bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromosome Errors in Human Eggs Shape Natural Fertility Over Reproductive Life Span
Authors: Gruhn Jennifer R. , Zielinska Agata P. , Shukla Vallari , Blanshard Robert , Capalbo Antonio , Cimadomo Danilo , Nikiforov Dmitry , Chan Andrew Chi-Ho , Newnham Louise J. , Vogel Ivan , Scarica Catello , Krapchev Marta , Taylor Deborah , Kristensen Stine Gry , Cheng Junping , Ernst Erik , Bjørn Anne-Mette Bay , Colmorn Lotte Berdiin , Blayney Martyn , Elder Kay , Liss Joanna , Hartshorne Geraldine , Grøndahl Marie Louise , Rienzi Laura , Ubaldi Filippo , McCoy Rajiv , Lukaszuk Krzysztof , Andersen Claus Yding , Schuh Melina , Hoffmann Eva R.
Published: July 2020

(Abstracted from Science 2019;365:1466–1469)

While it is understood that young females (≥13 years to early 20s) and women of advancing maternal age (AMA, mid-30s or older) have reduced fertility rates, the exact mechanisms behind this feature of the fertility curve remain unclear. Because chromosomal errors and aneuploidy cause a significant amount of pregnancy loss and congenital disorders in women of advanced maternal age, meiotic error rates throughout the entire reproductive life span may shape natural fertility.
Specific Birth Defects in Pregnancies of Women With Diabetes: National Birth Defects Prevention Study, 1997–2011
Authors: Tinker Sarah C. , Gilboa Suzanne M. , Moore Cynthia A. , Waller D. Kim , Simeone Regina M. , Kim Shin Y. , Jamieson Denise J. , Botto Lorenzo D. , Reefhuis Jennita
Published: July 2020

(Abstracted from Am J Obstet Gynecol 2020;222:176.e1–176.e11)

The National Birth Defects Prevention Study (NBDPS) was one of the first analyses to report the association between diabetes and birth defects. The study’s data of approximately 18,000 deliveries from October 1997 to December 2003 showed strong associations with many birth defects, primarily with pregestational diabetes but also with gestational diabetes.
Cutaneous Melanocytic Tumors With Concomitant NRAS Q61R and IDH1 R132C Mutations
Authors: Macagno Nicolas , Pissaloux Daniel , Etchevers Heather , Haddad Véronique , Vergier Beatrice , Sierra-Fortuny Sandrine , Tirode Franck , de la Fouchardière Arnaud
Published: July 2020

We report a series of 6 melanocytic proliferations harboring both NRAS and IDH1 hotspot mutations. Clinically, there was no specific sex-ratio, ages ranged from 18 to 85 years, and the trunk and limbs were the most affected localizations. In half of the cases, progressive modification of a pre-existing nevus was reported. Morphologically, all tumors were predominantly based in the dermis and the most striking pathologic finding was the presence of a background architecture of congenital-type nevi with a superimposed biphasic pattern formed by dendritic pigmented melanocytes surrounding areas of nevoid melanocytes. This finding was further underscored by HMB45 staining, which was positive in the dendritic cells and negative in the nevoid melanocytes. Four cases displayed increased cellularity and 1 case showed increased dermal mitotic activity. DNA and RNA sequencing revealed NRAS

Q61R
and IDH1

R132C
comutations in all 6 cases, with homogenous expression data according to unsupervised clustering analysis. Array-comparative genomic hybridization revealed no copy number alteration for the 2 most cellular and mitogenic cases. All were surgically excised, available follow-up for 2 patients showed no relapse nor metastases. We hypothesize that the IDH1 mutation is a secondary event in a pre-existing NRAS-mutated nevus and could be in part responsible for the emergence of a pigmented dendritic dermal component. So far, such comutations have been reported in one benign melanocytic nevus and several melanomas. This combination could represent a new subgroup of intermediate prognosis (melanocytoma) with a distinctive morphology. Further acquisition of genomic anomalies could progressively lead to malignant transformation.
Factors Affecting Implementation of Evidence-Based Practices in Public Health Preparedness and Response
Authors: Kennedy Mallory , Carbone Eric G. , Siegfried Alexa L. , Backman Deborah , Henson John D. , Sheridan Jackie , Meit Michael B. , Thomas Erin V.
Published: July 2020

Context:

There is limited research on what factors are most salient to implementation of evidence-based practices (EBPs) among public health agencies in public health emergency preparedness and response (PHPR) and under what conditions EBP implementation will occur.

Objective:

This study assessed the conditions, barriers, and enablers affecting EBP implementation among the PHPR practice community and identified opportunities to support EBP implementation.

Design:

A Web-based survey gathered information from public health agencies. Data obtained from 228 participating agencies were analyzed.

Setting:

State, local, and territorial public health agencies across the United States.

Participants:

Preparedness program officials from 228 public health agencies in the United States, including Public Health Emergency Preparedness (PHEP) cooperative agreement awardees (PHEP awardees) and a random sample of local health departments (LHDs).

