bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromatin-associated protein complexes link DNA base J and transcription termination inLeishmania
Authors: Jensen Bryan C , Phan Isabelle Q. , McDonald Jacquelyn R. , Sur Aakash , Gillespie Mark A. , Ranish Jeffrey A. , Parsons Marilyn , Myler Peter J
Published: May 2020

Unlike most other eukaryotes,Leishmaniaand other trypanosomatid protozoa have largely eschewed transcriptional control of gene expression; relying instead on post-transcriptional regulation of mRNAs derived from polycistronic transcription units (PTUs). In these parasites, a novel modified nucleotide base (β-D-glucopyranosyloxymethyluracil) known as J plays a critical role in ensuring that transcription termination occurs only at the end of each PTU, rather than at the polyadenylation sites of individual genes. To further understand the biology of J-associated processes, we used tandem affinity purification (TAP-tagging) and mass spectrometry to reveal proteins that interact with the glucosyltransferase performing the final step in J synthesis. These studies identified four proteins reminiscent of subunits in the PTW/PP1 complex that controls transcription termination in higher eukaryotes. Moreover, bioinformatic analyses identified the DNA-binding subunit ofLeishmaniaPTW/PP1 as a novel J-binding protein (JBP3), which is also part of another complex containing proteins with domains suggestive of a role in chromatin modification/remodeling. Additionally, JBP3 associates (albeit transiently and/or indirectly) with the trypanosomatid equivalent of the PAF1 complex involved in regulation of transcription in other eukaryotes. Down-regulation of JBP3 expression levels inLeishmaniaresulted in a substantial increase in transcriptional read-through at the 3’ end of most PTUs. We propose that JBP3 recruits one or more of these complexes to the J-containing regions at the end of PTUs, where they halt progression of the RNA polymerase. This de-coupling of transcription termination from splicing of individual genes enables the parasites’ unique reliance on polycistronic transcription and post-transcriptional regulation of gene expression.

Importance

Leishmaniaparasites cause a variety of serious human diseases, with no effective vaccine and emerging resistance to current drug therapy. We have previously shown that a novel DNA base called J is critical for transcription termination at the ends of the polycistronic gene clusters that are a hallmark ofLeishmaniaand related trypanosomatids. Here, we describe a new J-binding protein (JBP3) associated with three different protein complexes that are reminiscent to those involved in control of transcription in other eukaryotes. However, the parasite complexes have been reprogrammed to regulate transcription and gene expression in trypanosomatids differently than in the mammalian hosts, providing new opportunities to develop novel chemotherapeutic treatments against these important pathogens.
Slc26a9P2ACre, a new CRE driver to regulate gene expression in the otic placode lineage and other FGFR2b-dependent epithelia
Authors: Urness Lisa D. , Wang Xiaofen , Li Chaoying , Quadros Rolen M. , Harms Donald W. , Gurumurthy Channabasavaiah B. , Mansour Suzanne L.
Published: May 2020

Pan-otic CRE drivers enable gene regulation throughout the otic placode lineage, comprising the inner ear epithelium and neurons. However, intersection of extra-otic gene-of-interest expression with the CRE lineage can compromise viability and impede auditory analyses. Furthermore, extant pan-otic CREs recombine in auditory and vestibular brain nuclei, making it difficult to ascribe resulting phenotypes solely to the inner ear. We previously identifiedSlc26a9as an otic placode-specific target of FGFR2b ligands, FGF3 and FGF10. We show here thatSlc26a9is otic-specific through E10.5, but not required for hearing. We targetedP2ACreto theSlc26a9stop codon, generatingSlc26a9P2ACremice, and observed CRE activity throughout the otic epithelium and neurons, with little activity evident in the brain. Notably, recombination was detected in many FGFR2b ligand-dependent epithelia. We generatedFgf10andFgf8conditional mutants, and activated an FGFR2b ligand trap from E17.5-P3. In contrast to analogous mice generated with other pan-otic CREs, these were viable. Auditory thresholds were elevated in mutants, and correlated with cochlear epithelial cell losses. Thus,Slc26a9P2ACreprovides a useful complement to existing pan-otic CRE drivers, particularly for postnatal analyses.

Summary statement

We describe a new pan-otic CRE driver,Slc26a9P2ACre, with little activity in the brain or middle ear, and demonstrate its utility by manipulating FGF signaling and assessing hearing loss.
Comparison of Decision Modeling Approaches for Health Technology and Policy Evaluation
Authors: Graves John , Garbett Shawn , Zhou Zilu , Schildcrout Jonathan S. , Peterson Josh
Published: May 2020

