bluuebunny/crossref_metadata_2025 huggingface dataset:
The Efficacy of the Stellate Ganglion Block as a Treatment Modality for Posttraumatic Stress Disorder Among Active Duty Combat Veterans: A Pilot Program Evaluation
Authors: Odosso Richard J , Petta Lorene
Published: November 2020

Introduction

The lifetime prevalence for development of Posttraumatic Stress Disorder (PTSD) among military combat veterans has been estimated to be as high as 17%, or more than double the national average. The stellate ganglion block (SGB) has been proposed as a PTSD treatment modality that may potentially affect positive change in the attitude of a service member (SM) toward mental health treatment, lead to improved clinical outcomes, promote the likelihood of a return to a productive job performance, and decrease the economic burden of PTSD treatment on the Department of Defense.

Materials and Methods

A pilot program to determine the efficacy of the SGB was conducted in a single, closed-unit of active duty combat veterans with a statistically high prevalence of PTSD-related symptoms associated with combat deployments. A retrospective project-level program evaluation was completed to assess the effectiveness of the treatment in reducing symptoms, the level of SM acceptance of the procedure, and the SM perceived response to the SGB treatment. The project-level program evaluation methodology was based on the suggestions of the W.K. Kellogg Foundation Evaluation Handbook. The primary design and context of the evaluation was viewed from an outcome evaluation perspective and format, with focus on both individual and system-level outcomes. The outcome evaluation addressed: 1) the measured outcomes and critical findings of the procedure during the pilot, 2) feasibility of and recommendation for replication of the pilot, and 3) the quality improvement potential of the SGB as part of a clinical pathway for the care and treatment of PTSD in SMs.

Results

Program evaluation analysis demonstrated that the SGB exhibited success in both rate and level of response, reduced stigma relative to acceptance of the treatment, and SMs verbalized a high perceived value of the treatment. However, the effect of the procedure was shown to peak and plateau with a regression to baseline at roughly the 3-month timeframe, with a reciprocal decrease in perceived value.

Conclusion

The most significant benefit of the SGB appears to be its ability to act as a gateway to treatment and to facilitate active participation and compliance by the SM during its “window” of efficacy. Additional research, including RCTs are required to continue to evaluate its efficacy relative to symptom-specific effectiveness, effectiveness of sequential procedures, and effectiveness when combined with other nonpharmaceutical treatment modalities. Moreover, the application of an accepted medical procedure as a mental health (MH) therapy with marked reduction in stigma, encourages pursuit of additional such treatment methods that reduce stigma and promote active SM participation in PTSD management.
A theoretical framework for BL Her stars – I. Effect of metallicity and convection parameters on period–luminosity and period–radius relations
Authors: Das Susmita , Kanbur Shashi M , Smolec Radoslaw , Bhardwaj Anupam , Singh Harinder P , Rejkuba Marina
Published: November 2020

We present a new grid of convective BL Herculis models using the state-of-the-art 1D non-linear radial stellar pulsation tool mesa-rsp. We investigate the impact of metallicity and four sets of different convection parameters on multiwavelength properties. Non-linear models were computed for periods typical for BL Her stars, i.e. 1 ≤ P(d) ≤ 4 covering a wide range of input parameters – metallicity (−2.0 dex ≤ [Fe/H] ≤ 0.0 dex), stellar mass (0.5–0.8 M⊙), luminosity (50–300 L⊙), and effective temperature (full extent of the instability strip; in steps of 50 K). The total number of BL Her models with full-amplitude stable pulsations used in this study is 10 280 across the four sets of convection parameters. We obtain their multiband (UBVRIJHKLL′M) light curves and derive new theoretical period–luminosity (PL), period–Wesenheit (PW), and period–radius (PR) relations at mean light. We find that the models computed with radiative cooling show statistically similar slopes for PL, PW, and PR relations. Most empirical relations match well with the theoretical PL, PW, and PR relations from the BL Her models computed using the four sets of convection parameters. However, PL slopes of the models with radiative cooling provide a better match to empirical relations for BL Her stars in the Large Magellanic Cloud in the HKS bands. For each set of convection parameters, the effect of metallicity is significant in U and B bands and negligible in infrared bands, which is consistent with empirical results. No significant metallicity effects are seen in the PR relations.
The evolution of the size–mass relation at z = 1–3 derived from the complete Hubble Frontier Fields data set
Authors: Yang Lilan , Roberts-Borsani Guido , Treu Tommaso , Birrer Simon , Morishita Takahiro , Bradač Maruša
Published: November 2020

