions with divergent regeneration systems. To address this question, we compared the tooth regeneration processes in two ray-finned fishes: zebrafish (Danio rerio) and threespine stickleback (Gasterosteus aculeatus). These two teleost species diverged approximately 250 million years ago, and demonstrate some stark differences in dental morphology and regeneration. Here we find that the successional dental lamina in zebrafish sharply upregulates Wnt signaling andLef1expression during early morphogenesis stages of tooth development. Additionally, the naïve zebrafish successional dental lamina expresses a battery of nine genes (Bmpr1a, Bmp6, CD34, Gli1, Igfbp5a, Lgr4, Lgr6, Nfatc1, andPitx2). We also find that, despite the absence of a histologically distinct successional dental lamina in stickleback tooth fields, new tooth germs also sharply upregulate Wnt signaling andLef1expression, and additionally express the same battery of nine genes in the basalmost endodermal cell layer from which replacement tooth epithelia arise. Thus, two fish systems that either have an organized successional dental lamina (zebrafish) or lack a morphologically distinct successional dental lamina (sticklebacks) deploy similar genetic programs during tooth regeneration.

Conclusions

We propose that the expression domains described here delineate a highly conserved “successional dental epithelium” (SDE). Furthermore, a set of orthologous genes is known to mark hair follicle epithelial stem cells in mice, suggesting that regenerative systems in other epithelial appendages may utilize a related epithelial progenitor cell type, despite the highly derived nature of the resulting functional organs.
Antihypertensive effect of brain-targeted mechanical intervention with passive head motion
Authors: Murase Shuhei , Sakitani Naoyoshi , Maekawa Takahiro , Yoshino Daisuke , Takano Kouji , Konno Ayumu , Hirai Hirokazu , Saito Taku , Tanaka Sakae , Shinohara Keisuke , Kishi Takuya , Yoshikawa Yuki , Sakai Takamasa , Ayaori Makoto , Inanami Hirohiko , Tomiyasu Koji , Takashima Atsushi , Ogata Toru , Tsuchimochi Hirotsugu , Sato Shinya , Saito Shigeyoshi , Yoshino Kohzoh , Matsuura Yuiko , Funamoto Kenichi , Ochi Hiroki , Shinohara Masahiro , Nagao Motoshi , Sawada Yasuhiro
Published: September 2020

Physical exercise is known to be beneficial for various brain functions. However, the mechanisms behind the positive effects of exercise on the brain remain to be elucidated. Here we show that passive head motion in hypertensive rats, which reproduces the mechanical accelerations generated in their heads during moderate-velocity treadmill running, decreases the expression of angiotensin II type 1 receptor (AT1R) in astrocytes in the rostral ventrolateral medulla (RVLM), thereby lowering blood pressure. Passive head motion generates interstitial fluid movement that is estimated to exert shear stress with an average magnitude of <1 Pa on the cells in the rat medulla. Fluid shear stress of a sub-Pa magnitude decreases AT1R expression in cultured astrocytes. In hypertensive rats, inhibition of interstitial fluid movement following hydrogel introduction to the RVLM eliminates the antihypertensive effects of passive head motion and treadmill running. Furthermore, vertically oscillating chair riding by hypertensive adult humans, which reproduces the mechanical accelerations generated in their heads during light jogging or fast walking, lowers their blood pressure. Our findings indicate that moderate mechanical intervention can have antihypertensive effects by modulating the function of RVLM astrocytes through interstitial fluid shear stress. We anticipate that mechanical regulation is responsible for a variety of the positive effects of physical exercise on human health, particularly those related to brain functions.
Is there a need for preoperative α-blocker in patients missed preoperative diagnosis of extra-adrenal retroperitoneal paraganglioma undergoing paraganglioma resection? A retrospective study of 167 cases at a single center
Authors: Liu Yi , Jin Xinye , Gao Jie , Jiang Shan , Liu Lei , Lou Jing-Sheng , Wang Bo , Zhang Hong , Fu Qiang
Published: September 2020

Background

Preoperative α-adrenergic blockade is believed to decrease perioperative risks and mortality in adrenal pheochromocytoma surgeries. The aim of this study is to evaluate the effects of the preoperative α-adrenergic blockade on patients’ outcomes in extra-adrenal retroperitoneal paraganglioma surgeries.