We discuss tradeoffs and errors associated with approaches to modeling health economic decisions. Through an application in pharmacogenomic (PGx) testing to guide drug selection for individuals with a genetic variant, we assessed model accuracy, optimal decisions and computation time for an identical decision scenario modeled four ways: using (1) coupled-time differential equations [DEQ]; (2) a cohort-based discrete-time state transition model [MARKOV]; (3) an individual discrete-time state transition microsimulation model [MICROSIM]; and (4) discrete event simulation [DES]. Relative to DEQ, the Net Monetary Benefit for PGx testing (vs. a reference strategy of no testing) based on MARKOV with rate-to-probability conversions using commonly used formulas resulted in different optimal decisions. MARKOV was nearly identical to DEQ when transition probabilities were embedded using a transition intensity matrix. Among stochastic models, DES model outputs converged to DEQ with substantially fewer simulated patients (1 million) vs. MICROSIM (1 billion). Overall, properly embedded Markov models provided the most favorable mix of accuracy and run-time, but introduced additional complexity for calculating cost and quality-adjusted life year outcomes due to the inclusion of “jumpover” states after proper embedding of transition probabilities. Among stochastic models, DES offered the most favorable mix of accuracy, reliability, and speed.
The Effects of Nurse Specialty Certification and Medical Treatments on Glycemic Control Outcomes: A Retrospective Study
Authors: Ojeda Maria M.
Published: May 2020

AIMS

To describe and explore the impact of the presence of specialty certified nurses on the unit on glycemic control among non-critically ill hospitalized patients with Diabetes mellitus.

BACKGROUND

Poor glycemic control during hospitalization has been associated adverse patient outcomes. Staff nurses administer much of the diabetes-specific care delivered to patients during hospitalization. Nurse specialty certification is a recognized indicator of nursing care quality.

METHODS

A retrospective sample of medical records data was analyzed to describe and explore the impact of specialty certified nurses on glycemic control among a group of 293 non-critically ill hospitalized patients with Diabetes mellitus. Regression analysis was performed to assess the impact of the percentage of certified nurses on the unit as a mediator or moderator of the relationship between medical treatments and glycemic control outcomes.

RESULTS

Increases in the percentage of specialty certified nurses on the unit were associated with significant decreases in mean blood glucose levels among patients who received a basal-bolus insulin regimen or enteral nutritional feedings.

CONCLUSIONS

Patients who received specific medical treatments during hospitalization had superior outcomes when nursing care was delivered during times in which the relative proportion of certified nurses on the unit were higher.
Continuous Electroencephalography (cEEG) Characteristics and Acute Symptomatic Seizures in COVID-19 Patients
Authors: Louis Shreya , Dhawan Andrew , Newey Christopher , Nair Dileep , Jehi Lara , Hantus Stephen , Punia Vineet
Published: May 2020

Background

Neurological manifestations of COVID-19 have only recently been described, with a paucity of literature reporting the potential relationship between COVID-19 and acute symptomatic seizures. Two prior studies found no clinical or electrographic seizures in their cohorts of COVID-19 patients with altered mental status (AMS) and clinical seizure-like events (SLEs).

Methods

In this retrospective cohort study, 22 critically-ill COVID-19 patients above the age of 18 years who underwent EEG (electroencephalography) monitoring between April 20th, 2020 and May 20th, 2020 were studied. 19 patients underwent continuous EEG (cEEG) for at least 24 hours, and 3 patients underwent routine EEGs (<1 hour). Demographics including age, gender, comorbid medical, and neurological conditions were collected. Clinical variables included EEG findings, anti-seizure medications, discharge disposition, and survival.

Findings

17 patients underwent EEG monitoring for unexplained altered mental status changes and 5 patients underwent monitoring for a seizure-like event. 5 patients had epileptiform abnormalities on EEG (4 patients on cEEG, 1 on routine EEG); and only 2 of 5 epileptic EEG patients had a prior history of epilepsy. 2 patients in our cohort had electrographic seizures in the absence of prior epilepsy history. No patients with epileptiform abnormalities or electrographic seizures had acutely abnormal neuroimaging on CT or MRI.

Interpretation

Encephalopathic COVID-19 positive patients had a range of EEG abnormalities, and a higher proportion of patients in this series had electrographic seizures than previous literature suggests. This may be influenced by the duration of monitoring with cEEG and the use of a 21 channel electrode system. cEEG findings may help to guide antiseizure medical therapy, as well as the workup of altered mental status in the setting of unremarkable neuroimaging.

Funding

No funding was used for this study.
Predictions for Europe for the Covid-19 pandemic from a SIR model
Authors: Bhanot Gyan , DeLisi Charles
Published: May 2020

We develop and apply a simplified SIR model to current data for the 2019-2020 SARS-Cov-2/Covid-19 pandemic for the United Kingdom (UK) and eight European countries: Norway, Sweden, Denmark, the Netherlands, France, Germany, Italy and Spain. The most important result of the model was the identification and segregation of pandemic characteristics into two distinct groups: those that are invariant across countries, and those that are highly variable. Amongst the former is the infective period TL, which was very similar for all countries, with an average value of days. The other invariants were TR, the average time between contacts and R = NC, the average number of contacts while infective. We find days and . In contrast to these invariants, there was a highly variable time lag TD between the peak in the daily number of infected individuals and the peak in the daily number of deaths, ranging from a low of TD = 4 days for Italy and Denmark, to a high of TD = 17 for Norway. The mortality probability among identified cases was also highly variable, ranging from low values 3.5%, 5% and 5% for Norway, Denmark and Germany respectively to high values of 18%, 18% and 20% for France, Sweden and the UK respectively. Our analysis predicts that the number of deaths per million population until the pandemic ends (defined as when the daily number of deaths is less than 5) will be lowest for Norway (45 deaths/million) and highest for the United Kingdom (628 deaths/million). Finally, we observe a small but detectable effect of average temperature on the probability α of infection in each contact, with higher temperatures associated with lower infectivity.
On the true numbers of COVID-19 infections: behind the available data
Authors: Qadmiry M.E. , Tahri E.H. , Hassouni Y.
Published: May 2020

