bluuebunny/crossref_metadata_2025 huggingface dataset:
Is the Cranial Sagittal Vertical Axis (Cr-SVA) a Better Midterm Predictor of Clinical Results Than C7-SVA in Adult Patients Operated on Spinal Deformity After a Minimum 2-Year Follow-Up?
Authors: Gomez-Rice Alejandro , Madrid Cristina , Izquierdo Enrique , Marco-Martínez Fernando , Tresguerres Jesús A.F. , Sanchez-Mariscal Felisa
Published: July 2020

Study Design:

This is nonconcurrent prospective study approved by the Institutional Research Ethics Committee

Objective:

The purpose of this study is to determine if the cranial sagittal vertical axis (Cr-SVA) measured in full spine standing radiographs is a better predictor of clinical results than the C7 sagittal vertical axis (C7-SVA) in adult patients operated on spinal deformity with a minimum 2-year follow-up after surgery.

Summary of Background Data:

The Cr-SVA has recently been described as a better predictor of health-related quality of life outcomes than the C7-SVA for patients with adult spinal deformity (ASD) before undergoing surgery. This has not been confirmed in patients after ASD surgery.

Methods:

Inclusion criteria were age at surgery more than 25 years and a minimum 2-year follow-up after a ≥5 level fusion for ASD. Full-length standing lateral radiographs (including nasion-inion line, spine, and femoral heads) and Scoliosis Research Society 22 Questionnaire and SF36 questionnaires were available for every patient at the final follow-up. The distance from the Cr-SVA to the posterior corner of S1 (Cr-SVA-S) and to the centers of the hip (Cr-SVA-H) was measured and also the C7-SVA, lumbar lordosis, pelvic incidence, pelvic tilt, and PI-LL.

Results:

Sixty-five patients (58 female individuals) operated on ASD in a single institution were included. Age at surgery was 61 years (26–67). The mean follow-up was 53 months (24–120). Spearman rank-order test showed several significant correlations. After multivariable analysis, only Cr-SVA-S and age persisted as predictors for Scoliosis Research Society (SRS) image scores, Cr-SVA-H for SRS satisfaction, Cr-SVA-H and age for SRS total scores, Cr-SVA-H and age for SF36 Physical Function, Cr-SVA-S for SF36 Role Physical, Cr-SVA-H for SF36 Bodily Pain, and Cr-SVA-H for SF36 Role Emotional.

Conclusions:

The Cr-SVA measured in full spine standing radiographs seems to be a better predictor of health-related quality of life outcomes than the C7-SVA for adults operated on spinal deformity >2 years after surgery.
Long-term results in the patients with traumatic hip fracture-dislocation: Important prognostic factors
Authors: Ma Hsuan-Hsiao , Huang Chung-Chin , Pai Fu-Yuan , Chang Ming-Chau , Chen Wei-Ming , Huang Tung-Fu
Published: July 2020

Background:

Traumatic hip dislocation with or without acetabular fractures can lead to various outcomes of the hip. Long-term follow-up studies on traumatic hip dislocation are few. We conducted a retrospective study of the treatment and long-term outcomes in patients with hip dislocation to determine prognostic factors.

Methods:

From 2001 to 2016, we enrolled 38 patients in our study. All the patients had been diagnosed through radiography or computed tomography. Emergent closed reduction was performed initially. We hypothesized that poor outcomes, including osteonecrosis and traumatic osteoarthritis, are related to specific factors.

Results:

All the patients had posterior dislocation initially. Closed reduction or open reduction due to irreducible after closed reduction was performed within 6 hours of dislocation in most patients. In total, nine patients had poor outcomes of the hip, including osteonecrosis and traumatic osteoarthritis and total hip arthroplasty. Specific factors that lead to poor outcomes were patient age and timing of reduction.

Conclusion:

Although end results in severe traumatic hip dislocation are disappointing, conservatism in applying the secondary reconstructive procedure is desirable. In our series, crucial factors for long-term prognosis were patient age and timing of hip reduction.
Workplace Violence Interventions Used by Home Healthcare Workers
Authors: Small Tamara F. , Gillespie Gordon Lee , Kean Emily B. , Hutton Scott
Published: July 2020

The threat of workplace violence (WPV) is a significant occupational hazard for home healthcare workers (HHCWs). The purpose of this integrative review is to examine WPV interventions used by HHCWs to stay safe while working in the patient's home and community. The methodology used was the integrative review by Whittemore and Knafl (2005), which allows for inclusion of experimental and non-experimental research, reflecting the state of the science on interventions used by HHCWs to mitigate and prevent WPV. A total of 17 articles pertained to interventions used by HHCWs. Interventions were further categorized by WPV Type. There are a number of interventions used for Type I and II WPV. However, interventions for Type III WPV are minimal and interventions for Type IV WPV are obsolete. Safety and health training were shown to be significant in increasing HHCWs' confidence and knowledge about WPV prevention. Researchers demonstrated safety and health training are effective in promoting a safe work environment and reducing incidents of WPV. This review begins to fill the gap in the literature on interventions used by HHCWs to mitigate and prevent WPV.
Sepsis
Authors: Durning Marijke Vroomen
Published: July 2020