Results:

Respondents indicated that EBP is necessary and improves PHPR functions and tasks and that staff are interested in improving skills for EBP implementation. Top system-level barriers to EBP implementation were insufficient funding, lack of EBP, and lack of clarity regarding which practices are evidence based. PHEP awardees were significantly more likely to report a lack of EBP in the field, whereas LHDs were significantly more likely to report a lack of incentives. The top organizational-level barrier was insufficient staff. Most respondents indicated their agency culture supports EBP; however, LHDs were significantly more likely to report a lack of support from supervisors and leadership. Few respondents reported individual barriers to EBP implementation.

Conclusions:

Findings indicate an opportunity to improve dissemination strategies, communication efforts, and incentives to support EBP implementation in PHPR. Potential strategies include improving awareness of and accessibility to EBPs through targeted dissemination efforts; building organizational capacity to support EBP implementation, particularly staff capacity, knowledge, and skills; and identifying funding and incentives to promote EBP uptake and sustainment.
Association Between Accreditation Engagement and Using The Community Guide for Preventive Services by Local Health Departments
Authors: Roba Assegid Aga , Williams Brianna C. , Waterfield Kristie C. , Shah Gulzar H.
Published: July 2020

Background:

Accreditation is one of the macro trends shaping the future of public health practice, and The Community Guide to Preventive Services is a decision-making tool used to select evidence-based interventions. Although local health departments (LHDs) seeking accreditation use The Community Guide, the relationship between the two remains unknown. The purpose of this study was to determine whether accreditation engagement is associated with the extent to which LHDs use The Community Guide.

Methods:

Data from the National Association of County and City Health Officials' 2016 Profile of LHDs were examined for associations between accreditation engagement and the use of The Community Guide.

Results:

Whereas 52.8% of LHDs used The Community Guide sometimes or consistently, only 21.5% were engaged in the accreditation process. Engaged LHDs were more likely to use The Community Guide consistently (adjusted odds ratios: 8.2; 95% confidence interval, 4.0-16.4) or sometimes (adjusted odds ratios: 3.6; 95% confidence interval, 2.4-5.3) than those not engaged at all. Local health departments serving a population of more than 50 000, organized with a county or mixed level of jurisdiction, and those having a top executive with a masters' or a doctoral degree, were more likely to report some use of The Community Guide.

Conclusions:

The extent that LHDs utilize The Community Guide is positively associated with the level of their accreditation engagement. Capacity building and policy measures could encourage LHDs to seek accreditation thereby increasing the use of The Community Guide for evidence-informed practice. Future studies should identify causal factors predicting the use of The Community Guide.
A Quality Initiative to Improve Appropriate Use of Initial Outpatient Echocardiography Among Pediatric Cardiologists
Authors: Frandsen Erik L. , Kourtidou Soultana , Tieder Joel S. , Alberda Erin , Soriano Brian D.
Published: July 2020

Introduction:

Appropriate use criteria (AUC) guide initial transthoracic echocardiogram (TTE) use in outpatient pediatrics. We sought to improve pediatric cardiologist TTE ordering appropriateness (mean AUC score) with a quality improvement initiative.

Methods:

The outcome of interest was the prospective AUC score for all initial outpatient TTEs ordered between November 2016 and August 2017, categorized per the AUC: “appropriate” (score 7–9), “may be appropriate” (4–6), “rarely appropriate” (1–3). Interventions included a didactic review of 2014 AUC and participant documentation of AUC criteria for each TTE. Participants met quarterly to evaluate outcome, process, and balancing measures, intervention effectiveness, and to identify and mitigate barriers.

Results:

Twenty-two pediatric cardiologists participated. TTE appropriateness level before (n = 216) and after (n = 557) intervention was high. There was no significant difference in mean baseline and post-intervention AUC score (7.42 ± 1.87 versus 7.16 ± 2.87, P = 0.1), nor in TTE sensitivity (27% versus 25%, P > 0.1) as a balancing measure. Among baseline studies, 81% were “appropriate,” and 6% “rarely appropriate.” Among post-intervention studies, 76% were “appropriate,” and 11% “rarely appropriate.” Barriers identified to implementing AUC include TTE indications not specified by current AUC, expectations of referring provider or parent to perform TTE, consistent provider application of AUC, and ability of AUC to capture comprehensive clinical judgment.

Conclusions:

Although the mean AUC appropriateness level was high, we were able to identify significant barriers to the implementation of AUC. Future efforts should focus on the reduction of “rarely appropriate” TTE ordering.
Draconibacterium mangrovi sp. nov., isolated from mangrove sediment
Authors: Hu Yuzhong , Guo Yu , Lai Qiliang , Dong Le , Huang Zhaobin
Published: July 2020

A marine bacterial strain, designated GM2-18T, was isolated from mangrove sediment sampled at Luoyang River estuary, Quanzhou, PR China. Cells were Gram-stain-negative, slightly curved long rod-shaped and facultatively anaerobic with no flagellum. Catalase activity was found to be weak-positive and oxidase-positive. It had no ability to degrade or hydrolyse substrates including skimmed milk, cellulose, starch and Tweens (40, 60 and 80). The 16S rRNA gene sequence of strain GM2-18T had maximum similarity values to ‘