In December-2019 China reported several cases of a novel coronavirus later called COVID-19. In this work, we will use a probabilistic method for approximating the true daily numbers of infected. Based on two distribution functions to describe the spontaneous recovered cases on the one hand and the detected cases on the other hand. The impact of the underlying variables of these functions is discussed. The detected rate is predicted to be between 5.3% and 12%, which means that there would be about 68 million infected until now (25-May 2020), rather than the officially declared number of 5.37 million worldwide cases.
Serological identification of SARS-CoV-2 infections among children visiting a hospital during the initial Seattle outbreak
Authors: Dingens Adam S. , Crawford Katharine H. D. , Adler Amanda , Steele Sarah L. , Lacombe Kirsten , Eguia Rachel , Amanat Fatima , Walls Alexandra C. , Wolf Caitlin R. , Murphy Michael , Pettie Deleah , Carter Lauren , Qin Xuan , King Neil P. , Veesler David , Krammer Florian , Dickerson Jane A. , Chu Helen Y. , Englund Janet A. , Bloom Jesse D.
Published: May 2020

Children are strikingly underrepresented in COVID-19 case counts1–3. In the United States, children represent 22% of the population but only 1.7% of confirmed SARS-CoV-2 cases1. One possibility is that symptom-based viral testing is less likely to identify infected children, since they often experience milder disease than adults1,4–7. To better assess the frequency of pediatric SARS-CoV-2 infection, we serologically screened 1,775 residual samples from Seattle Children′s Hospital collected from 1,076 children seeking medical care during March and April of 2020. Only one child was seropositive in March, but seven were seropositive in April for a period seroprevalence of ≈ 1%. Most seropositive children (6/8) were not suspected of having had COVID-19. The sera of seropositive children had neutralizing activity, including one that neutralized at a dilution >1:18,000. Therefore, an increasing number of children seeking medical care were infected by SARS-CoV-2 during the early Seattle outbreak despite few positive viral tests.
Mental health outcomes and associations during the coronavirus disease 2019 pandemic: A cross-sectional survey of the US general population
Authors: Kantor Bella Nichole , Kantor Jonathan
Published: May 2020

Pandemic coronavirus disease 2019 (COVID-19) may lead to significant mental health stresses, potentially with modifiable risk factors. To determine the presence of and magnitude of associations between baseline associations and anxiety and depression in the US general population, we performed an internet-based cross-sectional survey of an age-, sex-, and race-stratified representative sample from the US general population. Degrees of anxiety, depression, and loneliness were assessed using the 7-item Generalized Anxiety Disorder scale (GAD-7), the 9-item Patient Health Questionnaire (PHQ-9), and the 8-item UCLA Loneliness Scale, respectively. Unadjusted and multivariable logistic regression analyses were performed to determine associations with baseline demographic characteristics. A total of 1,005 finished surveys were returned of the 1,020 started, yielding a completion rate of 98.5% in the survey panel. The mean (SD) age of respondents was 45 (16), and 494 (48.8%) were male. Baseline demographic data were similar between those that were (n=663, 66.2%) and were not (n=339, 33.8%) under a shelter in place/ stay at home order, with the exception of sex and geographic location. Overall, 264 subjects (26.8%) met criteria for an anxiety disorder based on a GAD-7 cutoff of 10; a cutoff of 7 yielded 416 subjects (41.4%) meeting clinical criteria for anxiety. On multivariable analysis, male sex (OR 0.65, 95% CI [0.49, 0.87]) and living in a larger home (OR 0.46, 95% CI [0.24, 0.88]) were associated with a decreased odds of meeting anxiety criteria. Rural location (OR 1.39, 95% CI [1.03, 1.89]), loneliness (OR 4.92, 95% CI [3.18, 7.62]), and history of hospitalization (OR 2.04, 95% CI [1.38, 3.03]), were associated with increased odds of meeting anxiety criteria. 232 subjects (23.6%) met criteria for clinical depression. On multivariable analysis, male sex (OR 0.71, 95% CI [0.53, 0.95]), increased time outdoors (OR 0.51, 95% CI [0.29, 0.92]), and living in a larger home (OR 0.35, 95% CI [0.18, 0.69]), were associated with decreased odds of meeting depression criteria. Having lost a job (OR 1.64, 95% CI [1.05, 2.54]), loneliness (OR 10.42, 95% CI [6.26, 17.36]), and history of hospitalization (OR 2.42, 95% CI [1.62, 3.62]), were associated with an increased odds of meeting depression criteria. Income, media consumption, and religiosity were not associated with mental health outcomes. Anxiety and depression are common in the US general population in the context of the COVID-19 pandemic, and are associated with potentially modifiable factors.
Combining two large clinical cohorts (AIBL and ADNI) to identify multiple lipid metabolic pathways in prevalent and incident Alzheimer’s disease
Authors: Huynh Kevin , Lim Wei Ling Florence , Giles Corey , Jayawardana Kaushala S , Salim Agus , Mellett Natalie A , Smith Alex , Olshansky Gavriel , Drew Brian G , Chatterjee Pratishtha , Martins Ian , Laws Simon M , Bush Ashley I , Rowe Christopher C , Villemagne Victor L , Ames David , Masters Colin L , Arnold Matthias , Nho Kwangsik , Saykin Andrew J , Baillie Rebecca , Han Xianlin , Kaddurah-Daouk Rima , Martins Ralph N , Meikle Peter J
Published: May 2020

Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising of many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 lipid species across 32 lipid (sub)classes) allows for detailed isomeric and isobaric lipid separation. We applied the methodology to examine plasma samples from the Australian Imaging, Biomarkers and Lifestyle flagship study of aging (AIBL, n = 1112) and serum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 800) studies. Cross sectional analysis using both cohorts identified concordant unique peripheral signatures associated with AD. Specific pathways include; sphingolipids, including GM3gangliosides, where their acyl composition drove the major associations, and lipids previously associated with dysfunctional lipid metabolism in cardiometabolic disease including the phosphatidylethanolamine and triglyceride classes. Infomation derived from improved isomeric seperation highlighted pathway-specific changes with ether lipids including plasmalogens implicating perixosmal dysfunction in disease pathology. Longitudinal analysis revealed similar lipid signitures in both AIBL and ADNI cohorts with future disease onset. We utilised the two independent studies to train and validate multivariate lipid models that significantly improved disease classification and prediction. Together our results provide a holistic view of the lipidome and its relationship with AD using a comprehensive lipidomics approach, providing targets for further mechanistic investigation.
Systematic Discovery of Pseudomonad Genetic Factors Involved in Sensitivity to Tailocins
Authors: Carim Sean , Azadeh Ashley L. , Kazakov Alexey E. , Price Morgan N. , Walian Peter J. , Chakraborty Romy , Deutschbauer Adam M. , Mutalik Vivek K. , Arkin Adam P.
Published: May 2020

Tailocins are bactericidal protein complexes produced by a wide variety of bacteria to compete against closely related strains. Like tailed bacteriophages, with whom they share an evolutionary and morphological relationship, tailocins bind and kill a narrow spectrum of target cells. Thanks to their high specificity, tailocins have garnered recent attention for their potential as precision antibacterial agents. Nevertheless, the field currently lacks a systematic investigation of genetic determinants of tailocin sensitivity. Here, we employed barcoded transposon-insertion mutant libraries and comparative genomics to assess genetic contributions to tailocin sensitivity in pseudomonads. Our mutant screens identified O-specific antigen (OSA) composition and display as most important in defining sensitivity to our tailocins. Additionally, the screens suggest lipopolysaccharide (LPS) thinning as a mechanism by which resistant strains can become more sensitive to tailocins. Our comparative genomics analyses show a loose relationship between OSA biosynthetic genes and tailocin sensitivity, as well as sensitivity nuances that require further investigation. Overall, our data reinforces the model that LPS molecules can act as either a receptor for, or shield against, tailocin binding and killing. This work offers insight into the specificity of tailocins and tailocin-mediated competition, informing the potential use of tailocins in microbiome manipulation and antibacterial therapy.
Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities
Authors: Mehtonen Juha , Teppo Susanna , Lahnalampi Mari , Kokko Aleksi , Kaukonen Riina , Oksa Laura , Bouvy-Liivrand Maria , Malyukova Alena , Laukkanen Saara , Mäkinen Petri I. , Rounioja Samuli , Ruusuvuori Pekka , Sangfelt Olle , Lund Riikka , Lönnberg Tapio , Lohi Olli , Heinäniemi Merja
Published: May 2020

Tight regulatory loops orchestrate commitment to B-cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention.

We compared normal B-lineage differentiation andin vivoleukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis andin vivoduring chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion.

We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated with natural killer cell inactivation and depletion in the leukemic immune microenvironment. Moreover, our results suggest that the abundance of G1 cell cycle state at diagnosis and lack of differentiation-associated regulatory network changes during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment-resistance, we show that selective inhibitors of ETS-transcription factors could effectively reduce cell viability.

Our data provide a detailed picture of the transcription factor activities that characterize both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.
Diffusion assessment through image processing: beyond the point-source paradigm
Authors: Postnikov Eugene B. , Namykin Anton A. , Semyachkina-Glushkovskaya Oxana V. , Postnov Dmitry E.
Published: May 2020

The quantification of transport processes of different substances in the brain’s parenchyma is important in the context of understanding brain functioning. Most of the currently used methods for assessment of the effective diffusion coefficient rely on the point-source paradigm.