Sepsis is a life-threatening response to infection that affects over 1.7 million people annually in the United States. Although sepsis can strike healthy and active people of all ages, those at highest risk are older adults, infants, and people with chronic illnesses or an impaired immune system. Many people who had sepsis recover and resume life as it was before. However, others require some level of postdischarge home healthcare. Up to 60% of survivors, particularly of severe sepsis and septic shock, are left with cognitive and/or physical limitations. About one-third of all sepsis survivors and more than 40% of older survivors are rehospitalized within 3 months of the initial sepsis diagnosis, most commonly due to a repeat episode of sepsis or another infection. Quality home healthcare follow-up of sepsis patients is paramount in lowering readmission rates, preventing reoccurrence of sepsis, and assisting patients and families during the postsepsis phase of healthcare.
Is Noninvasive Vagus Nerve Stimulation a Safe and Effective Alternative to Medication for Acute Migraine Control?
Authors: Blech Benzion , Starling Amaal J. , Marks Lisa A. , Wingerchuk Dean M. , O’Carroll Cumara B.
Published: July 2020

Background:

Noninvasive neuromodulation devices have been used for a variety of headache disorders, including cluster and migraine, since recently being cleared by the Federal Drug Administration. Although these devices have been touted as low-risk options for improved headache control, the data behind actual efficacy endpoints remain unclear.

Objective:

To critically assess current evidence regarding the efficacy of the noninvasive vagus nerve stimulator (nVNS) device for acute migraine management.

Methods:

The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions.

Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of headache.

Results:

A randomized, double-blind, sham-controlled clinical trial was selected for critical appraisal. In this trial, the primary endpoint (pain freedom at 120 min after use of nVNS for first acute migraine attack) was not met when compared with sham device (30.4% for nVNS vs. 19.7% for sham; P=0.067). However, there were statistically significant differences found for various secondary endpoints favoring nVNS, such as pain freedom rates at 30 and 60 minutes, pain relief at 120 minutes, and mean percentage pain score reduction rates at 60 and 120 minutes.

Conclusions:

When comparing nVNS with sham, no statistically significant differences were found with regards to the primary endpoint of pain freedom at 120 minutes, although differences were found with various secondary endpoints and post hoc analysis. nVNS is likely a safe alternative to medications.
Strong Correlation Between Prevalence of Severe Vitamin D Deficiency and Population Mortality Rate from COVID-19 in Europe
Authors: Pugach Isaac Z. , Pugach Sofya
Published: July 2020

Background

SARS-CoV-2 virus causes a very wide range of COVID-19 disease severity in humans: from completely asymptomatic to fatal, and the reasons behind it are often not understood. There is some data that Vitamin D may have protective effect, so authors decided to analyze European country-wide data to determine if Vitamin D levels are associated with COVID-19 population death rate.

Methods

To retrieve the Vitamin D levels data, authors analyzed the Vitamin D European population data compiled by 2019 ECTS Statement on Vitamin D Status published in the European Journal of Endocrinology. For the data set to used for analysis, only recently published data, that included general adult population of both genders ages 40-65 or wider, and must have included the prevalence of Vitamin D deficiency.

Results

There were 10 countries data sets that fit the criteria and were analyzed. Severe Vitamin D deficiency was defined as 25(OH)D less than 25 nmol/L (10 ng/dL). Pearson correlation analysis between death rate per million from COVID-19 and prevalence of severe Vitamin D deficiency shows a strong correlation with r = 0.76, p = 0.01, indicating significant correlation. Correlation remained significant, even after adjusting for age structure of the population. Additionally, over time, correlation strengthened, and r coefficient asymptoticaly increased.

Conclusions

Authors recommend universal screening for Vitamin D deficiency, and further investigation of Vitamin D supplementation in randomized control studies, which may lead to possible treatment or prevention of COVID-19.
MGATRx: Discovering Drug Repositioning Candidates Using Multi-view Graph Attention
Authors: Yella Jaswanth Kumar , Jegga Anil G
Published: July 2020

In-silico drug repositioning or predicting new indications for approved or late-stage clinical trial drugs is a resourceful and time-eficient strategy in drug discovery. However, inferring novel candidate drugs for a disease is challenging, given the heterogeneity and sparseness of the underlying biological entities and their relationships (e.g., disease/drug annotations). By integrating drug-centric and disease-centric annotations as multi-views, we propose a multi-view graph attention network for indication discovery (MGATRx). Unlike most current similarity-based methods, we employ graph attention network on the heterogeneous drug and disease data to learn the representation of nodes and identify associations. MGATRx outperformed four other state-of-art methods used for computational drug repositioning. Further, several of our predicted novel indications are either currently investigated or are supported by literature evidence, demonstrating the overall translational utility of MGATRx.
Perturbation robustness analyses reveal important parameters in variant interpretation pipelines
Authors: Wang Yaqiong , Adhikari Aashish N. , Sunderam Uma , Kvale Mark N. , Currier Robert J. , Gallagher Renata C. , Kwok Pui-Yan , Puck Jennifer M. , Srinivasan Rajgopal , Brenner Steven E.
Published: July 2020

Motivation

Genome sequencing is being used routinely in clinical and research applications, but subsequent variant interpretation pipelines can vary widely. A systematic approach for exploring parameter choices and selection plays an important role in designing robust pipelines for specific clinical applications.