We measure the size–mass relation and its evolution between redshifts 1 < z < 3, using galaxies lensed by six foreground Hubble Frontier Fields clusters. The power afforded by strong gravitation lensing allows us to observe galaxies with higher angular resolution beyond current facilities. We select a stellar mass limited sample and divide them into star-forming or quiescent classes based on their rest-frame UVJ colours from the ASTRODEEP catalogues. Source reconstruction is carried out with the recently released lenstruction software, which is built on the multipurpose gravitational lensing software lenstronomy. We derive the empirical relation between size and mass for the late-type galaxies with $M_{*}\gt 3\times 10^{9}\, \mathrm{M}_{\odot }$ at 1 < z < 2.5 and $M_{*}\gt 5\times 10^{9}\, \mathrm{M}_{\odot }$ at 2.5 < z < 3, and at a fixed stellar mass, we find galaxy sizes evolve as $R \rm _{eff} \propto (1+z)^{-1.05\pm 0.37}$. The intrinsic scatter is <0.1 dex at z < 1.5 but increases to ∼0.3 dex at higher redshift. The results are in good agreement with those obtained in blank fields. We evaluate the uncertainties associated with the choice of lens model by comparing size measurements using five different and publicly available models, finding the choice of lens model leads to a 3.7 per cent uncertainty of the median value, and ∼25  per cent scatter for individual galaxies. Our work demonstrates the use of strong lensing magnification to boost resolution does not introduce significant uncertainties in this kind of work, and paves the way for wholesale applications of the sophisticated lens reconstruction technique to higher redshifts and larger samples.
DIANA-miRGen v4: indexing promoters and regulators for more than 1500 microRNAs
Authors: Perdikopanis Nikos , Georgakilas Georgios K , Grigoriadis Dimitris , Pierros Vasilis , Kavakiotis Ioannis , Alexiou Panagiotis , Hatzigeorgiou Artemis
Published: November 2020

Deregulation of microRNA (miRNA) expression plays a critical role in the transition from a physiological to a pathological state. The accurate miRNA promoter identification in multiple cell types is a fundamental endeavor towards understanding and characterizing the underlying mechanisms of both physiological as well as pathological conditions. DIANA-miRGen v4 (www.microrna.gr/mirgenv4) provides cell type specific miRNA transcription start sites (TSSs) for over 1500 miRNAs retrieved from the analysis of >1000 cap analysis of gene expression (CAGE) samples corresponding to 133 tissues, cell lines and primary cells available in FANTOM repository. MiRNA TSS locations were associated with transcription factor binding site (TFBSs) annotation, for >280 TFs, derived from analyzing the majority of ENCODE ChIP-Seq datasets. For the first time, clusters of cell types having common miRNA TSSs are characterized and provided through a user friendly interface with multiple layers of customization. DIANA-miRGen v4 significantly improves our understanding of miRNA biogenesis regulation at the transcriptional level by providing a unique integration of high-quality annotations for hundreds of cell specific miRNA promoters with experimentally derived TFBSs.
APOBEC1 cytosine deaminase activity on single-stranded DNA is suppressed by replication protein A
Authors: Wong Lai , Vizeacoumar Frederick S , Vizeacoumar Franco J , Chelico Linda
Published: November 2020

Many APOBEC cytidine deaminase members are known to induce ‘off-target’ cytidine deaminations in 5′TC motifs in genomic DNA that contribute to cancer evolution. In this report, we characterized APOBEC1, which is a possible cancer related APOBEC since APOBEC1 mRNA is highly expressed in certain types of tumors, such as lung adenocarcinoma. We found a low level of APOBEC1-induced DNA damage, as measured by γH2AX foci, in genomic DNA of a lung cancer cell line that correlated to its inability to compete in vitro with replication protein A (RPA) for ssDNA. This suggests that RPA can act as a defense against off-target deamination for some APOBEC enzymes. Overall, the data support the model that the ability of an APOBEC to compete with RPA can better predict genomic damage than combined analysis of mRNA expression levels in tumors and analysis of mutation signatures.
Biological Effective Dose as a Predictor of Hypopituitarism After Single-Fraction Pituitary Adenoma Radiosurgery: Dosimetric Analysis and Cohort Study of Patients Treated Using Contemporary Techniques
Authors: Graffeo Christopher S , Perry Avital , Link Michael J , Brown Paul D , Young William F , Pollock Bruce E
Published: November 2020

BACKGROUND

Hypopituitarism is the most frequent complication after pituitary adenoma stereotactic radiosurgery (SRS) and is correlated with increasing radiation to the pituitary gland. Biological effective dose (BED) is a dosimetric parameter that incorporates a time component to adjust for mechanisms of deoxyribonucleic acid repair activated during treatment.

OBJECTIVE

To assess mean gland BED as a predictor of post-SRS hypopituitarism, as compared to mean gland dose, in a contemporary cohort study of patients undergoing single-fraction SRS for pituitary adenoma.

METHODS

Cohort study of 97 patients undergoing single-fraction SRS from 2007 to 2014. Eligible patients had no prior pituitary irradiation, normal pre-SRS endocrine function, and >24 mo of endocrine follow-up. Cox proportional hazards analysis was used to assess mean gland dose and BED as predictors of new post-SRS hypopituitarism.

RESULTS

Median post-SRS follow-up was 48 mo (interquartile range [IQR], 34-68). A total of 27 patients (28%) developed new hypopituitarism at a median 22 mo (IQR, 12-36). Actuarial rates of new endocrinopathy were 17% at 2 yr (95% CI 10%-25%) and 31% at 5 yr (95% CI 20%-42%). On univariate analysis, sex (P = .02), gland volume (P = .03), mean gland dose (P < .0001), and BED significantly predicted new hypopituitarism (P < .0001). After adjusting for sex and gland volume, BED > 45 Gy2.47and mean gland dose > 10 Gy were significantly associated increased risk of hypopituitarism (hazard ratio [HR] = 14.32, 95% CI = 4.26-89.0,P < .0001; HR = 11.91, 95% CI = 3.54-74.0,P < .0001).