We propose a method for the quantitative characterization of the diffusion process in the brain’s parenchyma using a set of images recorded in the experiment during the spreading of a fluorescent dye. Our method exploits the frame-wise comparison of experimental data with a set of images that would be observed for an ideal diffusion process within the same topology. We obtain this reference set of images using blurring the image with an appropriate kernel function, and the degree of such blurring correlates with the spreading process of a dye. We demonstrate the applicability of the proposed method using (i) the simulated surrogate data, (ii) the set of experimentally recorded fluorescent images of the isolated event of blood-brain barrier (BBB) opening, and (iii) the images of massive multi-source spreading of fluorescent dye.
Histone lysine crotonylation regulates cell-fate determination of neural stem/progenitor cells by activating bivalent promoters
Authors: Dai Shang-Kun , Liu Pei-Pei , Du Hong-Zhen , Liu Xiao , Xu Ya-Jie , Liu Cong , Wang Ying-Ying , Teng Zhao-Qian , Liu Chang-Mei
Published: May 2020

Histone lysine crotonylation (Kcr), an evolutionarily conserved and widely expressed non-acetyl short-chain lysine acylation, plays important roles in transcriptional regulation and disease development. However, its genome-wide distribution, correlation with gene expression, and dynamic changes during developmental processes are largely unknown. In this study, we find that histone Kcr is mainly distributed in active promoters, has a ge-nome-wide positive correlation with transcriptional activity, and regulates transcription of genes participating in metabolism and proliferation. Moreover, elevated histone Kcr activates bivalent promoters to stimulate gene expression in neural stem/progenitor cells (NSPCs), through increasing chromatin openness and recruitment of RNA polymerase II (Pol II). Functionally, these activated genes remodel transcriptome and promote neuronal differentiation.

Author summary

Overall, histone Kcr marks active promoters with high gene expression and modifies the local chromatin environment to allow gene activation, which influences neuronal cell fate. It may represent a unique active histone mark involved in neural developmental regulation.
Light-Sheet Fluorescence Imaging Charts the Gastrula Origin of Vascular Endothelial Cells in Early Zebrafish Embryos
Authors: Pang Meijun , Bai Linlu , Zong Weijian , Wang Xu , Bu Ye , Xiong Connie , Zheng Jiyuan , Li Jieyi , Gao Weizheng , Feng Zhiheng , Chen Liangyi , Zhang Jue , Cheng Heping , Zhu Xiaojun , Xiong Jing-Wei
Published: May 2020

It remains challenging to construct a complete cell lineage map of the origin of vascular endothelial cells in any vertebrate embryo. Here, we report the application ofin totolight-sheet fluorescence imaging of embryos to tracing the origin of vascular endothelial cells (ECs) at single-cell resolution in zebrafish. We first adapted a previously-reported method to mount embryos and light-sheet imaging, created analignment,fusion, andextraction all-in-one software (AFEIO) for processing big data, and performed quantitative analysis of cell lineage relationships using commercially-available Imaris software. Our data revealed that vascular ECs originated from broad regions of the gastrula along the dorsal-ventral and anterior-posterior axes, of which the dorsal-anterior cells contributed to cerebral ECs, the dorsal-lateral cells to anterior trunk ECs, and the ventral-lateral cells to posterior trunk and tail ECs. Therefore, this work, to our knowledge, charts the first comprehensive map of the gastrula origin of vascular ECs in zebrafish, and has potential applications for studying the origin of any embryonic organs in zebrafish and other model organisms.
Dopamine neurons of the VTA encode active conspecific interaction and promote social learning through social reward prediction error
Authors: Prévost-Solié Clément , Girard Benoit , Righetti Beatrice , Tapparel Malika , Bellone Camilla
Published: May 2020

Social interactions motivate behavior in many species, facilitating learning, foraging and cooperative behavior. However, how the brain encodes the reinforcing properties of social interactions remains elusive. Here using in vivo recording in freely moving mice, we show that Dopamine (DA) neurons of the Ventral Tegmental Area (VTA) increase their activity during active interactions with unfamiliar conspecific. Using a social instrumental task, we then show that VTA DA neuron activity signals social reward prediction error and drives social reinforcement learning. Thereby, our findings propose that VTA DA neurons are a neural substrate for a social learning signal driving motivated behavior.

One Sentence Summary

DA neurons are a substrate for social reward learning through the Social Reward Prediction Error.
Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling
Authors: Israelow Benjamin , Song Eric , Mao Tianyang , Lu Peiwen , Meir Amit , Liu Feimei , Madel Alfajaro Mia , Wei Jin , Dong Huiping , Homer Robert J , Ring Aaron , Wilen Craig B , Iwasaki Akiko
Published: May 2020

Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-Cov-2) has caused over 5,000,000 cases of Coronavirus disease (COVID-19) with significant fatality rate.1–3Due to the urgency of this global pandemic, numerous therapeutic and vaccine trials have begun without customary safety and efficacy studies.4Laboratory mice have been the stalwart of these types of studies; however, they do not support infection by SARS-CoV-2 due to the inability of its spike (S) protein to engage the mouse ortholog of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis,5these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and antibody production and exhibit pathologic findings found in COVID-19 patients as well as non-human primate models. Moreover, we show that type I interferons are unable to control SARS-CoV2 replication and drive pathologic responses. Thus, the hACE2-AAV mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds. This represents a much-needed platform for rapidly testing prophylactic and therapeutic strategies to combat COVID-19.
Digit ratio (2D:4D) and Congenital Adrenal Hyperplasia (CAH): Systematic Literature Review and Meta-Analysis
Authors: Richards Gareth , Browne Wendy V. , Aydin Ezra , Constantinescu Mihaela , Nave Gideon , Kim Mimi S. , Watson Steven J.
Published: May 2020