Results

We present a framework to be applied in scenarios with limited data whereby expert knowledge informs pipeline refinement. Starting from initial reference variant interpretation pipelines with commonly used parameters, we derived pipelines by perturbing the parameters one by one to determine which parameters can yield meaningful changes in a pipeline’s performance. We updated the reference pipeline by fixing the value of parameters which have small impact on the pipeline’s performance. Then we conducted new rounds of perturbation as the process converged, yielding a stable pipeline which is robust. We applied the framework for genetic disease prediction in de-identified exomes from a cohort of 138 individuals with rare Mendelian inborn errors of metabolism (IEMs) and systematically explored how perturbing different parameters affected the pipeline’s sensitivity and specificity. For this application, we perturbed commonly used parameters in variant interpretation pipelines, including choices of genes, variant callers, transcript models, databases of allele frequencies, databases of curated disease variants, and tools for variant impact prediction. Our analyses showed that choice of variant callers, variant impact prediction tools, MAF threshold, and MAF databases can meaningfully alter results from a pipeline. This work informs the development of exome analysis pipelines designed for newborn metabolic disorder screening and suggests the general application of perturbation analysis in genome interpretation pipeline design.
Multi-Tissue Neocortical Transcriptome-Wide Association Study Implicates 8 Genes Across 6 Genomic Loci in Alzheimer’s Disease
Authors: Gockley Jake , Montgomery Kelsey S. , Poehlman William L. , Wiley Jesse C. , Liu Yue , Gerasimov Ekaterina , Greenwood Anna K , Sieberts Solveig K. , Wingo Aliza P. , Wingo Thomas S. , Mangravite Lara M. , Logsdon Benjamin A.
Published: July 2020

Background

Alzheimer’s disease (AD), an incurable neurodegenerative disease, currently affecting 1.75% of the United States population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD-risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION Transcriptome Wide Association Study (TWAS) pipeline to ingest expression from multiple neocortical regions, provide a set of 6780 gene weights which are abstracatable across the neocortex, and leverage these to find 8 genes from six loci with associated AD risk validated through summary mendelian randomization (SMR) utilizing IGAP summary statistics.

Method

A combined dataset of 2003 genotypes clustered to Central European (CEU) ancestry was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles across 6 Neo-cortical tissues (TCX=248, FP=50, IFG=41, STG=34, PHG=34, DLPFC=461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene’s surroundingcis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and provide support for cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues.

Results

Cis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N=6775 (99.92%), Bonferroni: N=6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05); APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, KNOP1.

Conclusion

We provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes.
Mapping extinction risk in the global functional spectra across the tree of life
Authors: Carmona Carlos P. , Tamme Riin , Pärtel Meelis , de Bello Francesco , Brosse Sébastien , Capdevila Pol , González-M. Roy , González-Suárez Manuela , Salguero-Gómez Roberto , Vásquez-Valderrama Maribel , Toussaint Aurèle
Published: July 2020

Although one quarter of the species of plants and vertebrates are threatened with extinction, little is known about how the potential effect of extinctions on the global diversity of ecological strategies. Using trait and phylogenetic information for more than 75,000 species of plants, mammals, birds, reptiles, amphibians and freshwater fishes, we characterized the global functional spectra of each of these groups. Mapping of extinction risk within these spectra revealed that larger species with slower pace of life are universally threatened. Simulated potential extinctions revealed extensive internal reorganizations in the global functional spectra, which are particularly severe for mammals and amphibians. Considering the disproportionate importance of the largest species for ecological processes, our results emphasize the importance of actions to prevent the extinction of the megabiota.
Centromere evolution in the fungal genusVerticillium
Authors: Seidl Michael F , Kramer H Martin , Cook David E , Fiorin Gabriel Lorencini , van den Berg Grardy CM , Faino Luigi , Thomma Bart PHJ
Published: July 2020

Centromeres are chromosomal regions that are crucial for chromosome segregation during mitosis and meiosis, and failed centromere formation can contribute to chromosomal anomalies. Despite this conserved function, centromeres differ significantly between and even within species. Thus far, systematic studies into the organization and evolution of fungal centromeres remain scarce. In this study, we identified the centromeres in each of the ten species of the fungal genusVerticilliumand characterized their organization and evolution. Chromatin immunoprecipitation of the centromere-specific histone CenH3 (ChIP-seq) and chromatin conformation capture (Hi-C) followed by high-throughput sequencing identified eight conserved, large (∼150 kb), AT-, and repeat-rich regional centromeres that are embedded in heterochromatin in the plant pathogenV. dahliae. Using Hi-C, we similarly identified repeat-rich centromeres in the otherVerticilliumspecies. Strikingly, a single repetitive element is strongly associated with centromeric regions in some but not allVerticilliumspecies. Extensive chromosomal rearrangements occurred duringVerticilliumevolution, yet only a minority could be linked to centromeres, suggesting that centromeres played a minor role in chromosomal evolution. Nevertheless, the size and organization of centromeres differ considerably between species, and centromere size was found to correlate with the genome-wide repeat content. Overall, our study highlights the contribution of repetitive elements to the diversity and rapid evolution of centromeres within the fungal genusVerticillium.