CONCLUSION

BED predicted hypopituitarism more reliably than mean gland dose after pituitary adenoma SRS, but additional studies are needed to confirm these results.
Machine Learning-Driven Metabolomic Evaluation of Cerebrospinal Fluid: Insights Into Poor Outcomes After Aneurysmal Subarachnoid Hemorrhage
Authors: Koch Matthew , Acharjee Animesh , Ament Zsuzsanna , Schleicher Riana , Bevers Matthew , Stapleton Christopher , Patel Aman , Kimberly W Taylor
Published: November 2020

BACKGROUND

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with a high mortality and poor neurologic outcomes. The biologic underpinnings of the morbidity and mortality associated with aSAH remain poorly understood.

OBJECTIVE

To ascertain potential insights into pathological mechanisms of injury after aSAH using an approach of metabolomics coupled with machine learning methods.

METHODS

Using cerebrospinal fluid (CSF) samples from 81 aSAH enrolled in a retrospective cohort biorepository, samples collected during the peak of delayed cerebral ischemia were analyzed using liquid chromatography-tandem mass spectrometry. A total of 138 metabolites were measured and quantified in each sample. Data were analyzed using elastic net (EN) machine learning and orthogonal partial least squares-discriminant analysis (OPLS-DA) to identify the leading CSF metabolites associated with poor outcome, as determined by the modified Rankin Scale (mRS) at discharge and at 90 d. Repeated measures analysis determined the effect size for each metabolite on poor outcome.

RESULTS

EN machine learning and OPLS-DA analysis identified 8 and 10 metabolites, respectively, that predicted poor mRS (mRS 3-6) at discharge and at 90 d. Of these candidates, symmetric dimethylarginine (SDMA), dimethylguanidine valeric acid (DMGV), and ornithine were consistent markers, with an association with poor mRS at discharge (P = .0005, .002, and .0001, respectively) and at 90 d (P = .0036, .0001, and .004, respectively). SDMA also demonstrated a significantly elevated CSF concentration compared with nonaneurysmal subarachnoid hemorrhage controls (P = .0087).

CONCLUSION

SDMA, DMGV, and ornithine are vasoactive molecules linked to the nitric oxide pathway that predicts poor outcome after severe aSAH. Further study of dimethylarginine metabolites in brain injury after aSAH is warranted.
Efficacy and safety of multiple intra-articular corticosteroid injections for osteoarthritis—a systematic review and meta-analysis of randomized controlled trials and observational studies
Authors: Ayub Shazeen , Kaur Jaspreet , Hui Michelle , Espahbodi Shima , Hall Michelle , Doherty Michael , Zhang Weiya
Published: November 2020

Objectives

To investigate the efficacy and safety of multiple intra-articular corticosteroid (IACS) injections for the treatment of OA.

Methods

We conducted electronic searches of several databases for randomized controlled trials (RCTs) and observational studies. Standard mean difference was calculated for efficacy, whereas hazard ratio (HR) was used for adverse effects. Results were combined using the random effects model. Heterogeneity was measured using I2 statistics.

Results

Six RCTs were included for efficacy assessment. The use of multiple IACS appeared to be better than comparator (standard mean difference for pain −0.47, 95% CI −0.62, 0.31). However, there was considerable heterogeneity (I2 92.6%) and subgroup analysis by comparator showed no separation of regular IACS from placebo, though timing of pain assessments was questionable. Fourteen RCTs and two observational studies were assessed for the safety of multiple IACS. Minor local adverse events were similar in both groups. One RCT found that regular IACS every 3 months for 2 years caused greater cartilage loss compared with saline injection (−0.21 vs 0.10 mm). One cohort study found that multiple IACS injections associated with worsening of joint space narrowing (HR 3.02, 95% CI 2.25, 4.05) and increased risk of joint replacement (HR 2.54, 95% CI 1.81, 3.57).

Conclusion

Multiple IACS injections are no better than placebo for OA pain according to current evidence. The preliminary finding of a detrimental effect on structural OA progression warrants further investigation. Efficacy and safety of multiple IACS reflecting recommended best practice has yet to be assessed.
Ten-year analysis of the risk of severe outcomes related to low-dose glucocorticoids in early rheumatoid arthritis
Authors: Roubille Camille , Coffy Amandine , Rincheval Nathalie , Dougados Maxime , Flipo René-Marc , Daurès Jean-Pierre , Combe Bernard
Published: November 2020

Objectives

To explore the 10-year tolerability profile of glucocorticoids (GC) use in patients with early RA.

Methods

Analysis of 10-year outcome from the early arthritis ESPOIR cohort. Patients were stratified in two groups, without or with GC treatment at least once during their follow-up. The primary outcome was a composite of deaths, cardiovascular diseases (CVD), severe infections and fractures. The weighted Cox time-dependent analysis model was used with inverse probability of treatment weighting (IPTW) propensity score method.

Results

Among the 608 patients [480 women, mean age of 47.5  (12.1) years], 397 (65%) received low-dose GC [median 1.9 mg/day (IQR 0.6–4.2), mean cumulative prednisone dose 8468 mg (8376), mean duration 44.6 months (40.1)]. In univariate analysis, over 95 total events (10 deaths, 18 CVDs, 32 fractures and 35 severe infections), patients taking GC experienced more events (n = 71) than those without GC (n = 24) (P =0.035). Highest cumulative exposure of GC (≥8.4 g) was associated with highest risk of occurrence of the primary outcome (24.3%, P =0.007), CVDs (7.9%, P =0.001) and severe infections (9.9%, P =0.024). The risk of events over time was significantly associated with GC, age, hypertension and ESR. The risk associated with GC treatment increased between the first follow-up visit [hazard ratio (HR) at 1 year = 0.46, 95% CI: 0.23, 0.90] and 10 years (HR = 6.83, 95% CI: 2.29, 20.35).