The ratio of length between the second and fourth fingers (2D:4D) is commonly used as an indicator of prenatal sex hormone exposure. Several approaches have been used to try to validate the measure, including examining 2D:4D in people with congenital adrenal hyperplasia (CAH), a suite of conditions characterised by elevated adrenal androgen production secondary to defective steroidogenesis. We present here a systematic review that examines the relationship between these two variables. Twelve articles relating to nine CAH cohorts were identified, and 2D:4D comparisons have been made between cases and controls in eight of these cohorts. Altogether, at least one 2D:4D variable has been compared between n=251 females with CAH and n=358 unaffected females, and between n=108 males with CAH and n=204 unaffected males. A previous meta-analysis (Hönekopp & Watson, 2010) reported lower right hand (R2D:4D) and left hand (L2D:4D) digit ratios in patients with CAH relative to sex-matched controls. Our meta-analysis showed the same direction of results; however, the effects were only statistically significant for R2D:4D in males and L2D:4D in females (R2D:4D: females,p= 0.072,g= 0.591; males,p= 0.019,g= 0.513; L2D:4D: females,p= 0.020,g= 0.245; males,p= 0.334,g= 0.218), and the average effect size had reduced by 46.70%. We also found no evidence to suggest the right-left difference in 2D:4D (D[R-L]) is associated with prenatal sex hormone exposure.
A refined set of rRNA-targeted oligonucleotide probes for in situ detection and quantification of ammonia-oxidizing bacteria
Authors: Lukumbuzya Michael , Kristensen Jannie Munk , Kitzinger Katharina , Pommerening-Röser Andreas , Nielsen Per Halkjær , Wagner Michael , Daims Holger , Pjevac Petra
Published: May 2020

Ammonia-oxidizing bacteria (AOB) of the betaproteobacterial genera Nitrosomonas and Nitrosospira are key nitrifying microorganisms in many natural and engineered ecosystems. Since many AOB remain uncultured, fluorescence in situ hybridization (FISH) with rRNA-targeted oligonucleotide probes has been one of the most widely used approaches to study the community composition, abundance, and other features of AOB directly in environmental samples. However, the established and widely used AOB-specific 16S rRNA-targeted FISH probes were designed up to two decades ago, based on much smaller rRNA gene sequence datasets than available today. Several of these probes cover their target AOB lineages incompletely and suffer from a weak target specificity, which causes cross-hybridization of probes that should detect different AOB lineages. Here, a set of new highly specific 16S rRNA-targeted oligonucleotide probes was developed and experimentally evaluated that complements the existing probes and enables the specific detection and differentiation of the known, major phylogenetic clusters of betaproteobacterial AOB. The new probes were successfully applied to visualize and quantify AOB in activated sludge and biofilm samples from seven pilot- and full-scale wastewater treatment systems. Based on its improved target group coverage and specificity, the refined probe set will facilitate future in situ analyses of AOB.
Genomic structural and transcriptional variation of Oryctes rhinoceros nudivirus (OrNV) in Coconut Rhinoceros Beetle
Authors: Etebari Kayvan , Parry Rhys , Beltran Marie Joy B. , Furlong Michael J.
Published: May 2020

Oryctes rhinoceros nudivirus (OrNV) is a large circular double-stranded DNA virus which has been used as a biological control agent to suppress Coconut Rhinoceros Beetle (Oryctes rhinoceros) in Southeast Asia and the Pacific Islands. Recently a new wave ofO. rhinocerosincursions in Oceania in previously non-infested areas is thought to be related to the presence of low virulence isolates of OrNV or virus tolerant haplotypes of beetles. In this study, chronically infectedO. rhinocerosadults were field collected from the Philippines, Fiji, Papua New Guinea and the Solomon Islands. We extracted total RNA from these samples to investigate the global viral gene expression profiles and comparative genomic analysis of structural variations between the four different populations. Maximum likelihood phylogenic analysis indicated that OrNV strains from the Solomon Islands and the Philippines are closely related to while OrNV strains from PNG and Fiji formed a distinct adjacent clade. We detected several polymorphic sites with a frequency higher than 35% in 892 positions of the viral genome. The highest number of structural variants, including single nucleotide variants (SNV), insertion, deletion and non-synonymous mutations, were found in strains from Fiji and PNG when compared to complete recently sequenced Solomon Islands OrNV reference genome. Non-synonymous mutations were detected in several hypothetical proteins, and 15 nudivirus core genes such asOrNV_gp034(DNA Helicase),lef-8, lef-4andvp91. For examination of the global gene expression profile of OrNV in chronically infected populations, we found limited evidence of variation between geographic populations. Only a few genes such asOrNV_gp01(DNA polymerase B),OrNV_gp022andOrNV_gp107(Pif-3) were differentially expressed among different strains. Additionally, small RNA sequencing from the Solomon Islands population suggests that OrNV is targeted by the host RNA interference (RNAi) response with abundant 21nt small RNAs. Additionally, we identified a highly abundant putative 22 nt miRNA from the 3’ of a pre-miRNA-like hairpin originating fromOrNV-gp-098. These findings provide valuable resources for future studies to improve our understanding of the OrNV genetic variation. Some of these structural changes are specific to the geographic population and could be related to particular phenotypic characteristics of the strain, such as viral pathogenicity or transmissibility, and this requires further investigation.
Ambient air pollutants, meteorological factors and their interactions affect confirmed cases of COVID-19 in 120 Chinese cities
Authors: Zhou Jianli , Qin Linyuan , Liu Nan
Published: May 2020