Draconibacterium filum

’ F2T,

Draconibacterium sediminis

JN14CK-3T and

Draconibacterium orientale

FH5T of 98.0, 97.8 and 97.4 %, respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain GM2-18T was affiliated to the genus

Draconibacterium

and formed a clade with an uncultured bacterium clone identified from mangrove environment. Average nucleotide identity values and DNA–DNA hybridization estimates of strain GM2-18T compared to its

Draconibacterium

relatives strongly supported that it belonged to a new species. The respiratory quinone was menaquinone MK-7. The major fatty acids (>10 %) consisted of iso-C15 : 0, anteiso-C15 : 0 and C17 : 1
 ω6c. The polar lipids were phosphatidylethanolamine, a phospholipid and several unidentified lipids. The genomic size of strain GM2-18T was 5.9 Mb and the G+C content was 40.8 mol%. Gene prediction and annotation of strain GM2-18T indicated that there was a nitrogen-fixing gene cluster encoding nitrogenase molybdenum-iron protein and related proteins responsible for nitrogen fixation. Based on the above characteristics, strain GM2-18T represents a novel species within the genus

Draconibacterium

. Thus, Draconibacterium mangrovi sp. nov. is proposed with type strain GM2-18T (=MCCC 1K04382T=KCTC 72879T), isolated from mangrove sediment.
Chloroplast-derived photo-oxidative stress causes changes in H2O2andEGSHin other subcellular compartments
Authors: Ugalde José Manuel , Fuchs Philippe , Nietzel Thomas , Cutolo Edoardo A. , Vothknecht Ute C. , Holuigue Loreto , Schwarzländer Markus , Müller-Schüssele Stefanie J. , Meyer Andreas J.
Published: July 2020

Metabolic fluctuations in chloroplasts and mitochondria can trigger retrograde signals to modify nuclear gene expression. Mobile signals likely to be involved are reactive oxygen species (ROS), which can operate protein redox switches by oxidation of specific cysteine residues. Redox buffers such as the highly reduced glutathione pool serve as reservoirs of reducing power for several ROS scavenging and ROS-induced damage repair pathways. Formation of glutathione disulfide (GSSG) and a shift of the glutathione redox potential (EGSH) towards less negative values is considered a hallmark of several stress conditions. Here we used the herbicide methyl viologen (MV) to generate ROS locally in chloroplasts of intact Arabidopsis seedlings and recorded dynamic changes inEGSHand H2O2levels with the genetically-encoded biosensors Grx1-roGFP2 (forEGSH) and roGFP2-Orp1 (for H2O2) targeted to chloroplasts, the cytosol or mitochondria. Treatment of seedlings with MV caused a rapid oxidation in chloroplasts and subsequently also in the cytosol and mitochondria. The MV-induced oxidation was significantly boosted by illumination with actinic light and largely abolished by inhibitors of photosynthetic electron transport. In addition, MV also induced an autonomous oxidation in the mitochondrial matrix in an electron transport chain activity-dependent manner that was milder than the oxidation triggered in chloroplasts by the combination of MV and light.In vivoredox biosensing resolves the spatiotemporal dynamics of compartmental responses to local ROS generation and provide a basis for understanding how compartment-specific redox dynamics may operate in retrograde signaling and stress acclimation in plants.

One sentence summary

Methyl viologen-induced photooxidative stress causes an increase of H2O2and oxidation of glutathione in chloroplasts, cytosol and mitochondria as well as autonomous oxidation in mitochondria.
Severe COVID-19 is associated with elevated serum IgA and antiphospholipid IgA-antibodies
Authors: Ali Omar Hasan , Bomze David , Risch Lorenz , Brugger Silvio D. , Paprotny Matthias , Weber Myriam , Thiel Sarah , Kern Lukas , Albrich Werner C. , Kohler Philipp , Kahlert Christian R. , Vernazza Pietro , Bühler Philipp K. , Schüpbach Reto A. , Gómez-Mejia Alejandro , Popa Alexandra M. , Bergthaler Andreas , Penninger Josef M. , Flatz Lukas
Published: July 2020

Background

While the pathogenesis of coronavirus disease 2019 (COVID-19) is becoming increasingly clear, there is little data on IgA response, the first line of bronchial immune defense.

Objective

To determine, whether COVID-19 is associated with a vigorous total IgA response and whether IgA autoantibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome (APS), our approach focused on antiphospholipid antibodies (aPL).

Materials and methods

In this retrospective cohort study we compared clinical data and aPL from 64 patients with COVID-19 from three independent centers (two in Switzerland, one in Liechtenstein). Samples were collected from April 9, 2020 to May 1, 2020. Total IgA and aPL were measured with FDA-approved commercially available clinical diagnostic kits.

Results

Clinical records of the 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID,n=26 [41%]), a discovery cohort with severe illness (sdCOVD,n=14 [22%]) and a confirmation cohort with severe illness (scCOVID,n=24 [38%]). Severe illness was significantly associated with increased total IgA (sdCOVID,P=0.01; scCOVID,P<0.001). Total IgG levels were similar in both cohorts. Among aPL, both cohorts with severe illness significantly correlated with elevated anti-Cardiolipin IgA (sdCOVID and scCOVID,P<0.001), anti-Cardiolipin IgM (sdCOVID,P=0.003; scCOVID,P<0.001), and anti-Beta2 Glycoprotein-1 IgA (sdCOVID and scCOVID,P<0.001). Systemic lupus erythematosus was excluded from all patients as a potential confounder of APS.