IMPORTANCE

The genusVerticilliumcontains ten species of plant-associated fungi, some of which are notorious pathogens.Verticilliumspecies evolved by frequent chromosomal rearrangements that contribute to genome plasticity. Centromeres are instrumental for separation of chromosomes during mitosis and meiosis, and failed centromere functionality can lead to chromosomal anomalies. Here, we used a combination of experimental techniques to identify and characterize centromeres in each of theVerticilliumspecies. Intriguingly, we could strongly associate a single repetitive element to the centromeres of some of theVerticilliumspecies. The presence of this element in the centromeres coincides with increased centromere sizes and genome-wide repeat expansions. Collectively, our findings signify a role of repetitive elements in the function, organization and rapid evolution of centromeres in a set of closely related fungal species.
The transcription factor Pdr802 regulates Titan cell formation, quorum sensing, and pathogenicity ofCryptococcus neoformans
Authors: Reuwsaat Julia C. V. , Agustinho Daniel P. , Motta Heryk , Brown Holly , Chang Andrew L. , Brent Michael R. , Kmetzsch Livia , Doering Tamara L.
Published: July 2020

Cryptococcus neoformansis a ubiquitous, opportunistic fungal pathogen that kills almost 200,000 people worldwide each year. It is acquired when mammalian hosts inhale the infectious propagules; these are deposited in the lung and, in the context of immunocompromise, may disseminate to the brain and cause lethal meningoencephalitis. Once inside the host,C. neoformansundergoes a variety of adaptive processes, including secretion of virulence factors, expansion of a polysaccharide capsule that impedes phagocytosis, and the production of giant (Titan) cells. The transcription factor Pdr802 is one regulator of these responses to the host environment. Expression of the corresponding gene is highly induced under host-like conditionsin vitroand is critical forC. neoformansdissemination and virulence in a mouse model of infection. Direct targets of Pdr802 include the quorum sensing proteins Pqp1, Opt1 and Liv3; the transcription factors Stb4, Zfc3 and Bzp4, which regulate cryptococcal brain infectivity and capsule thickness; the calcineurin targets Had1 and Crz1, important for cell wall remodeling andC. neoformansvirulence; and additional genes related to resistance to host temperature and oxidative stress, and to urease activity. Notably, cryptococci engineered to lack Pdr802 showed a dramatic increase in Titan cells, which are not phagocytosed and have diminished ability to directly cross biological barriers. This explains the limited dissemination ofpdr802mutant cells to the central nervous system and the consequently reduced virulence of this strain. The role of Pdr802 as a negative regulator of Titan cell formation is thus critical for cryptococcal pathogenicity.

IMPORTANCE

The pathogenic yeastCryptococcus neoformanspresents a worldwide threat to human health, especially in the context of immunocompromise, and current antifungal therapy is hindered by cost, limited availability, and inadequate efficacy. After the infectious particle is inhaled,C. neoformansinitiates a complex transcriptional program that integrates cellular responses and enables adaptation to the host lung environment. Here we describe the role of the transcription factor Pdr802 in the response to host conditions and its impact onC. neoformansvirulence. We identified direct targets of Pdr802 and also discovered that it regulates cellular features that influence movement of this pathogen from the lung to the brain, where it causes fatal disease. These findings advance our understanding of a serious disease.
A phenome-wide association study (PheWAS) of COVID-19 outcomes by race using the electronic health records data in Michigan Medicine
Authors: Salvatore Maxwell , Gu Tian , Mack Jasmine A. , Sankar Swaraaj Prabhu , Patil Snehal , Valley Thomas S. , Singh Karandeep , Nallamothu Brahmajee K. , Kheterpal Sachin , Lisabeth Lynda , Fritsche Lars G. , Mukherjee Bhramar
Published: July 2020

Background

We perform a phenome-wide scan to identify pre-existing conditions related to COVID-19 susceptibility and prognosis across the medical phenome and how they vary by race.

Methods

The study is comprised of 53,853 patients who were tested/positive for COVID-19 between March 10 and September 2, 2020 at a large academic medical center.

Results

Pre-existing conditions strongly associated with hospitalization were renal failure, pulmonary heart disease, and respiratory failure. Hematopoietic conditions were associated with ICU admission/mortality and mental disorders were associated with mortality in non-Hispanic Whites. Circulatory system and genitourinary conditions were associated with ICU admission/mortality in non-Hispanic Blacks.