Conclusion

The 10-year analysis of this prospective early RA cohort supports a dose and time-dependent impact of low-dose GC treatment, with a long-term high risk of severe outcomes.

Trial registration

(ClinicalTrials.gov Identifier: NCT03666091).
Learning Speech Production and Perception through Sensorimotor Interactions
Authors: Shamma Shihab , Patel Prachi , Mukherjee Shoutik , Marion Guilhem , Khalighinejad Bahar , Han Cong , Herrero Jose , Bickel Stephan , Mehta Ashesh , Mesgarani Nima
Published: November 2020

Action and perception are closely linked in many behaviors necessitating a close coordination between sensory and motor neural processes so as to achieve a well-integrated smoothly evolving task performance. To investigate the detailed nature of these sensorimotor interactions, and their role in learning and executing the skilled motor task of speaking, we analyzed ECoG recordings of responses in the high-γ band (70–150 Hz) in human subjects while they listened to, spoke, or silently articulated speech. We found elaborate spectrotemporally modulated neural activity projecting in both “forward” (motor-to-sensory) and “inverse” directions between the higher-auditory and motor cortical regions engaged during speaking. Furthermore, mathematical simulations demonstrate a key role for the forward projection in “learning” to control the vocal tract, beyond its commonly postulated predictive role during execution. These results therefore offer a broader view of the functional role of the ubiquitous forward projection as an important ingredient in learning, rather than just control, of skilled sensorimotor tasks.
Neuroprotective effect of nerolidol in traumatic brain injury associated behavioural comorbidities in rats
Authors: Kaur Amandeep , Jaiswal Gagandeep , Brar Jasdeep , Kumar Puneet
Published: November 2020

Traumatic brain injury (TBI) is an insult to the brain from an external mechanical force, leading to temporary/permanent secondary injuries, i.e. impairment of cognitive, physical, and psycho-social functions with altered consciousness. The leading mechanism responsible for neuronal damage following TBI is an increase in oxidative reactions initiated by free radicals generated by the injury along with various other mechanisms. Nerolidol is reported to have potent antioxidant and anti-neuroinflammatory properties. The present study was designed to explore the neuroprotective effect of nerolidol in weight-drop-induced TBI in rats. Animals were injured on the 1st day by dropping a free-falling weight of 200 gm from a height of 1 m through a guide pipe onto the exposed skull. After 14 days of injury, nerolidol (25, 50, and 100 mg/kg, i.p.) treatment was given for the next 14 days. Locomotor activity and motor coordination were evaluated using an actophotometer and rotarod, respectively. Cognitive impairment was observed through the Morris Water Maze and Object Recognition Test. On the 29th day, animals were sacrificed, and their brains were collected for the biochemical estimation. The weight drop model significantly decreased locomotor activity, motor coordination, increased Acetylcholinesterase (AChE) activity, oxidative stress, and induced cognitive deficits in TBI rats. Nerolidol significantly improved locomotor activity, reversed motor incoordination and cognitive impairment, and reduced the AChE activity and oxidative/nitrosative stress. The present study demonstrates the promising neuroprotective effects of nerolidol, which might improve the quality of life of TBI patients.
RDP5: a computer program for analyzing recombination in, and removing signals of recombination from, nucleotide sequence datasets
Authors: Martin Darren P , Varsani Arvind , Roumagnac Philippe , Botha Gerrit , Maslamoney Suresh , Schwab Tiana , Kelz Zena , Kumar Venkatesh , Murrell Ben
Published: November 2020

For the past 20 years, the recombination detection program (RDP) project has focused on the development of a fast, flexible, and easy to use Windows-based recombination analysis tool. Whereas previous versions of this tool have relied on considerable user-mediated verification of detected recombination events, the latest iteration, RDP5, is automated enough that it can be integrated within analysis pipelines and run without any user input. The main innovation enabling this degree of automation is the implementation of statistical tests to identify recombination signals that could be attributable to evolutionary processes other than recombination. The additional analysis time required for these tests has been offset by algorithmic improvements throughout the program such that, relative to RDP4, RDP5 will still run up to five times faster and be capable of analyzing alignments containing twice as many sequences (up to 5000) that are five times longer (up to 50 million sites). For users wanting to remove signals of recombination from their datasets before using them for downstream phylogenetics-based molecular evolution analyses, RDP5 can disassemble detected recombinant sequences into their constituent parts and output a variety of different recombination-free datasets in an array of different alignment formats. For users that are interested in exploring the recombination history of their datasets, all the manual verification, data management and data visualization components of RDP5 have been extensively updated to minimize the amount of time needed by users to individually verify and refine the program’s interpretation of each of the individual recombination events that it detects.
The value of multimodality imaging in hypertensive heart disease
Authors: Saeed Sahrai , Tadic Marijana , Grytaas Marianne , Mancia Giuseppe , Larsen Terje H.
Published: November 2020