Conclusions

Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA-response triggered in the bronchial mucosa induces systemic autoimmunity.
COVID-19 Vulnerability of Transgender Women With and Without HIV Infection in the Eastern and Southern U.S.
Authors: Poteat Tonia C. , Reisner Sari L. , Miller Marissa , Wirtz Andrea L.
Published: July 2020

Background

COVID-19 is a new global pandemic and people with HIV may be particularly vulnerable. Gender identity is not reported, therefore data are absent on the impact of COVID-19 on transgender people, including transgender people with HIV. Baseline data from the American Cohort to Study HIV Acquisition Among Transgender Women in High Risk Areas (LITE) Study provide an opportunity to examine pre-COVID vulnerability among transgender women.

Setting

Atlanta, Baltimore, Boston, Miami, New York City, Washington, DC

Methods

Baseline data from LITE were analysed for demographic, psychosocial, and material factors that may affect risk for COVID-related harms.

Results

The 1020 participants had high rates of poverty, unemployment, food insecurity, homelessness, and sex work. Transgender women with HIV (n=273) were older, more likely to be Black, had lower educational attainment, and were more likely to experience material hardship. Mental and behavioural health symptoms were common and did not differ by HIV status. Barriers to healthcare included being mistreated mistreatment, uncomfortable providers, and past negative experiences; as well as material hardships, such as cost and transportation. However, most reported access to material and social support – demonstrating resilience.

Conclusions

Transgender women with HIV may be particularly vulnerable to pandemic harms. Mitigating this harm would have positive effects for everyone, given the highly infectious nature of this coronavirus. Collecting gender identity in COVID-19 data is crucial to inform an effective public health response. Transgender-led organizations’ response to this crisis serve as an important model for effective community-led interventions.
Initial Experience in Predicting the Risk of Hospitalization of 496 Outpatients with COVID-19 Using a Telemedicine Risk Assessment Tool
Authors: O’Keefe James B. , Tong Elizabeth J. , Taylor Thomas H. , O’Keefe Ghazala A. Datoo , Tong David C.
Published: July 2020

Title

Initial Experience in Validation of a Telemedicine Risk Assessment Tool for Hospitalization of Patients with COVID-19

Importance

Risk assessment of patients with acute coronavirus disease 2019 (COVID-19) in a telemedicine context is not well described. In the setting of large numbers of patients, a risk assessment tool may guide resource allocation not only for patient care but also for maximum healthcare and public health benefit.

Objective

To determine whether a risk prediction tool developed and implemented in March 2020 (“COVID-19 Telemedicine Risk Tier Assessment”) accurately predicts subsequent hospitalizations.

Design

Retrospective cohort study, enrollment from March 24 to May 26, 2020 with follow-up calls until hospitalization or clinical improvement (final call date range March 27 to June 19, 2020)

Setting

Single center “Virtual Outpatient Management Clinic” (VOMC) assessing and managing outpatients from a large quaternary medical system in Atlanta, Georgia

Participants

496 patients with COVID-19 confirmed by nasopharyngeal sampling in isolation at home at the time of diagnosis. Exclusion criteria included: (1) hospitalization prior to VOMC enrollment, (2) immediate discharge from VOMC with no follow-up calls due to resolution.

Exposure

Acute COVID-19 illness

Main Outcome and Measures

Hospitalization was the outcome. Days to hospitalization was the metric. Survival analysis using Cox regression was used to determine factors associated with hospitalization.

Results

The risk-assessment rubric assigned 496 outpatients to tiers as follows: Tier 1, 237 (47.8%); Tier 2, 185 (37.3%); Tier 3, 74 (14.9%). Subsequent hospitalizations numbered 3 (1%), 15 (7%), and 17 (23%) and for Tiers 1-3, respectively. From a Cox regression model with age ≥ 60, gender, and self-reported obesity as covariates, the adjusted hazard ratios using Tier 1 as reference were: Tier 2 HR=3.74 (95% CI, 1.06-13.27; P=0.041); Tier 3 HR=10.87 (95% CI, 3.09-38.27; P<0.001). Tier was the strongest predictor of time to hospitalization.

Conclusions and Relevance

A telemedicine risk assessment tool prospectively applied to an outpatient population with COVID-19 identified both low-risk (Tier 1) and high-risk (Tier 3) patients with better performance than individual risk factors alone. This approach may be appropriate for optimum allocation of resources.
Multi-layered network-based pathway activity inference using directed random walks: application to predicting clinical outcomes in urologic cancer
Authors: Kim So Yeon , Choe Eun Kyung , Shivakumar Manu , Kim Dokyoon , Sohn Kyung-Ah
Published: July 2020

Motivation

To better understand the molecular features of cancers, a comprehensive analysis using multi-omics data has been conducted. Additionally, a pathway activity inference method has been developed to facilitate the integrative effects of multiple genes. In this respect, we have recently proposed a novel integrative pathway activity inference approach, iDRW, and demonstrated the effectiveness of the method with respect to dichotomizing two survival groups. However, there were several limitations, such as a lack of generality. In this study, we designed a directed gene-gene graph using pathway information by assigning interactions between genes in multiple layers of networks.

