bluuebunny/crossref_metadata_2025 huggingface dataset:
Sphingolipids with 2-hydroxy fatty acids aid in plasma membrane nanodomain organization and oxidative burst
Authors: Ukawa Tomomi , Banno Fumihiko , Ishikawa Toshiki , Kasahara Kota , Nishina Yuuta , Inoue Rika , Tsujii Keigo , Yamaguchi Masatoshi , Takahashi Takuya , Fukao Yoichiro , Kawai-Yamada Maki , Nagano Minoru
Published: March 2022

Plant sphingolipids mostly possess 2-hydroxy fatty acids (HFA), the synthesis of which is catalyzed by FA 2-hydroxylases (FAHs). In Arabidopsis (Arabidopsis thaliana), two FAHs (FAH1 and FAH2) have been identified. However, the functions of FAHs and sphingolipids with HFAs (2-hydroxy sphingolipids) are still unknown because of the lack of Arabidopsis lines with the complete deletion of FAH1. In this study, we generated a FAH1 mutant (fah1c) using CRISPR/Cas9-based genome editing. Sphingolipid analysis of fah1c, fah2, and fah1cfah2 mutants revealed that FAH1 hydroxylates very long-chain FAs (VLCFAs), whereas the substrates of FAH2 are VLCFAs and palmitic acid. However, 2-hydroxy sphingolipids are not completely lost in the fah1cfah2 double mutant, suggesting the existence of other enzymes catalyzing the hydroxylation of sphingolipid FAs. Plasma membrane (PM) analysis and molecular dynamics simulations revealed that hydroxyl groups of sphingolipid acyl chains play a crucial role in the organization of nanodomains, which are nanoscale liquid-ordered domains mainly formed by sphingolipids and sterols in the PM, through hydrogen bonds. In the PM of the fah1cfah2 mutant, the expression levels of 26.7% of the proteins, including defense-related proteins such as the pattern recognition receptors (PRRs) brassinosteroid insensitive 1-associated receptor kinase 1 and chitin elicitor receptor kinase 1, NADPH oxidase respiratory burst oxidase homolog D (RBOHD), and heterotrimeric G proteins, were lower than that in the wild-type. In addition, reactive oxygen species (ROS) burst was suppressed in the fah1cfah2 mutant after treatment with the pathogen-associated molecular patterns flg22 and chitin. These results indicated that 2-hydroxy sphingolipids are necessary for the organization of PM nanodomains and ROS burst through RBOHD and PRRs during pattern-triggered immunity.
Self-Leadership Is Critical for All Physical Therapists
Authors: Green-Wilson Jennifer , Tschoepe Barbara A , Zeigler Stacey L , Sebelski Chris A , Clark Diane
Published: March 2022

Evidence that supports the explicit need to develop leadership skills at all levels of clinical practice is prevalent,1–8 yet intentional development of “self-leadership” within health care, and particularly within physical therapy, remains slow, fragmented, and inconsistent. Delineation and standardization of the definition of leadership, and the approach to developing leadership skills in individuals practicing within health care continues to be debated, producing several key dilemmas. Moreover, there is a lingering misperception that developing leadership capacity is reserved for physical therapists who assume positional or formal roles as “leaders” within communities, health care organizations, practices, or teams. This misperception focuses leadership development on “leading others” rather than “leading self.” Similarly, challenges exist between balancing the leadership development needs of the leader as a positional role and the act of “leading” as physical therapists practice and engage within all levels of care and within different communities—as individuals and within teams. This tension further complicates when and how best to prepare physical therapists to meet this essential skill set in clinical practice. The purpose of this perspective is to describe nonpositional self-leadership and its importance to physical therapy practice, to propose common or contemporary leadership-related terminology, and to suggest a framework for leadership development. Through accomplishing these purposes, readers may be encouraged to change and adopt recommendations.
Variation in Racial and Ethnic Representation of Heart Transplant Recipients, Waitlists, and Local Census Demographics Across Transplant Centers in the US
Authors: Thomas Edward
Published: March 2022