Conclusions

Understanding pre-existing clinical diagnoses related to COVID-19 outcomes informs the need for targeted screening to support specific vulnerable populations to improve disease prevention and healthcare delivery.
Modeling impact and cost-effectiveness of gene drives for malaria elimination in the Democratic Republic of the Congo
Authors: Metchanun Nawaphan , Borgemeister Christian , Amzati Gaston , von Braun Joachim , Nikolov Milen , Selvaraj Prashanth , Gerardin Jaline
Published: July 2020

Malaria elimination will be challenging in countries that currently continue to bear high malaria burden. Sex-ratio distorting gene drives, such as driving-Y, could play a role in an integrated elimination strategy if they can effectively suppress vector populations. Using a spatially explicit, agent-based model of malaria transmission in eight representative provinces of the Democratic Republic of the Congo, we predict the impact and cost-effectiveness of integrating driving-Y gene drive mosquitoes in malaria elimination strategies that include existing interventions such as insecticide-treated nets and case management of symptomatic malaria. Gene drive mosquitoes could eliminate malaria and were the most cost-effective intervention overall if the drive component was highly effective with at least 95% X-shredding and associated cost of deployment below 7.17 $int per person per year. Suppression gene drive could be a cost-effective supplemental intervention for malaria elimination, but tight constraints on drive effectiveness and cost ceilings may limit its feasibility.
Modeling the early phase of the Belgian COVID-19 epidemic using a stochastic compartmental model and studying its implied future trajectories
Authors: Abrams Steven , Wambua James , Santermans Eva , Willem Lander , Kuylen Elise , Coletti Pietro , Libin Pieter , Faes Christel , Petrof Oana , Herzog Sereina A. , Beutels Philippe , Hens Niel
Published: July 2020

Following the onset of the ongoing COVID-19 pandemic throughout the world, a large fraction of the global population is or has been under strict measures of physical distancing and quarantine, with many countries being in partial or full lockdown. These measures are imposed in order to reduce the spread of the disease and to lift the pressure on healthcare systems. Estimating the impact of such interventions as well as monitoring the gradual relaxing of these stringent measures is quintessential to understand how resurgence of the COVID-19 epidemic can be controlled for in the future. In this paper we use a stochastic age-structured discrete time compartmental model to describe the transmission of COVID-19 in Belgium. Our model explicitly accounts for age-structure by integrating data on social contacts to (i) assess the impact of the lockdown as implemented on March 13, 2020 on the number of new hospitalizations in Belgium; (ii) conduct a scenario analysis estimating the impact of possible exit strategies on potential future COVID-19 waves. More specifically, the aforementioned model is fitted to hospital admission data, data on the daily number of COVID-19 deaths and serial serological survey data informing the (sero)prevalence of the disease in the population while relying on a Bayesian MCMC approach. Our age-structured stochastic model describes the observed outbreak data well, both in terms of hospitalizations as well as COVID-19 related deaths in the Belgian population. Despite an extensive exploration of various projections for the future course of the epidemic, based on the impact of adherence to measures of physical distancing and a potential increase in contacts as a result of the relaxation of the stringent lockdown measures, a lot of uncertainty remains about the evolution of the epidemic in the next months.
Effects of simulated cochlear-implant processing on voice quality distinction: Evidence from analysis of disordered voices
Authors: Arjmandi Meisam K. , Ghasemzadeh Hamzeh , Dilley Laura C.
Published: July 2020

The ability to discern variations in voice quality from speech is important for effective talker identification and robust speech processing; yet, little is known about how faithfully acoustic information relevant to variations in talkers’ voice quality is transmitted through a cochlear implant (CI) device. The present study analyzed unprocessed and CI-simulated versions of sustained /a/ vowel sounds from two groups of individuals with normal and disordered voice qualities in order to explore the effects of CI speech processing on acoustic information relevant for the distinction of voice quality. The CI-simulated voices were created by processing the vowel sounds along with 4-, 8-, 12-, 16-, 22-, and 32-channel noise-vocoders. The variations in voice quality for each voice sound was characterized by calculating mel-frequency cepstral coefficients (MFCCs). The effects of simulated CI speech processing on the acoustic distinctiveness between normal and disordered voices were then measured by calculating the Mahalanobis distance (MD) metric, as well as accuracy of support vector machines (SVMs) applied to MFCC features. The results showed that CI speech processing, as simulated by noise vocoding, is highly detrimental to the acoustic information involved in conveying voice quality distinctions. This supports the view that listeners with CIs will likely experience difficulties in perceiving voice quality variations due to the reduced spectral resolution, shedding light on challenges listeners with CIs may face for effective recognition and processing of talkers’ voices.
Nested PCR for the detection of Taenia solium DNA in stool samples
Authors: Franco-Muñoz C , Arévalo A , Duque-Beltran S
Published: July 2020

The traditional parasitological method to diagnose taeniasis is the microscopic observation of eggs in stool samples. However, this method does not allow differentiation between Taenia saginata and Taenia solium. This aim of this study was to achieve the detection of T. solium DNA by polymerase chain reaction (PCR) and to evaluate the cross-reaction with other species of the genus Taenia and other intestinal parasites. DNA was extracted from adult T. solium cestodes by cryolysis in liquid nitrogen and with the DNA stool extraction kit from Qiagen. The detection limit of the test was evaluated by DNA dilutions in water and in stool samples. DNA was extracted from proglottids of T. saginata and T. crassiceps and from stool samples containing other intestinal parasites using ethanol treatment, alkaline lysis, and the DNA stool extraction kit. Nested PCR was used to amplify a previously described fragment of the Tso31 gene, and the PCR products were analyzed by electrophoresis in 2% agarose gels followed by staining with GelRed. The nested PCR of the Tso31 gene allowed the detection of T. solium DNA in stool samples with a detection limit of 20 pg of parasite DNA. PCR showed no cross-reaction with T. saginata, T. crassiceps, or other intestinal parasites of public health importance in Colombia.
Empirical Evidence for Cognitive Subgroups in Body Dysmorphic Disorder
Authors: Malcolm Amy , Brennan Sarah N. , Grace Sally A. , Pikoos Toni D. , Toh Wei Lin , Labuschagne Izelle , Buchanan Ben , Kaplan Ryan A. , Castle David J. , Rossell Susan L.
Published: July 2020