Results

As a proof-of-concept study, it was evaluated using three genomic profiles of urologic cancer patients. The proposed integrative approach achieved improved outcome prediction performances compared with a single genomic profile alone and other existing pathway activity inference methods. The integrative approach also identified common/cancer-specific candidate driver pathways as predictive prognostic features in urologic cancers. Furthermore, it provides better biological insights into the prioritized pathways and genes in an integrated view using a multi-layered gene-gene network. Our framework is not specifically designed for urologic cancers and can be generally applicable for various datasets.

Availability

iDRW is implemented as the R software package. The source codes are available athttps://github.com/sykim122/iDRW.
Comparative Evaluation of 19 Reverse Transcription Loop-Mediated Isothermal Amplification Assays for Detection of SARS-CoV-2
Authors: Dong Yajuan , Wu Xiuming , Li Shenwei , Lu Renfei , Wan Zhenzhou , Qin Jianru , Yu Guoying , Jin Xia , Zhang Chiyu
Published: July 2020

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has caused a global pandemics. To facilitate the detection of SARS-CoV-2 infection, various RT-LAMP assays using 19 sets of primers had been developed, but never been compared. We performed comparative evaluation of the 19 sets of primers using 4 RNA standards and 29 clinical samples from COVID-19 patients. Six of 15 sets of primers were firstly identified to have faster amplification when tested with four RNA standards, and were further subjected to parallel comparison with the remaining four primer sets using 29 clinical samples. Among these 10 primer sets, Set-4 had the highest positive detection rate of SARS-CoV-2 (82.8%), followed by Set-10, Set-11, Set-13 and Set-14 (75.9%), and Set-14 showed the fastest amplification speed (< 8.5 minutes), followed by Set-17 (< 12.5 minutes). Based on the overall detection performance, Set-4, Set-10, Set-11, Set-13, Set-14 and Set-17 that target Nsp3, S, S, E, N and N gene regions of SARS-CoV-2, respectively, are determined to be better than the other primer sets. Two RT-LAMP assays with the Set-14 primers in combination with any one of four other primer sets (Set-4, Set-10, Set-11, and Set-13) are recommended to be used in the COVID-19 surveillance.
Microtubules tune mechanosensitive cell responses
Authors: Seetharaman Shailaja , Vianay Benoit , Roca Vanessa , De Pascalis Chiara , Boëda Batiste , Dingli Florent , Loew Damarys , Vassilopoulos Stéphane , Théry Manuel , Etienne-Manneville Sandrine
Published: July 2020

Mechanotransduction is a process by which cells sense the mechanical properties of their surrounding environment and adapt accordingly to perform cellular functions such as adhesion, migration and differentiation. Integrin-mediated focal adhesions are major sites of mechanotransduction and their connection with the actomyosin network is crucial for mechanosensing as well as the generation and transmission of forces onto the substrate. Despite having emerged as major regulators of cell adhesion and migration, the contribution of microtubules to mechanotransduction still remains elusive. Here, we show that actomyosin-dependent mechanosensing of substrate rigidity controls microtubule acetylation, a tubulin post-translational modification, by promoting the recruitment of the alpha-tubulin acetyl transferase (αTAT1) to focal adhesions. Microtubule acetylation, in turn, promotes GEF-H1 mediated RhoA activation, actomyosin contractility and traction forces. Our results reveal a fundamental crosstalk between microtubules and actin in mechanotransduction, which contributes to mechanosensitive cell adhesion and migration.
Modeling Alpha-Synuclein Pathology in a Human Brain-Chip to Assess Blood-Brain Barrier Disruption in Parkinson’s Disease
Authors: Pediaditakis Iosif , Kodella Konstantia R. , Manatakis Dimitris V. , Hinojosa Chris D. , Manolakos Elias S. , Rubin Lee L. , Hamilton Geraldine A. , Karalis Katia
Published: July 2020

Parkinson’s disease and related synucleinopathies are characterized by the abnormal accumulation of alpha-synuclein aggregates, loss of dopaminergic neurons, and gliosis in the substantia nigra. Although clinical evidence andin vitrostudies indicate disruption of the Blood-Brain Barrier in Parkinson’s disease, the mechanisms mediating the endothelial dysfunction remain elusive. Lack of relevant models able to recapitulate the order of events driving the development of the disease in humans has been a significant bottleneck in the identification of specific successful druggable targets. Here we leveraged the Organs-on-Chips technology to engineer a human Brain-Chip representative of the substantia nigra area of the brain containing dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow. Our αSyn fibril-induced model was capable of reproducing several key aspects of Parkinson’s disease, including accumulation of phosphorylated αSyn (pSer129-αSyn), mitochondrial impairment, neuroinflammation, and compromised barrier function. This model is poised to enable research into the dynamics of cell-cell interactions in human synucleinopathies and to serve as testing platform for novel therapeutic interventions, including target identification and target validation.
Centennial clonal stability of asexualDaphniain Greenland lakes despite climate variability
Authors: Dane Maison , Anderson N. John , Osburn Christopher L. , Colbourne John K. , Frisch Dagmar
Published: July 2020