Hypertensive heart disease (HHD) includes left ventricular (LV) functional and structural remodeling. For a long time, this involved only LV diastolic dysfunction and LV hypertrophy. However, development of imaging technique enabled more detailed insights into LV mechanics. Its impairment seems to be the first step in the cascade of HHD. Tissue characterization, obtained by cardiac magnetic resonance, opened a completely new chapter in the assessment of HHD. We report a case of a 47-year-old man who was referred to our department for a newly detected heart failure. CT angiography excluded relevant coronary disease and cardiac magnetic resonance revealed focuses of fibrosis in interventricular septum, in addition severely dilated LV with severely reduced ejection fraction. Considering the fact that the patient had longstanding uncontrolled arterial hypertension and that other causes of cardiac remodeling and dysfunction were excluded, we hypothesized that the multimodality imaging approach enabled prompt diagnosis of HHD.
Joint Hypermobility Does Not Increase the Risk of Developing Hip Pain, Cartilage Defects, or Retirement in Professional Ballet Dancers Over 5 years
Authors: Mayes Susan , Smith Peter , Stuart Debbie , Cook Jill
Published: November 2020

Objective:

This study aimed to evaluate the risk of developing hip pain, cartilage defects, and retirement in hypermobile ballet dancers over 5 years.

Design:

Prospective cohort study.

Setting:

Professional Ballet Company.

Participants:

Forty ballet dancers (57.5% women) were assessed at baseline and 21 dancers at 5 years.

Independent Variable:

Baseline evaluation of generalised joint hypermobility (GJH) (GJH = Beighton score ≥5/9).

Outcome Measures:

Cartilage defects on hip 3T magnetic resonance imaging and pain (the Copenhagen Hip and Groin Outcome Score: HAGOS) at baseline and follow-up, hip-related injury incidence, and retirement over 5 years.

Results:

Twelve dancers retired by follow-up, none due to hip injury or GJH. At baseline, 17 (42.5%) dancers were hypermobile, 18 (45%) had cartilage defects, and 15 (37.5%) reported hip pain (HAGOS pain <100). Cartilage defect prevalence was lower in GJH (n = 1) than non-GJH dancers (n = 17, P < 0.001). Beighton scores <5/9 were predictive of cartilage defect presence at baseline, independent of age and sex (P = 0.006). At follow-up, cartilage defects progressed in 2 dancers, one was hypermobile. Baseline and follow-up HAGOS pain scores were similar in GJH and non-GJH dancers (P > 0.05 for all). Hip-related injury over 5 years was reported by a similar number of GJH (n = 7) and non-GJH dancers (n = 6, P = 0.7). Hypermobility was more prevalent in active dancers (n = 12) than dancers who retired (n = 2), independent of age, rank, and sex (P = 0.03).

Conclusions:

Hypermobile dancers are at no greater risk of reporting hip pain and injury or retirement over 5 years, and cartilage defect prevalence was much lower in GJH than non-GJH dancers.
Evaluation of Daily Lives of Children and Adolescents with Celiac Disease and Nursing Approaches
Authors: Taşdelen Baş Melike , Çavuşoğlu Hicran
Published: November 2020

The incidence of celiac disease has been increasing in recent years. Celiac disease is an autoimmune enteropathy that emerges mostly in the childhood period. This disorder is a chronic condition of the small intestine due to gluten intake in individuals with genetic predisposition. In the treatment of celiac disease, gluten-free diet therapy is applied. However, the adaptation process to the diet may create difficulties for patients. Compliance with diet is much more difficult among patients with celiac disease in childhood and adolescence than in adult patients. Children and adolescents face distinct difficulties in their homes, at school, and in their social lives. Besides following dietary treatment, children and adolescents living with celiac disease need peer support to manage their daily routines. In this article, we aimed to discuss the problems experienced by children and adolescents living with celiac disease and nursing approaches to these problems.
Evolutionary analysis of SARS-CoV-2 spike protein for its different clades
Authors: Pereson Matías J. , Flichman Diego M. , Martínez Alfredo P. , Baré Patricia , Garcia Gabriel H. , DI Lello Federico A.
Published: November 2020

Objective

The spike protein of SARS-CoV-2 has become the main target for antiviral and vaccine development. Despite its relevance, there is scarce information about its evolutionary traces. The aim of this study was to investigate the diversification patterns of the spike for each clade of SARS-CoV-2 through different approaches.

Methods

Two thousand and one hundred sequences representing the seven clades of the SARS-CoV-2 were included. Patterns of genetic diversifications and nucleotide evolutionary rate were estimated for the spike genomic region.

Results

The haplotype networks showed a star shape, where multiple haplotypes with few nucleotide differences diverge from a common ancestor. Four hundred seventy nine different haplotypes were defined in the seven analyzed clades. The main haplotype, named Hap-1, was the most frequent for clades G (54%), GH (54%), and GR (56%) and a different haplotype (named Hap-252) was the most important for clades L (63.3%), O (39.7%), S (51.7%), and V (70%). The evolutionary rate for the spike protein was estimated as 1.08 x 10−3nucleotide substitutions/site/year. Moreover, the nucleotide evolutionary rate after nine months of pandemic was similar for each clade.