Objective

Current understanding of cognitive functioning in body dysmorphic disorder (BDD) is limited, owing to few studies, small sample sizes, and assessment across only limited cognitive domains. Existing research has also shown inconsistent findings, with both intact and impaired cognition reported in BDD, which might point toward cognitive heterogeneity in the disorder. This study aimed to examine the cognitive profile of BDD in a large sample across eight cognitive domains, and to explore whether cognitive subgroups might be identified within BDD.

Methods

Cognitive domains of inhibition/flexibility, working memory, speed of processing, reasoning and problem-solving, visual and verbal learning, attention/vigilance and social cognition were assessed and compared between 65 BDD patients and 70 healthy controls. Then, hierarchical clustering analysis was conducted on the BDD group’s cognitive data.

Results

Group-average comparisons demonstrated significantly poorer cognitive functioning in BDD than healthy controls in all domains except for attention/vigilance and social cognition. Cluster analysis identified two divergent cognitive subgroups within our BDD cohort characterised by i) broadly intact cognitive function with mild selective impairments (72.3%), and ii) broadly impaired cognitive function (27.7%). However, the clusters did not significantly differ on clinical parameters or most sociodemographic characteristics.

Conclusion

Cognitively diverse subgroups were identified within BDD, yet these were obscured in group-average comparisons. However, subgroup profiles of cognitive functioning seem unrelated to the clinical presentation of BDD. Further research into the underlying mechanisms of cognition in BDD is warranted.

Significant Outcomes

Cognitive function varies widely among people with body dysmorphic disorder (BDD) and includes subgroups characterised by broadly intact or broadly impaired cognitive profiles.

However, reduced performances in visual learning and working memory as relative to healthy participants were identified across both BDD cognitive subgroups to differing degrees.

Clinical characteristics were not significantly different among the two BDD cognitive subgroups; what role cognitive functioning may play in the aetiology or presentation of BDD remains unclear.

Limitations

The output of clustering analysis is sensitive to the choice of variables entered and requires replication with analogous measures of cognition.

Psychiatric comorbidities and medications could have impacted cognitive performances in the BDD group in an unaccounted-for manner.

Data availability statement

Author elects to not share data.
Spatial and single-cell transcriptional landscape of human cerebellar development
Authors: Aldinger Kimberly A. , Thomson Zach , Haldipur Parthiv , Deng Mei , Timms Andrew E. , Hirano Matthew , Santpere Gabriel , Roco Charles , Rosenberg Alexander B. , Lorente-Galdos Belen , Gulden Forrest O. , O’Day Diana , Overman Lynne M. , Lisgo Steven N. , Alexandre Paula , Sestan Nenad , Doherty Dan , Dobyns William B. , Seelig Georg , Glass Ian A. , Millen Kathleen J.
Published: July 2020

Cerebellar development and function require precise regulation of molecular and cellular programs to coordinate motor functions and integrate network signals required for cognition and emotional regulation. However, molecular understanding of human cerebellar development is limited. Here, we combined spatially resolved and single-cell transcriptomics to systematically map the molecular, cellular, and spatial composition of early and mid-gestational human cerebellum. This enabled us to transcriptionally profile major cell types and examine the dynamics of gene expression within cell types and lineages across development. The resulting‘Developmental Cell Atlas of the Human Cerebellum’demonstrates that the molecular organization of the cerebellar anlage reflects cytoarchitecturally distinct regions and developmentally transient cell types that are insufficiently captured in bulk transcriptional profiles. By mapping disease genes onto cell types, we implicate the dysregulation of specific cerebellar cell types, especially Purkinje cells, in pediatric and adult neurological disorders. These data provide a critical resource for understanding human cerebellar development with implications for the cellular basis of cerebellar diseases.
SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response
Authors: Huang Jessie , Hume Adam J. , Abo Kristine M. , Werder Rhiannon B. , Villacorta-Martin Carlos , Alysandratos Konstantinos-Dionysios , Beermann Mary Lou , Simone-Roach Chantelle , Lindstrom-Vautrin Jonathan , Olejnik Judith , Suder Ellen L. , Bullitt Esther , Hinds Anne , Sharma Arjun , Bosmann Markus , Wang Ruobing , Hawkins Finn , Burks Eric J. , Saeed Mohsan , Wilson Andrew A. , Mühlberger Elke , Kotton Darrell N.
Published: July 2020