Climate and environmental condition drive biodiversity at many levels of biological organisation, from populations to ecosystems. Combined with palaeoecological reconstructions, palaeogenetic information on resident populations provides novel insights into evolutionary trajectories and genetic diversity driven by environmental variability. While temporal observations of changing genetic structure are often made of sexual populations, little is known about how environmental change affects the long-term fate of asexual lineages. Here, we provide information on obligately asexual, triploidDaphniapopulations from three Arctic lakes in West Greenland through the past 200-300 years to test the impact of a changing environment on the temporal and spatial population genetic structure. The contrasting ecological state of the lakes, specifically regarding salinity and habitat structure may explain the observed lake-specific clonal composition over time. Palaeolimnological reconstructions show considerable environmental fluctuations since 1700 (the end of the Little Ice Age), but the population genetic structure in two lakes was almost unchanged with at most two clones per time period. Their local populations were strongly dominated by a single clone that has persisted for 250-300 years. We discuss three possible explanations for the apparent population genetic stability: (1) the persistent clones are general purpose genotypes that thrive under broad environmental conditions, (2) clonal lineages evolved subtle genotypic differences that are unresolved by microsatellite markers, or (3) epigenetic modifications allow for clonal adaptation to changing environmental conditions. Our results will motivate research into the mechanisms of adaptation in these populations, as well as their evolutionary fate in the light of accelerating climate change in the polar regions.
SARS-CoV-2-induced humoral immunity through B cell epitope analysis and neutralizing activity in COVID-19 infected individuals in Japan
Authors: Yoshida Shota , Ono Chikako , Hayashi Hiroki , Shiraishi Satoshi , Tomono Kazunori , Arase Hisashi , Matsuura Yoshiharu , Nakagami Hironori
Published: July 2020

The aim of this study is to understand adaptive immunity to SARS-CoV-2 through the analysis of B cell epitope and neutralizing activity in coronavirus disease 2019 (COVID-19) patients. We obtained serum from thirteen COVID-19 patients. Most individuals revealed neutralizing activity against SARS-CoV-2 assessed by a pseudotype virus-neutralizing assay. The antibody production against the spike glycoprotein (S protein) or receptor-binding domain (RBD) of SARS-CoV-2 was elevated, with large individual differences, as assessed by ELISA. In the analysis of the predicted the linear B cell epitopes, two regions (671-690 aa. and 1146-1164 aa.), which were located in S1 and S2 but not in the RBD, were highly reactive with the sera from patients. In the further analysis of the B cell epitope within the S protein by utilizing a B cell epitope array, a hot spot in the N-terminal domain of the S protein but not the RBD was observed in individuals with neutralizing activity. Overall, the analysis of antibody production and B cell epitopes of the S protein from patient serum may provide a novel target for the vaccine development against SARS-CoV-2.
Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response
Authors: Johnson Kevin C. , Anderson Kevin J. , Courtois Elise T. , Barthel Floris P. , Varn Frederick S. , Luo Diane , Seignon Martine , Yi Eunhee , Kim Hoon , Estecio Marcos RH , Tang Ming , Navin Nicholas E. , Maurya Rahul , Ngan Chew Yee , Verburg Niels , De Witt Hamer Philip C , Bulsara Ketan , Samuels Michael L. , Das Sunit , Robson Paul , Verhaak Roel GW
Published: July 2020

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. Our analyses support that somatic copy number alterations (SCNAs) promote epigenetic instability and that SCNAs largely precede epigenetic and transcriptomic diversification during glioma evolution. We confirmed the link between genetic and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response.
Pharmacological insights into safety and efficacy determinants for the development of adenosine receptor biased agonists in the treatment of heart failure
Authors: Rueda Patricia , Merlin Jon , Chimenti Stefano , Feletou Michel , Paysant Jerome , White Paul J. , Christopoulos Arthur , Sexton Patrick M. , Summers Roger J. , Charman William N. , May Lauren T. , Langmead Christopher J.
Published: July 2020

Adenosine A1receptors (A1R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but drug development has been hampered by on-target side effects such as bradycardia and altered renal haemodynamics. Biased agonism has emerged as an attractive mechanism for A1R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A1R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of heart failure. We compare this agent with the well-characterised, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A1R biased agonist VCP746, previously shown to be safe and cardioprotective in pre-clinical models of heart failure. We show that like VCP746, neladenoson is biased away from Ca2+influx relative to NECA and the cAMP pathway at the A1R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A1R. In contrast to VCP746, which displays more ‘adenosine-like’ signalling at the A2BR, neladenoson was a highly selective A1R agonist, with biased, weak agonism at the A2BR. Together these results show that unwanted haemodynamic effects of A1R agonists can be avoided by compounds biased away from Ca2+influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A1R-mediated cAMP inhibition may be a poor indicator of effectiveness in chronic heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating heart failure in patients.