Methods

We searched our clinical database for the diagnosis extra-adrenal retroperitoneal paraganglioma by postoperative histopathology in the General Hospital of People’s Liberation Army from 2000 till 2017. And we recorded preoperative status of patients, preoperative medication preparation, intraoperative and postoperative cardiovascular events, intake and output, length of stay in ICU, length of hospital stay, and short time outcomes.

Results

The intraoperative morbidity of heart rate elevation and highest heart rate were higher in patients undergoing tumor manipulation with preoperative α-adrenergic blockade than those without (P<0.05), while there were no significant differences in intraoperative morbidity of blood pressure elevation and SAP decreased following tumorectomy in these two groups (P>0.05). There were no significant differences in postoperative complications and outcomes (P>0.05).

Conclusion

Under the current medical techniques, either with or without preoperative medicine, resection of extra-adrenal retroperitoneal paraganglioma could be carried out successfully.
Distribution, and abundances of Peleng Tarsier (Tarsius pelengensis), in Banggai Island group, Indonesia
Authors: Syahrullah Fakhri Naufal , Maddus Un , Mustari Abdul Haris , Indrawan Mochamad
Published: September 2020

The Peleng tarsier (Tarsius pelengensis) is a practically unknown prosimian, with a very narrow range limited to Banggai island-group, Central Sulawesi, Indonesia. It was classified as “Endangered” by IUCN in 2017. Detailed demographic and distribution information aboutT. pelengensisin the wild is not available even though they are crucial to setting up conservation priorities and strategies. The aim of this study was to analyze distribution, and population ofT. pelengensisacross the island group. Surveys were conducted over approximately five months in 2017 and 2018 across Peleng and the neighboring islands of Banggai, Labobo, and Bangkurung. It is now established that tarsiers occur on two of the major islands, namely Peleng and Banggai Island proper. Average density in Peleng and Banggai islands were estimated to be 247 individuals/km2, and this roughly fall within the broad ranges of tarsier densities in Sulawesi and offshore islands. In stark contrast to the only previously available supposition of distribution and conservation status (IUCN 2017), Tarsiers were found in nearly all elevations (0-937 m above sea level) and all habitats in Peleng island. There is also an entire newly discovered population in Banggai Island proper, which similarly distributed in varied habitats. Therefore, the conservation status of Peleng tarsier needs to be re-evaluated.
Independent recruitment of PRC1 and PRC2 by human XIST
Authors: Dixon-McDougall Thomas , Brown Carolyn J.
Published: September 2020

XIST establishes inactivation across its chromosome of origin, even when expressed from autosomal transgenes. To identify the regions of human XIST essential for recruiting heterochromatic marks we generated a series of overlapping deletions in an autosomal inducible XIST transgene. We examined the ability of each construct to enrich its unified XIST territory with the histone marks established by PRC1 and PRC2 as well as the heterochromatin factors MacroH2A and SMCHD1. PRC1 recruitment required four distinct regions of XIST, and these were completely distinct from the two domains crucial for PRC2 recruitment. Both the domains required and the impact of inhibitors suggest that PRC1 is required for SMCHD1 while PRC2 function is necessary for MacroH2A recruitment, although incomplete overlap of regions implicates a role for additional factors. The independence of the PRC1/PRC2 pathways, yet important of all regions tested, demonstrate both modularity and cooperativity across the XIST lncRNA.

Author Summary

XIST functions as a long, non-protein coding, RNA to initiate various pathways for the silencing of one of the two X chromosomes in female placental mammals. CRISPR-directed mutations of an inducible human XIST construct in somatic cells allowed us to discover which regions of the RNA are required for chromatin modification and protein recruitment. This was the first large-scale dissection of human XIST domains, and every function assessed was dependent on multiple regions of XIST, suggesting considerable interactions between domains of XIST. We observed similarities, but also differences, with the domains previously identified in mouse Xist and demonstrated the presence of independent pathways for chromosome reorganization in humans as well as ascribing new functionality to regions of XIST. The ability of XIST to inactivate large sections of chromosomes from which it is expressed makes it both an exciting potential therapeutic for chromosome number abnormalities as well as a paradigm for how non-coding RNA genes are able to regulate cellular biology.
Expansion of CD10negneutrophils and CD14+HLA-DRneg/lowmonocytes driving proinflammatory responses in patients with acute myocardial infarction
Authors: Fraccarollo Daniela , Neuser Jonas , Möller Julian , Riehle Christian , Galuppo Paolo , Bauersachs Johann
Published: September 2020