The most severe and fatal infections with SARS-CoV-2 result in the acute respiratory distress syndrome, a clinical phenotype of coronavirus disease 2019 (COVID-19) that is associated with virions targeting the epithelium of the distal lung, particularly the facultative progenitors of this tissue, alveolar epithelial type 2 cells (AT2s). Little is known about the initial responses of human lung alveoli to SARS-CoV-2 infection due in part to inability to access these cells from patients, particularly at early stages of disease. Here we present anin vitrohuman model that simulates the initial apical infection of the distal lung epithelium with SARS-CoV-2, using AT2s that have been adapted to air-liquid interface culture after their derivation from induced pluripotent stem cells (iAT2s). We find that SARS-CoV-2 induces a rapid global transcriptomic change in infected iAT2s characterized by a shift to an inflammatory phenotype predominated by the secretion of cytokines encoded by NF-kB target genes, delayed epithelial interferon responses, and rapid loss of the mature lung alveolar epithelial program. Over time, infected iAT2s exhibit cellular toxicity that can result in the death of these key alveolar facultative progenitors, as is observedin vivoin COVID-19 lung autopsies. Importantly, drug testing using iAT2s confirmed an antiviral dose-response to remdesivir and demonstrated the efficacy of TMPRSS2 protease inhibition, validating a putative mechanism used for viral entry in human alveolar cells. Our model system reveals the cell-intrinsic responses of a key lung target cell to infection, providing a physiologically relevant platform for further drug development and facilitating a deeper understanding of COVID-19 pathogenesis.
Direct visualization of translational GTPase factor-pool formed around the archaeal ribosomal P-stalk by high-speed atomic force microscopy
Authors: Imai Hirotatsu , Uchiumi Toshio , Kodera Noriyuki
Published: July 2020

The ribosomal stalk protein plays an essential role in the recruitment of translational GTPase factors EF1A and EF2 to the ribosome and their GTP hydrolysis for efficient translation elongation. However, due to the flexible nature of the ribosomal stalk, its structural dynamics and mechanism of action remain unclear. Here, we applied high-speed atomic force microscopy (HS-AFM) to directly visualize the action of the archaeal ribosomal stalk (P-stalk). HS-AFM movies clearly demonstrated the wobbling motion of the P-stalk on the large ribosomal subunit, where the stalk base adopted two conformational states, a predicted canonical state, and a newly identified flipped state. Intriguingly, archaeal aEF1A and aEF2 molecules spontaneously assembled around the ribosomal P-stalk up to the maximum number of available binding sites. These results provide the first visual evidence for the factor-pooling mechanism and reveal that the ribosomal P-stalk promotes translation elongation by increasing the local concentration of translational GTPase factors.
Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM
Authors: Xu Cong , Wang Yanxing , Liu Caixuan , Zhang Chao , Han Wenyu , Hong Xiaoyu , Wang Yifan , Hong Qin , Wang Shutian , Zhao Qiaoyu , Wang Yalei , Yang Yong , Chen Kaijian , Zheng Wei , Kong Liangliang , Wang Fangfang , Zuo Qinyu , Huang Zhong , Cong Yao
Published: July 2020

The recent outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid international spread pose a global health emergency. The trimeric spike (S) glycoprotein interacts with its receptor human ACE2 to mediate viral entry into host-cells. Here we present cryo-EM structures of an uncharacterized tightly closed SARS-CoV-2 S-trimer and the ACE2-bound-S-trimer at 2.7-Å and 3.8-Å-resolution, respectively. The tightly closed S-trimer with inactivated fusion peptide may represent the ground prefusion state. ACE2 binding to the up receptor-binding domain (RBD) within S-trimer triggers continuous swing-motions of ACE2-RBD, resulting in conformational dynamics of S1 subunits. Noteworthy, SARS-CoV-2 S-trimer appears much more sensitive to ACE2-receptor than SARS-CoV S-trimer in terms of receptor-triggered transformation from the closed prefusion state to the fusion-prone open state, potentially contributing to the superior infectivity of SARS-CoV-2. We defined the RBD T470-T478 loop and residue Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2, and provided structural basis of the spike D614G-mutation induced enhanced infectivity. Our findings offer a thorough picture on the mechanism of ACE2-induced conformational transitions of S-trimer from ground prefusion state towards postfusion state, thereby providing important information for development of vaccines and therapeutics aimed to block receptor binding.
Stochastic Analysis Demonstrates the Dual Role of Hfq in ChaperoningE. coliSugar Shock Response
Authors: Bianchi David M. , Brier Troy A. , Poddar Anustup , Azam Muhammad S. , Vanderpool Carin K. , Ha Taekjip , Luthey-Schulten Zaida
Published: July 2020

Small RNAs (sRNAs) play a crucial role in the regulation of bacterial gene expression by silencing the translation of target mRNAs. SgrS is an sRNA that relieves glucose-phosphate stress, or “sugar shock” inE. coli. The power of single cell measurements is their ability to obtain population level statistics that illustrate cell-to-cell variation. Here, we utilize single molecule super-resolution microscopy in singleE. colicells coupled with stochastic modeling to analyze glucose-phosphate stress regulation by SgrS. We present a kinetic model that captures the combined effects of transcriptional regulation, gene replication and chaperone mediated RNA silencing in the SgrS regulatory network. This more complete kinetic description, simulated stochastically, recapitulates experimentally observed cellular heterogeneity and characterizes the binding of SgrS to the chaperone protein Hfq as a slow process that not only stabilizes SgrS but also may be critical in restructuring the sRNA to facilitate association with its targetptsGmRNA.
Identification of novel HPFH-like mutations by CRISPR base editing that elevates the expression of fetal hemoglobin
Authors: Ravi Nithin Sam , Wienert Beeke , Wyman Stacia K. , Vu Jonathan , Pai Aswin Anand , Balasubramanian Poonkuzhali , Nakamura Yukio , Kurita Ryo , Marepally Srujan , Thangavel Saravanabhavan , Velayudhan Shaji R. , Srivastava Alok , DeWitt Mark A. , Corn Jacob E. , Mohankumar Kumarasamypet M.
Published: July 2020