ONE-SENTENCE SUMMARY

Biased agonists that preference against calcium influx relative to the cyclic AMP pathway, when compared to a conventional agonist, confer clinical safety to A1adenosine receptor ligands.
Axiomatic-deductive theory of competition of complete competitors: coexistence, exclusion and neutrality in one model
Authors: Kalmykov Lev V. , Kalmykov Vyacheslav L.
Published: July 2020

Background

The long-standing contradiction between formulations of the competitive exclusion principle and natural diversity of trophically similar species is known as the biodiversity paradox. Earlier we found that coexistence of complete competitors is possible despite 100% difference in competitiveness, but only under certain conditions – at their moderate propagation and at the particular initial location of individuals. Here we verify a hypothesis that completely competing species with aggressive propagation may coexist with less than 100% difference in competitiveness regardless of random initial location of competing individuals in ecosystem.

Methods

We investigate a role of competitiveness differences in coexistence of two completely competing species by individual-based modeling based on a transparent artificial intelligence. We propose and investigate an individual-based model of ecosystem dynamics supplemented by a probabilistic determination of the competitiveness of competing individuals without cooperative effects and with cooperative effects based on the numerical superiority of individuals of the species.

Results

We have found that two aggressively propagating complete competitors can stably coexist, despite one species has some advantage in competitiveness over the other and all other characteristics of the species are equal. The found competitive coexistence occurred regardless of the initial random location of individuals in the ecosystem. When colonization of a free habitat started from a single individual of each species, then the complete competitors coexisted up to 31% of their difference in competitiveness. And when on initial stage half of the territory was probabilistically occupied, the complete competitors coexisted up to 22% of their difference in competitiveness. In the experiments with cooperative dependence on the numerical superiority of individuals of the species complete competitors stably co-existed despite 10% difference in basic competitiveness.

Discussion

The results additionally support our earlier reformulation of the competitive exclusion principle. Besides that, we revealed classical cases of competitive exclusion and “neutrality”. Our approach unifies models of competitive exclusion (“niche”), neutrality and coexistence of complete competitors in one theory. Our individual-based modeling of a complex system based on a transparent artificial intelligence opens up great prospects for a variety of theoretical and applied fields.
A meta-analysis of clinical cases of reversion mutations inBRCAgenes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance
Authors: Tobalina Luis , Armenia Joshua , Irving Elsa , O’Connor Mark J. , Forment Josep V.
Published: July 2020

Germline mutations in theBRCA1orBRCA2genes predispose to hereditary breast and ovarian cancer and, mostly in the case ofBRCA2, are also prevalent in cases of pancreatic and prostate malignancies. Tumours from these patients tend to lose both copies of the wild typeBRCAgene, which makes them exquisitely sensitive to platinum drugs and PARP inhibitors (PARPi), treatments of choice in these disease settings. Reversion secondary mutations with the capacity of restoring BRCA protein expression have been documented in the literature asbona fidemechanisms of resistance to these treatments. Here, we perform a detailed analysis of clinical cases of reversion mutations described inBRCA1andBRCA2, which underlines the different importance of BRCA protein domains in contributing to resistance and the potential key role of mutagenic end-joining DNA repair pathways in generating reversions. Our analyses suggest that pharmacological inhibition of these repair pathways could improve durability of drug treatments and highlights potential interventions to both prevent the appearance of reversions and provide new therapeutic opportunities after their acquisition.

Highlights

Comprehensive analysis of reversion mutations inBRCAgenes identified in clinical cases of resistance to platinum or PARPi

Revertant proteins devoid of parts of the original sequence, identifying key protein functions involved in resistance

Hypomorph revertant BRCA proteins suggest potential new therapeutic opportunities to overcome resistance

Prevalence of mutational end-joining DNA repair mechanisms leading to reversions, especially in those affectingBRCA2

Pharmacological inhibition of mutational end-joining DNA repair could improve durability of drug treatments
Wing musculature reconstruction in extinct flightless auks (PinguinusandMancalla) reveals incomplete convergence with penguins (Spheniscidae) due to differing ancestral states
Authors: Watanabe Junya , Field Daniel J. , Matsuoka Hiroshige
Published: July 2020

Despite longstanding interest in convergent evolution, factors that result in deviations from fully convergent phenotypes remain poorly understood. In birds, the evolution of flightless wing-propelled diving has emerged as a classic example of convergence, having arisen in disparate lineages including penguins (Sphenisciformes) and auks (Pan-Alcidae, Charadriiformes). Nevertheless, little is known about the functional anatomy of the wings of flightless auks because all such taxa are extinct, and their morphology is almost exclusively represented by skeletal remains. Here, in order to re-evaluate the extent of evolutionary convergence among flightless wing-propelled divers, wing muscles and ligaments were reconstructed in two extinct flightless auks, representing independent transitions to flightlessness:Pinguinus impennis(a crown-group alcid), andMancalla(a stem-group alcid). Extensive anatomical data were gathered from dissections of 12 species of extant charadriiforms and 4 aequornithine waterbirds including a penguin. It was found that the wings of both flightless auk taxa were characterized by an increased mechanical advantage of wing elevator/retractor muscles, and decreased mobility of distal wing joints, both of which are likely advantageous for wing-propelled diving and parallel similar functional specializations in penguins. However, the conformations of individual muscles and ligaments underlying these specializations differ markedly between penguins and flightless auks, instead resembling those in each respective group’s close relatives. Thus, the wings of these flightless wing-propelled divers can be described as convergent as overall functional units, but are incompletely convergent at lower levels of anatomical organization—a result of retaining differing conditions from each group’s respective volant ancestors. Detailed investigations such as this one may indicate that, even in the face of similar functional demands, courses of phenotypic evolution are dictated to an important degree by ancestral starting points.
Identification of a new regulation pathway of EGFR and E-cadherin dynamics
Authors: Proux-Gillardeaux Veronique , Advedissian Tamara , Perin Charlotte , Gelly Jean-Christophe , Viguier Mireille , Deshayes Fredérique
Published: July 2020