Emerging evidences have confirmed effects of meteorological factors on novel coronavirus disease 2019 (COVID-19). However, few studies verify the impact of air pollutants on this pandemic. This study aims to explore the association of ambient air pollutants, meteorological factors and their interactions effect confirmed case counts of COVID-19 in 120 Chinese cities. Here, we collected total confirmed cases of COVID-19 by combining with meteorological factors and air pollutants data from 15th January 2020 to 18th March 2020 in 120 Chinese cities. Spearman correlation analysis was employed to estimate the association between two variables; univariate and multivariate negative binomial regression analysis were applied to explore the effect of air pollutants and meteorological parameters on the COVID-19 confirmed cases. Positive associations were found between the confirmed cases of COVID-19 and carbon monoxide (CO), aerodynamic particulate matter with aerodynamic diameter ≤2.5 μm (PM2.5), relative humidity (RH) and air pressure (AP). And negative association was found for sulfur dioxide (SO2). In addition, multivariate negative binomial regression analysis suggested that confirmed cases of COVID-19 was positively correlated with ozone (O3) in lag 0 day while it was negatively associated with wind velocity (WV) in lag 14 days, and the pollutants-meteorological factors interactions also associate with COVID-19. In conclusions, air pollutants and meteorological factors and their interactions all associate with COVID-19.
Treatment Outcomes for Adult Patients with Localized Osteosarcoma Treated with Chemotherapy without Methotrexate
Authors: Silva MRM , Bonadio RC , Matos GDR , Toloi D , Nardo M , Munhoz RM , Zampieri CLCB , Reboledo Daniel , Correa LFM , Baptista AM , Feher O , Camargo VP
Published: May 2020

Background

Standard treatment for pediatric patients with localized osteosarcoma include high-dose methotrexate (HDMTX) and cure rates greater than 60% are observed. In adult patients, however, the toxicity profile limits the use of HDMTX and it is usually excluded from chemotherapy protocols for this group. We aimed to evaluate the outcomes of adult patients with localized osteosarcoma treated with chemotherapy without methotrexate.

Methods

In this retrospective cohort, we evaluated adult patients with high-grade osteosarcoma who received treatment with chemotherapy without methotrexate in a reference cancer center from 2007 to 2018. Outcomes analyzed were recurrence-free survival (RFS), overall survival (OS), and prognostic factors associated with overall survival.

Results

A total of 48 patients had localized disease and received treatment with chemotherapy without methotrexate. The majority of them received chemotherapy with a combination of cisplatin and doxorubicin (N=42, 87.5%). Median age was 27 years. (range 16.8 – 66.7) With a median follow-up of 29.2 months, median RFS was 29.9 months. Median OS was not reached. 5-year RFS and OS rates were 35.1% (95% CI 20.3 – 50.2%) and 71.6% (95% CI 52.3 – 84.2%), respectively. Patients who received cumulative doses of doxorubicin ≥ 375 mg/m2 had better OS than those who received lower doses (HR 0.26, 95% CI 0.07 – 0.94, P = 0.041). Similarly, patients who received ≥ 6 cycles of neoadjuvant/ adjuvant cisplatin tended to have better OS than those who received < 6 cycles (HR 0.30, 95% CI 0.08 – 1.09, P = 0.069).Nineteen patients received less than 6 cycles of cisplatin and doxorubicin mainly because of grade 3 or 4 toxicities (11), disease progression (6),patient refusal(1), physician choice(1).

Conclusion

In our study, adult patients with localized high-grade osteosarcoma who were treated with chemotherapy without methotrexate had unfavorable outcomes. The cumulative doxorubicin dose and the number of cisplatin/doxorubicin cycles were associated with improved OS. The investigation of additional treatment strategies is of utmost importance to improve adult patients outcomes.
Modelling the SARS-CoV-2 first epidemic wave in Greece: social contact patterns for impact assessment and an exit strategy from social distancing measures
Authors: Sypsa Vana , Roussos Sotirios , Paraskevis Dimitrios , Lytras Theodore , Sotirios Tsiodras S , Hatzakis Angelos
Published: May 2020