Immature neutrophils and HLA-DRneg/lowmonocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and functional characteristics after acute myocardial infarction (AMI) remain underexplored. We found an expansion of circulating immature CD16+CD66b+CD10negneutrophils and CD14+HLA-DRneg/lowmonocytes in patients with AMI, correlating with cardiac damage, function and serum levels of immune-inflammation markers. Increased frequency of immature CD10negneutrophils and elevated circulating levels of IFN-γ were linked, mainly in cytomegalovirus (CMV)-seropositive patients with high anti-CMV antibody titers and expanded CD4+CD28nullT-cells. At a mechanistic level, CD10negneutrophils enhance IFN-γ production by CD4+T-cells through induction of interleukin-12. Moreover, we showed that HLA-DRneg/lowmonocytes are not immunosuppressive but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Thus, the immunoregulatory functions of immature CD10negneutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation in patients with AMI.
Deciphering how interneuron specific 3 cells control oriens lacunosum-moleculare cells to contribute to circuit function
Authors: Guet-McCreight Alexandre , Skinner Frances K
Published: September 2020

The wide diversity of inhibitory cells across the brain makes them suitable to contribute to network dynamics in specialized fashions. However, the contributions of a particular inhibitory cell type in a behaving animal are challenging to untangle as one needs to both record cellular activities and identify the cell type being recorded. Thus, using computational modeling and theory to predict and hypothesize cell-specific contributions is desirable. Here, we examine potential contributions of interneuron-specific 3 (I-S3) cells - an inhibitory interneuron found in CA1 hippocampus that only targets other inhibitory interneurons - during simulated theta rhythms. We use previously developed multi-compartment models of oriens lacunosum-moleculare (OLM) cells, the main target of I-S3 cells, and explore how I-S3 cell inputs duringin vitroandin vivoscenarios contribute to theta. We find that I-S3 cells suppress OLM cell spiking, rather than engender its spiking via post-inhibitory rebound mechanisms, and contribute to theta frequency spike resonance during simulatedin vivoscenarios. To elicit recruitment similar toin vitroexperiments, inclusion of disinhibited pyramidal cell inputs is necessary, implying that I-S3 cell firing broadens the window for pyramidal cell disinhibition. Usingin vivovirtual networks, we show that I-S3 cells contribute to a sharpening of OLM cell recruitment at theta frequencies. Further, shifting the timing of I-S3 cell spiking due to external modulation shifts the timing of the OLM cell firing and thus disinhibitory windows. We propose a specialized contribution of I-S3 cells to create temporally precise coordination of modulation pathways.

New & Noteworthy

How information is processed across different brain structures is an important question that relates to the different functions that the brain performs. Using modelling and theoretical analyses, we show that an inhibitory cell type that only inhibits other inhibitory cells can broaden the window for disinhibition of excitatory cells, manage input pathway switching, and modulate inhibitory cell spiking. This work contributes to knowledge of how coordination between sensory and memory consolidation information can be attained.
Biochemical reconstitutions reveal principles of humanγ-TuRC assembly and function
Authors: Wieczorek Michal , Ti Shih-Chieh , Urnavicius Linas , Molloy Kelly R. , Aher Amol , Chait Brian T. , Kapoor Tarun M.
Published: September 2020

The formation of cellular microtubule networks is regulated by theγ-tubulin ring complex (γ-TuRC). This ∼2.3 MDa assembly of >31 proteins includesγ-tubulin and GCP2-6, as well as MZT1 and an actin-like protein in a “lumenal bridge”. The challenge of reconstituting theγ-TuRC has limited dissections of its assembly and function. Here, we report a complete biochemical reconstitution of the humanγ-TuRC (γ-TuRC-GFP), a ∼35S complex that nucleates microtubulesin vitro. We extend our approach to generate a stable subcomplex,γ-TuRCmini-GFP, which lacks MZT1 and actin. Using mutagenesis, we show thatγ-TuRCmini-GFP nucleates microtubules in a guanine nucleotide-dependent manner and proceeds with similar kinetics as reported for nativeγ-TuRCs. Electron microscopy reveals thatγ-TuRC-GFP resembles the nativeγ-TuRC architecture, whileγ-TuRCmini-GFP adopts a partial cone shape presenting only 8-10γ-tubulin subunits and lacks a well-ordered lumenal bridge. Our structure-function analysis suggests that the lumenal bridge facilitates the self-assembly of regulatory interfaces around a microtubule-nucleating “core” in theγ-TuRC.
Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice
Authors: Zhang Z , Park J. W. , Ahn I. S. , Diamante G. , Sivakumar N. , Arneson D. V. , Yang X. , van Veen J. E. , Correa S. M.
Published: September 2020

Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cell types that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating key aspects of the human physiological response. Single cell RNA sequencing reveals that tamoxifen treatment induces significant and widespread gene expression changes in different cell types of the hypothalamus, most strongly in neurons and ependymal cells. These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus ablated or reversed tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit changes in thermal regulation, bone density, or movement in response to tamoxifen treatment. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus and support a model in which hypothalamic ERα mediates several key side effects of tamoxifen therapy.
Renal proximal tubule cell state and metabolism are coupled by nuclear receptors
Authors: Park Jihwan , Dhillon Poonam , Hurtado Carmen , Li Lingzhi , Huang Shizheng , Zhao Juanjuan , Kang Hyun Mi , Shrestra Rojesh , Balzer Michael S. , Chatterjee Shatakshee , Prado Patricia , Han SeungYub , Liu Hongbo , Sheng Xin , Bartmanov Kirill , Rojas Juan P. , Prósper Felipe , Li Mingyao , Pei Liming , Kim Junhyong , Monserrat Nuria , Susztak Katalin
Published: September 2020

Kidney disease development is poorly understood due to the complex cellular interactions of more than 25 different cell types, each with specialized functions. Here, we used single cell RNA-sequencing to resolve cell type-specific and cell fraction changes in kidney disease.

Whole kidney RNA-sequencing results were strongly influenced by cell fraction changes, but minimally informative to detect cell type-specific gene expression changes. Cell type-specific differential expression analysis identified proximal tubule cells (PT cells) as the key vulnerable cell type in diseased kidneys. Through unbiased cell trajectory analyses, we show that PT cell differentiation state is altered in disease state. Lipid metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and reproducible association with PT cells state. The coupling of cell state and metabolism is established by nuclear receptors such as PPARA and ESRRA that not only control cellular metabolism but also the expression of PT cell-specific genes in mice and patient samples.
Knowledge, attitudes and practices of COVID 19 among Medical Laboratory Professionals in Zambia
Authors: Chawe Adon , Mfune Ruth L. , Siyapila Paul , Zimba Sharon D. , Vlahakis Pipina , Mwale Samson , Mwape Kapambwe , Kalolekesha Memory , Chileshe Misheck , Mutale Joseph , Mudenda Tobela , Manda Grace , Daka Victor
Published: September 2020

Background

COVID-19 is a novel disease that has spread to nearly every country worldwide. Medical laboratory professionals are key in the fight against COVID-19 as they provide confirmatory diagnosis which is the main basis upon which cases are identified and clinical management instituted. Lack of knowledge, poor attitude and unsafe laboratory practices could have negative implications towards the control of COVID-19. We conducted a quick online questionnaire to investigate the knowledge, attitudes and practices of medical laboratory personnel regarding COVID-19 in Zambia.

Methods

We conducted a cross sectional study among medical laboratory professionals in Zambia from 10th to 29th June, 2020. Data were collected using google forms and exported to SPSS version 23 for statistical analysis. Independent predictors of COVID-19 knowledge and practices were determined. Adjusted odds ratios and their 95% confidence intervals are reported.

Results

A total of 208 medical laboratory professionals participated in the study. There were more males (58.2%) than females. The majority of respondents had good knowledge (84.1%) and practice (75%) regarding COVID-19. Less than half (n=97, 46.6%) reported willingness to participate in a vaccination program. Predictors of good knowledge included; having a Bachelors degree (AOR: 5.0, CI: 1.15-23.9) and having prior COVID-19 related training (AOR: 8.83, CI: 2.03-38.4). Predictors of good practice included; having a masters or PhD qualification (AOR: 5.23, CI: 1.15-23.9) and having prior COVID-19 related training (AOR: 14.01, CI: 6.47-30.4).

Conclusion

Our findings revealed that medical laboratory professionals in Zambia have good knowledge and positive attitude towards COVID-19. However poor practices were observed There is need for continuous professional development (CPD) to ensure that medical laboratory professionals are well informed and aware of best practices to aid in curbing the pandemic.