EGFR plays key roles in multiple cellular processes such as cell differentiation, cell proliferation, migration and epithelia homeostasis. Phosphorylation of the receptor, intracellular signaling and trafficking are major events regulating EGFR functions. Galectin-7, a soluble lectin expressed in epithelia such as the skin, has been shown to be involved in cell differentiation. Through this study we demonstrate that galectin-7 regulates EGFR function by a direct interaction with its extracellular domain hence modifying its downstream signaling and endocytic pathway. From observations in mice we focused on the molecular mechanisms deciphering the glycosylation dependent interaction between EGFR and galectin-7. Interestingly, we also revealed that galectin-7 is a direct binder of both EGFR and E-cadherin bridging them together. Strikingly this study not only deciphers a new molecular mechanism of EGFR regulation but also points out a novel molecular interaction between EGFR and E-cadherin, two major regulators of the balance between proliferation and differentiation.

EGFR and E-cadherin are known to interact and to regulate epithelial homeostasis. In this study we unravel in the epidermis a new partner and regulator of EGFR which also binds E-cadherin reciprocally bridging their dynamics and functions.
Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool
Authors: Wang Richard , Ascanelli Camilla , Abdelbaki Ahmed , Fung Alex , Rasmusson Tim , Michaelides Iacovos , Roberts Karen , Lindon Catherine
Published: July 2020

Targeted protein degradation tools are becoming a new therapeutic modality, allowing small molecule ligands to be reformulated as heterobifunctional molecules (PROteolysis Targeting Chimeras, PROTACs) that recruit ubiquitin ligases to targets of interest, leading to ubiquitination and destruction of the targets. Several PROTACs against targets of clinical interest have been described, but detailed descriptions of the cell biology modulated by PROTACs are missing from the literature. Here we describe the functional characterization of a PROTAC derived from AURKA inhibitor MLN8237 (alisertib). We demonstrate efficient and specific destruction of both endogenous and overexpressed AURKA by Cereblon-directed PROTACs. At the subcellular level, we find differential targeting of AURKA on the mitotic spindle compared to centrosomes. The phenotypic consequences of PROTAC treatment are therefore distinct from those mediated by alisertib, and in mitotic cells differentially regulate centrosome- and chromatin-based microtubule spindle assembly pathways. In interphase cells PROTAC-mediated clearance of non-centrosomal AURKA modulates the cytoplasmic role played by AURKA in mitochondrial dynamics, whilst the centrosomal pool is refractory to PROTAC-mediated clearance. Our results point to differential sensitivity of subcellular pools of substrate, governed by substrate conformation or localization-dependent accessibility to PROTAC action, a phenomenon not previously described for this new class of degrader compounds.
Single-cell Long Non-coding RNA Landscape of T Cells in Human Cancer Immunity
Authors: Luo Haitao , Bu Dechao , Shao Lijuan , Li Yang , Sun Liang , Wang Ce , Wang Jing , Yang Wei , Yang Xiaofei , Dong Jun , Zhao Yi , Li Furong
Published: July 2020

The development of new therapeutic targets for cancer immunotherapies and the development of new biomarkers require deep understanding of T cells. To date, the complete landscape and systematic characterization of long noncoding RNAs (lncRNAs) in T cells in cancer immunity are lacking. Here, by systematically analyzing full-length single-cell RNA sequencing (scRNA-seq) data of more than 20,000 T cell libraries across three cancer types, we provide the first comprehensive catalog and the functional repertoires of lncRNAs in human T cells. Specifically, we developed a custom pipeline forde novotranscriptome assembly obtaining 9,433 novel lncRNA genes that increased the number of current human lncRNA catalog by 16% and nearly doubled the number of lncRNAs expressed in T cells. We found that a portion of expressed genes in single T cells were lncRNAs which have been overlooked by the majority of previous studies. Based on metacell maps constructed by MetaCell algorithm that partition scRNA-seq datasets into disjointed and homogenous groups of cells (metacells), 154 signature lncRNAs associated with effector, exhausted, and regulatory T cell states are identified, 84 of which are functionally annotated based on co-expression network, indicating that lncRNAs might broadly participate in regulation of T cell functions. Our findings provide a new point of view and resource for investigating the mechanisms of T cell regulation in cancer immunity as well as for novel cancer-immune biomarker development and cancer immunotherapies.