Conclusions

In conclusion, the present evolutionary analysis is relevant since the spike protein of SARS-CoV-2 is the target for most therapeutic candidates; besides, changes in this protein could have consequences on viral transmission, response to antivirals and efficacy of vaccines. Moreover, the evolutionary characterization of clades improves knowledge of SARS-CoV-2 and deserves to be assessed in more detail since re-infection by different phylogenetic clades has been reported.
Bile acid excess impairs thermogenic function in brown adipose tissue
Authors: Zhou Weinan , VanDuyne Philip , Zhang Chi , Riessen Ryan , Barragan Maribel , Rowitz Blair M. , Teran-Garcia Margarita , Boppart Stephen A. , Anakk Sayeepriyadarshini
Published: November 2020

Bile acids (BAs) not only facilitate fat digestion but also protect against obesity. Here, we show that a genetic mouse model for BA overload (Farnesoid X receptor; Small heterodimer double knockout (DKO)) exhibits mitochondrial dysfunction resulting in a thermogenic defect. By housing DKO mice at thermoneutrality, the poor mitochondrial function in brown fat protects them from diet-induced obesity. Compared to control, we find higher adipose BA levels with excess accumulation of taurocholic acid in the DKO mice. We report that the expression of genes responsible for BAde novosynthesis, conjugation and transporters and accumulation of BAs are present in both brown and white adipocytes. We determine that BA overload is sufficient to cause adipocyte mitochondrial dysfunction and induce the expression of cellular senescence genesin vitro. Taken together, we uncover that BA levels within the adipose tissue may modulate its overall function.

Highlights

Mouse model of BA overload exhibits adipose defects, which is partially restored by housing at thermoneutrality.

BAs are present in detectable concentrations in both BAT and WAT.

Adipocytes express genes responsible forde novosynthesis, conjugation and transport of BAs, and accumulate BAs.

Pathological accumulation of BAs impairs mitochondrial function leading to thermogenic defect.
A pipeline to characterize local cortical folds by mapping them to human-interpretable shapes
Authors: Roy Arnab , McMillen Tyler , Beiler Donielle L , Snyder William , Patti Marisa , Troiani Vanessa
Published: November 2020

Background

Variations in regional cortical folds across individuals have been examined using computationally-derived morphological measures, or by manual characterization procedures that map distinct variants of a regional fold to a set of human-interpretable shapes. Although manual mapping approaches have proven useful for identifying morphological differences of clinical relevance, such procedures are subjective and not amenable to scaling.

New Method

We propose a 3-step pipeline to develop computational models of manual mapping. The steps are: represent regional folds as feature vectors, manually map each feature vector to a shape-variant that the underlying fold represents, and train classifiers to learn the mapping.

Results

For demonstration, we chose a 2D-problem of detecting within slice discontinuity of medial and lateral sulci of orbitofrontal cortex (OFC); the discontinuity may be visualized as a broken H-shaped pattern, and is fundamental to OFC-type-characterization. The classifiers predicted discontinuities with 86-95% test-accuracy.

Comparison with Existing Methods

There is no existing pipeline that automates a manualcharacterizationprocess. For the current demonstration problem, we conduct multiple analyses using existing softwares to explain our design decisions, and present guidelines for using the pipeline to examine other regional folds using conventional or non-conventional morphometric measures.

Conclusion

We show that this pipeline can be useful for determining axial-slice discontinuity of sulci in the OFC and can learn structural-features that human-raters may rely on during manual-characterization.The pipeline can be used for examining other regional folds and may facilitate discovery of various statistically-reliable 2D or 3D human-interpretable shapes that are embedded throughout the brain.
Attitudes and Practices of Open Data, Preprinting, and Peer-review - a Cross Sectional Study on Croatian Scientists
Authors: Baždarić K , Vrkić I , Arh E , Mavrinac M , Gligora Marković M , Bilić-Zulle L , Stojanovski J , Malički M.
Published: November 2020

Attitudes towards open peer review, open data and use of preprints influence scientists’ engagement with those practices. Yet there is a relatively small number of validated questionnaires that measure these attitudes. The goal of our study was to construct and validate such a questionnaire. Using a sample of Croatian scientists (N=541), from a wide range of disciplines, we developed a questionnaire titled Attitudes towards Open data sharing, preprinting, and peer-review (ATOPP). The questionnaire has 21 item with a four-factor structure (attitudes towards: open data, preprint servers, open peer-review and open peer-review in small scientific communities). Based on the questionnaire, the attitudes of Croatian scientists towards these topics were generally neutral, with a median of 3.3 out of 5 of the total attitude score. Croatian scientist attitudes were lowest for open peer-review in small scientific communities (Md 2.0) and highest for open data (Md 3.9).
Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model for Phospholamban R14del cardiomyopathy
Authors: Kamel S.M. , van Opbergen C.J.M. , Koopman C.D. , Verkerk A.O. , Onderwater Y. L. , Chocron S. , Polidoro Pontalti C. , Vos M.A. , de Boer T.P. , van Veen T.A.B. , Bakkers J.
Published: November 2020

The heterozygous phospholamban (PLN) p.Arg14del (R14del) mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. The PLN R14del mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca2+dynamics. Little is known about the physiological processes preceding PLN R14del induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we addressed these issues using a knock-in PLN R14del zebrafish model. Hearts from adult zebrafish with the R14del mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography revealed contractile pulsus alternans before overt structural changes occurred, which correlated at the cellular level with action potential duration (APD) alternans. These functional alterations are preceded by diminished Ca2+transient amplitudes in embryonic hearts. We found that istaroxime treatment ameliorates thein vivoCa2+dysregulation, rescues the cellular APD alternans, while it improves cardiac relaxation. Thus, we present novel insight into the pathophysiology ofPLNR14del cardiomyopathy and identify istaroxime as a potential novel drug for its treatment.
HierCC: A multi-level clustering scheme for population assignments based on core genome MLST
Authors: Zhou Zhemin , Charlesworth Jane , Achtman Mark
Published: November 2020