Switching hemoglobin synthesis from defective adult beta-globin to fetal gamma-globin is an effective strategy for the treatment of beta-hemoglobinopathies. Fetal hemoglobin expression is down-regulated in the postnatal period due to the interplay of transcription regulators with theHBGpromoters. However, in the hereditary persistence of fetal hemoglobin (HPFH) condition, naturally occurring point mutations in theHBGpromoter causes continued expression of fetal globin even during adulthood. Inspired by this natural phenomenon, we screened the proximal promoter of humanHBGgenes using adenine and cytosine base editors to identify other nucleotide substitutions that could potentially lead to elevated levels of fetal globin. Both the base editors efficiently and precisely edited at the target sites with a minimal generation of indels and no deletion of one of the duplicatedHBGgenes. Through systematic tiling acrossthe HBGproximal promoter, we identified multiple novel target sites that resulted in a significant increase in fetal globin levels. Further, we individually validated the top eight potential target sites from both the base editors and observed robust elevation in the fetal globin levels up to 47 %, without any detrimental effects on erythroid differentiation. Our screening strategy resulted in the identification of multiple novel point mutations and also validated the known non-deletional HPFH mutations that could elevate the fetal globin expression at therapeutically relevant levels. Overall, our findings shed light on so far unknown regulatory elements within theHBGpromoter that normally mediates fetal globin silencing and identify additional targets for therapeutic upregulation of fetal hemoglobin.
Generation of stress fibers through myosin-driven re-organization of the actin cortex
Authors: Lehtimäki JI , Rajakylä EK , Tojkander S , Lappalainen P
Published: July 2020

Contractile actomyosin bundles, stress fibers, govern key cellular processes including migration, adhesion, and mechanosensing. Stress fibers are thus critical for developmental morphogenesis. The most prominent actomyosin bundles, ventral stress fibers, are generated through coalescence of pre-existing stress fiber precursors. However, whether stress fibers can assemble through other mechanisms has remained elusive. We report that stress fibers can also form without requirement of pre-existing actomyosin bundles. These structures, which we named cortical stress fibers, are embedded in the cell cortex and assemble preferentially underneath the nucleus. In this process, non-muscle myosin II pulses orchestrate the reorganization of cortical actin meshwork into regular bundles, which promote reinforcement of nascent focal adhesions, and subsequent stabilization of the cortical stress fibers. These results identify a new mechanism by which stress fibers can be generatedde novofrom the actin cortex, and establish role for stochastic myosin pulses in the assembly of functional actomyosin bundles.
Diversification of the restriction–modification system ofStreptococcus pyogenesthrough its acquisition of mobile elements
Authors: Ota Atsushi , Nishiuchi Yukiko , Nakanishi Noriko , Iijima Yoshio , Iwamoto Tomotada , Osaki Ken , Ogura Yoshitoshi , Toyoda Atsushi , Suzuki Yutaka , Hayashi Tetsuya , Ohge Hiroki , Mori Hirotada , Ato Manabu , Maruyama Fumito
Published: July 2020

Restriction–modification (RM) systems are typically regarded as “primitive immune systems” in bacteria. The roles of methylation in gene regulation, segregation, and mismatch repair are increasingly recognized. To analyze methyltransferase (MTase) diversity inStreptococcus pyogenes, we compared the RM system distribution in eight new complete genome sequences obtained here and in the database-deposited complete genome sequences of 51 strains. The MTase gene distribution showed that type I MTases often change DNA sequence specificity via switching target recognition domains between strains. The type II MTases in the included strains fell into two groups: a prophage-dominant one and a CRISPR-dominant one. Some highly variable type II MTases were found in the prophage region, suggesting that MTases acquired from phage DNA can generate methylome diversity. Additionally, to investigate the possible contribution of DNA methylation to phenotype, we compared the methylomes and transcriptomes from the four most closely related strains, the results of which suggest that phage-derived methylases possibly regulate the methylome, and, hence, regulate expression levels inS.pyogenes. Our findings will benefit further experimental work on the relationship between virulence genes and pathogenicity inS.pyogenes.
Decoding spontaneous pain from brain cellular calcium signals using deep learning
Authors: Yoon Heera , Bak Myeong Seong , Kim Seung Ha , Lee Ji Hwan , Chung Geehoon , Kim Sang Jeong , Kim Sun Kwang
Published: July 2020

We developed AI-bRNN (Average training, Individual test-bidirectional Recurrent Neural Network) to decipher spontaneous pain information from brain cellular calcium signals recorded by two-photon imaging in awake, head-fixed mice. The AI-bRNN determines the intensity and time point of spontaneous pain even during the chronic pain period and evaluates the efficacy of analgesics. Furthermore, it could be applied to different cell types and brain areas, and it distinguished between itch and pain, proving its versatility.