In Greece, a nationwide lockdown to mitigate the transmission of SARS-CoV-2 was imposed on March 23, 2020. As by the end of April the first epidemic wave is waning, it is important to assess the infection attack rate and quantify the impact of physical distancing. We implemented a survey to assess social mixing patterns before the epidemic and during lockdown. We estimated R0from surveillance data and assessed its decline as a result of physical distancing based on social contacts data. We applied a Susceptible-Exposed-Infectious-Recovered model to estimate the infection attack rate and the infection fatality ratio (IFR). As multiple social distancing measures were implemented simultaneously (schools/work/leisure), we assessed their overall impact as well as their relative contribution. R0was estimated 2·38 (95%CI: 2·01,2·80). By April 26th, the infection attack rate was 0·12% (95%CrI: 0·06%,0·26%) and the IFR 1·12% (95%CrI: 0·55%,2·31%). During lockdown, daily contacts were reduced by 86·9% and the effective reproduction number reached 0·46 (95%CrI: 0·35,0·57). The reduction in R0attributed to lockdown was 81·0% (95%CrI: 71·8%,86·0%) whereas the reduction attributed to each measure separately ranged between 10%-24%. We assessed scenarios with less disruptive social distancing measures as well as scenarios where measures are partially lifted after lockdown. This is the first impact assessment of the first wave of SARS-CoV-2 in a European country. It suggests that only multiple measures implemented simultaneously could reduce R0below 1. Measuring social mixing patterns can be a tool for real-time monitoring of the epidemic potential.
Factors associated with country-variation in COVID-19 morbidity and mortality worldwide: an observational geographic study COVID-19 morbidity and mortality country-variation
Authors: Bellali H , Chtioui N , Chahed M
Published: May 2020

Background

The world is threatened by the outbreak of coronavirus disease 19 (COVID-19) since December 2019. The number of cases and deaths increased dramatically in some countries from March 2020. The objective of our study was to examine potential associated factors with country-variation in COVID-19 morbidity and mortality in the world.

Methods

We performed a retrospective geographic study including all countries with the most recent available data on free access on the web. We analyzed univariate and multivariable correlation between both the number of reported cases and deaths by country and demographic, socioeconomic characteristics, lockdown as major control measure, average annual temperature and relative humidity. We performed simple linear regression, independent t test and ANOVA test for univariate analyses and negative binomial regression model for multivariable analyses.

Results

We analyzed data of 186 countries from all world regions. As of 13thApril 2020, a total of 1 804 302 COVID-19 cases and 113 444 deaths were reported. The reported number of COVID-19 cases and deaths by countries was associated with the number of days between the first case and lockdown, the number of cases at lockdown, life expectancy at birth, average annual temperature and the socio-economic level. Countries which never implemented BCG vaccination reported higher mortality than others.

Conclusions

The pandemic is still ongoing and poses a global health threat as there is no effective antiviral treatment or vaccines. Thus, timing of control measure implementation is a crucial factor in determining the spread of the epidemic. It should be a lesson for this pandemic and for the future.
Neural plate targeting by in utero nanoinjection (NEPTUNE) reveals a role forSptbn2in neurulation and abdominal wall closure
Authors: Mangold Katrin , Mašek Jan , He Jingyan , Lendahl Urban , Fuchs Elaine , Andersson Emma R
Published: May 2020

Gene variants associated with disease are efficiently identified with whole genome sequencing or GWAS, but validationin vivolags behind. We developed NEPTUNE (neuralplate targeting by inuteronanoinjection), to rapidly and flexibly introduce gene expression-modifying viruses to the embryonic murine neural plate prior to neurulation, to target the future adult nervous system. Stable integration in >95% of cells in the brain enabled long-term gain- or loss-of-function, and conditional expression was achieved using mini-promotors for cell types of interest. Using NEPTUNE, we silencedSptbn2, a gene associated with Spinocerebellar ataxia type 5 (SCA5) in humans. Silencing ofSptbn2induced severe neural tube defects and embryo resorption, suggesting thatSPTBN2in-frame and missense deletions in SCA5 reflect hypomorphic or neomorphic functions, not loss of function. In conclusion, NEPTUNE offers a novel, rapid and cost-effective technique to test gene function in brain development, and can reveal loss of function phenotypes incompatible with life.
Cryo-EM Structure of Native Human Uromodulin, a Zona Pellucida Module Polymer
Authors: Stsiapanava Alena , Xu Chenrui , Brunati Martina , Zamora-Caballero Sara , Schaeffer Céline , Han Ling , Carroni Marta , Yasumasu Shigeki , Rampoldi Luca , Wu Bin , Jovine Luca
Published: May 2020

Assembly of extracellular filaments and matrices mediating fundamental biological processes such as morphogenesis, hearing, fertilization and antibacterial defense is driven by a ubiquitous polymerization module known as zona pellucida (ZP) “domain”. Despite the conservation of this element from hydra to human, no information is available on the filamentous conformation of any ZP module protein. Here we report the cryo-electron microscopy structure of uromodulin (UMOD)/Tamm-Horsfall protein, the most abundant protein in human urine and an archetypal ZP module-containing molecule, in its mature homopolymeric state. UMOD forms a one-start helix with an unprecedented 180-degree twist between subunits enfolded by interdomain linkers that have completely reorganized as a result of propeptide dissociation. Lateral interaction between filaments in the urine generates sheets exposing a checkerboard of binding sites to capture uropathogenic bacteria, and UMOD-based models of mammalian and avian heteromeric egg coat filaments identify a common sperm-binding region at the interface between subunits.
The data universe of structural biology
Authors: Berman Helen M. , Vallat Brinda , Lawson Catherine L.
Published: May 2020

The Protein Data Bank (PDB) has grown from a small data resource for crystallographers to a worldwide resource serving structural biology. The history of the growth of the PDB and the role that the community has played in developing standards and policies are described. This article also illustrates how other biophysics communities are collaborating with the worldwide PDB to create a network of interoperating data resources. This network will expand the capabilities of structural biology and enable the determination and archiving of increasingly complex structures.