Motivation

Routine infectious disease surveillance is increasingly based on large-scale whole genome sequencing databases. Real-time surveillance would benefit from immediate assignments of each genome assembly to hierarchical population structures. Here we present HierCC, a scalable clustering scheme based on core genome multi-locus typing that allows incremental, static, multi-level cluster assignments of genomes. We also present HCCeval, which identifies optimal thresholds for assigning genomes to cohesive HierCC clusters. HierCC was implemented in EnteroBase in 2018, and has since genotyped >400,000 genomes fromSalmonella, Escherichia, YersiniaandClostridioides.

Availability

Implementation:http://enterobase.warwick.ac.uk/and Source codes:https://github.com/zheminzhou/HierCC

Contact

zhemin.zhou@warwick.ac.uk

Supplementary information

Supplementary data are available atBioinformaticsonline.
Chemical composition and insecticidal activity of Aeollanthus pubescens Benth leaf essential oil on the malaria vector Anopheles gambiae (Diptera: Culicidae)
Authors: Bohounton Roméo Barnabé , Djogbénou Luc Salako , Djihinto Oswald Yédjinnavênan , Dedome Oronce Sedjro-Ludolphe , Sovegnon Pierre Marie , Barea Bruno , Adomou Aristide , Villeneuve Pierre , Tchobo Fidèle Paul
Published: November 2020

The use of synthetic insecticides is responsible for many cases of resistance in insects. Therefore, the use of natural molecules of ecological interest with insecticidal properties turns out to be an alternative approach to the use of synthetic insecticides. This study aims at investigating the larvicidal, adulticidal activity and the composition of the essential oil of Aeollanthus pubescens Benth on the major malaria vector Anopheles gambiae.

The leaves of Aeollanthus pubescens were collected in the South of the Republic of Benin. Three reference strains of Anopheles gambiae s.s. such as Kisumu, Kiskdr and Acerkis were used. The chemical composition of the essential oil was analysed by gas chromatography coupled to mass spectrometry. Larvae were exposed to the essential oil extract for 24 h. Adult mosquitoes were exposed to the fragment nets coated with the essential oil for 3 min. Larval mortality and adult survivorship were monitored.

Fourteen components were identified representing 98.31% of the total of oil. The major components were carvacrol (51.06 %), thymyle acetate (14.01 %) and γ-terpinene (10.60 %). The essential oil has remarkable larvicidal properties with LC50 of 29.26, 22.65, and 28.37 ppm respectively on Kisumu, Acerkis and Kiskdr strains. With the fragment net treated at 165 µg/cm2, the KDT50 of both Acerkis (1.71 s, p < 0.001) and Kiskdr (2.67 s, p < 0.001) individuals were significantly lower than that of Kisumu (3.77 s). The lifespan of the three mosquito strains decreased respectively to one day for Kisumu (p < 0.001), two days for Acerkis (p < 0.001) and three days for Kiskdr (p < 0.001) compared to their control.

Our findings show that the Aeollanthus pubescens essential oil is an efficient larvicide and adulticide against malaria vector Anopheles gambiae. This bioinsecticidal activity is a promising discovery for the control of the resistant malaria-transmitting vectors.
Selective BCL-XL Antagonists Eliminate Infected Cells from a Primary Cell Model of HIV Latency but not from Ex Vivo Reservoirs
Authors: Ren Yanqin , Huang Szu Han , Macedo Amanda B. , Ward Adam R. , Alberto Winiffer D. Conce , Klevorn Thais , Leyre Louise , Chan Dora , Truong Ronald , Rohwetter Thomas , Zumbo Paul , Dündar Friederike , Betel Doron , Kovacs Colin , Benko Erika , Bosque Alberto , Jones R. Brad
Published: November 2020

HIV persists, despite antiviral immune responses and effective antiretroviral therapy, in viral reservoirs that seed rebound viremia if therapy is interrupted. Previously, we showed that the BCL-2 protein contributes to HIV persistence by conferring a survival advantage to reservoir-harboring cells. Here, we demonstrate that many of the BCL-2 family members are overexpressed in HIV-infected CD4+ T-cells, indicating increased tension between pro-apoptotic and pro-survival family members – as well as raising the possibility that the inhibition of pro-survival members may disproportionately affect the survival of HIV-infected cells. Based on these results, we chose to further study BCL2L1 (encoding the protein BCL-XL), due to its consistent overexpression and the availability of selective antagonists. Infection of primary CD4+ T-cells with either a clinical isolate, a CCR5-tropic strain, or a CXCR4-tropic strain of HIV resulted in increased BCL-XL protein expression; and treatment with two selective BCL-XL antagonists, A-1155463 and A-1551852, led to disproportionate cell death compared to uninfected CD4+ T-cells. In a primary cell model of latency, both BCL-XL antagonists drove significant reductions in total HIV DNA and in infectious cell frequencies both alone and in combination with the latency reversing agent bryostatin-1, with little off-target cytotoxicity. However, these antagonists, with or without bryostatin-1, or in combination with the highly potent latency reversing agent combination PMA + ionomycin, failed to reduce total HIV DNA and infectious reservoirs in ex vivo CD4+ T-cells from ART-suppressed donors. Our results add to growing evidence that bonafide reservoir-harboring cells are resistant to multiple “kick and kill” modalities - relative to latency models - and uncover BCL-XL antagonists as a facile approach to probing mechanistic underpinnings. We also interpret our results as encouraging of further exploration of BCL-XL antagonists for cure, where combination approaches may unlock the ability to eliminate ex vivo reservoirs.
Efficient GNE myopathy disease modeling with mutation specific phenotypes in human pluripotent stem cells by base editors
Authors: Park Ju-Chan , Kim Jumee , Jang Hyun-Ki , Lee Seung-Yeon , Kim Keun-Tae , Park Seokwoo , Lee Hyun Sik , Choi Hee-Jung , Park Soon-Jung , Moon Sung-Hwan , Bae Sangsu , Cha Hyuk-Jin
Published: November 2020

Despite the great potential of disease modeling with the isogenic pairs of human pluripotent stem cells (hPSCs), the extremely low efficiency of precise gene editing in hPSCs remains a technical hurdle for this approach. Herein, we took advantage of currently available base editors (BEs) to epitomize the isogenic disease model from hPSCs. Using this method, we established 14 hPSCs that harbor point mutations on the GNE gene, including four different mutations found in GNE myopathy patients. Due to lesser activation of p53 by BEs than Cas9, a higher editing efficiency with BEs was achieved. Four different mutations in the epimerase or kinase domains of GNE revealed mutation-specific hyposialylation, which was closely correlated to pathological clinical phenotypes. These mutation-specific hyposialylation patterns were evident in GNE protein structure modeling. Furthermore, treatment with a drug candidate currently under clinical trials showed a mutation-specific drug response in GNE myopathy disease models. These data suggest that isogenic disease models from hPSCs using BEs could serve as a useful tool for mimicking the pathophysiology of GNE myopathy and for predicting drug responses.
Comprehensive benchmarking of metagenomic classification tools for long-read sequencing data
Authors: Marić Josip , Križanović Krešimir , Riondet Sylvain , Nagarajan Niranjan , Šikić Mile
Published: November 2020

Background

Long reads have gained popularity in the analysis of metagenomics data. Therefore, we comprehensively assessed metagenomics classification tools on the species taxonomic level. We analysed kmer-based tools, mapping-based tools and two general-purpose long reads mappers. We evaluated more than 20 pipelines which use either nucleotide or protein databases and selected 13 for an extensive benchmark. We prepared seven synthetic datasets to test various scenarios, including the presence of a host, unknown species and related species. Moreover, we used available sequencing data from three well-defined mock communities, including a dataset with abundance varying from 0.0001% to 20% and six real gut microbiomes.

Results

General-purpose mappers Minimap2 and Ram achieved similar or better accuracy on most testing metrics than best-performing classification tools. They were up to ten times slower than the fastest kmer-based tools requiring up to four times less RAM. All tested tools were prone to report organisms not present in datasets, except CLARK-S, and they underperformed in the case of the high presence of the host’s genetic material. Tools which use a protein database performed worse than those based on a nucleotide database. Longer read lengths made classification easier, but due to the difference in read length distributions among species, the usage of only the longest reads reduced the accuracy.

The comparison of real gut microbiome datasets shows a similar abundance profiles for the same type of tools but discordance in the number of reported organisms and abundances between types. Most assessments showed the influence of database completeness on the reports.

Conclusion

The findings indicate that kmer-based tools are well-suited for rapid analysis of long reads data. However, when heightened accuracy is essential, off-the-shelf mappers demonstrate slightly superior performance, albeit at a considerably slower pace. Nevertheless, a combination of diverse categories of tools and databases will likely be necessary to analyse complex samples. Discrepancies observed among tools when applied to real gut datasets, as well as a reduced performance in cases where unknown species or a significant proportion of the host genome is present in the sample, highlight the need for continuous improvement of existing tools. Additionally, regular updates and curation of databases are important to ensure their effectiveness.
A developmentally programmed splicing failure attenuates the DNA damage response during mammalian zygotic genome activation
Authors: Wyatt Christopher D. R. , Pernaute Barbara , Gohr André , Miret-Cuesta Marta , Goyeneche Lucia , Rovira Quirze , Bogdanovic Ozren , Bonnal Sophie , Irimia Manuel
Published: November 2020

The transition from maternal to embryonic transcriptional control is a crucial step in embryogenesis. However, how alternative splicing is regulated during this process and how it contributes to early development is unknown. Using transcriptomic data from pre-implantation stages of human, mouse and cow, we show that the stage of zygotic genome activation (ZGA) exhibits the highest levels of exon skipping diversity reported for any cell or tissue type. Interestingly, much of this exon skipping is temporary, leads to disruptive non-canonical isoforms, and occurs in genes enriched for DNA damage response in the three species. We identified two core spliceosomal components, Snrpb and Snrpd2, as regulators of these patterns. These genes have low maternal expression at the time of ZGA and increase sharply thereafter. Consistently, microinjection of Snrpb/d2 mRNA into mouse zygotes reduces the levels of temporary exon skipping at ZGA, and leads to an increase in etoposide-induced DNA damage response. Altogether, our results suggest that mammalian embryos undergo an evolutionarily conserved and developmentally programmed specific splicing failure at the time of genome activation that attenuates cellular responses to DNA damage at these early stages.