As the uses and needs for heart transplants around the world continue to rise, it’s vital to investigate how the recent boom in demand comparative to availability affects racial and ethnic groups, especially in the representation in heart transplant waitlists and recipients. Here, comparisons between the racial/ethnic representation in heart transplant waitlists and recipients at heart transplant centers through the Scientific Registry for Transplant Recipients (SRTR) are drawn, comparative to the racial/ethnic representation in the location that these centers are located. Findings point towards the overrepresentation of White individuals in both waitlists and recipients, and underrepresentation in all other ethnic minorities --except African Americans-- in waitlists and recipients comparative to their demographic representation in the location of the centers. This difference in representation is largest for Hispanics/Latinos and those that the SRTR classify as “Other”. Though just a snapshot of representation between 07/01/2019 and 06/30/2020, this may point to various systemic issues in the accessibility of care of minorities, especially during the COVID-19 pandemic, that need to be addressed as the general populous ages and heart transplants are increasingly relied upon as a treatment for cardiovascular conditions and failure.
An observational study of uptake and adoption of the NHS App in England
Authors: Tewolde Salina , Costelloe Céire , PowelI John , Papoutsi Chrysanthi , Reidy Claire , Gudgin Bernard , Shenton Craig , Greaves Felix
Published: March 2022

Objectives

This study aimed to evaluate patterns of uptake and adoption of the NHS App. Data metrics from the NHS App were used to assess acceptability by looking at total app downloads, registrations, appointment bookings, GP health records viewed, and prescriptions ordered. The impact of the UK COVID-19 lockdown and introduction of the COVID Pass were also explored to assess App usage and uptake.

Methods

Descriptive statistics and an interrupted time series analysis were used to look at monthly NHS App metrics at a GP practice level from January 2019-May 2021 in the population of England. Interrupted time series models were used to identify changes in level and trend among App usage and the different functionalities before and after the first COVID-19 lockdown. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were used for reporting and analysis.

Results

Between January 2019 and May 2021, there were a total of 8,524,882 NHS App downloads and 4,449,869 registrations. There was a 4-fold increase in app downloads from April 2021 (650,558 downloads) to May 2021 (2,668,535 downloads) when the COVID Pass feature was introduced. Areas with the highest number of App registrations proportional to the GP patient population occurred in Hampshire, Southampton and Isle of Wight CCG, and the lowest in Blackburn with Darwen CCG. After the announcement of the first lockdown (March 2020), a positive and significant trend in the number of login sessions was observed at 602,124 (p=0.004)** logins a month. National NHS App appointment bookings ranged from 298 to 42,664 bookings per month during the study period. The number of GP health records viewed increased by an average of 371,656 (p=0.001)** views per month and the number of prescriptions ordered increased by an average of 19934 (p<0.001)*** prescriptions per month following the first lockdown.

Conclusion

This analysis has shown that uptake and adoption of the NHS App was positive post lockdown, and increased significantly due to the COVID Pass feature being introduced, but further research is needed to measure the extent to which it improves patient experience and influences health service access and care outcomes.
Meta-analysis fine-mapping is often miscalibrated at single-variant resolution
Authors: Kanai Masahiro , Elzur Roy , Zhou Wei ,   Global Biobank Meta-analysis Initiative, Daly Mark J , Finucane Hilary K
Published: March 2022

Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWAS) into a more powerful whole. To resolve causal variants, meta-analysis studies typically apply summary statistics-based fine-mapping methods as they are applied to single-cohort studies. However, it is unclear whether heterogeneous characteristics of each cohort (e.g., ancestry, sample size, phenotyping, genotyping, or imputation) affect fine-mapping calibration and recall. Here, we first demonstrate that meta-analysis fine-mapping is substantially miscalibrated in simulations when different genotyping arrays or imputation panels are included. To mitigate these issues, we propose a summary statistics-based QC method, SLALOM, that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics based on ancestry-matched local LD structure. Having validated SLALOM performance in simulations and the GWAS Catalog, we applied it to 14 disease endpoints from the Global Biobank Meta-analysis Initiative and found that 67% of loci showed suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci were significantly depleted for having likely causal variants, such as nonsynonymous variants, as a lead variant (2.7x; Fisher’s exact P = 7.3 × 10−4). Compared to fine-mapping results in individual biobanks, we found limited evidence of fine-mapping improvement in the GBMI meta-analyses. Although a full solution requires complete synchronization across cohorts, our approach identifies likely spurious results in meta-analysis fine-mapping. We urge extreme caution when interpreting fine-mapping results from meta-analysis.
Identification of novel genetic variants in the malaria vaccine candidate PfRh5: structure-guided insights into potential function
Authors: Mangou Khadidiatou , Moore Adam J. , Thiam Laty Gaye , Ba Aboubacar , Orfanó Alessandra , Desamours Ife , Ndegwa Duncan Ndungu , Goodwin Justin , Guo Yicheng , Sheng Zizhang , Patel Saurabh D. , Diallo Fatoumata , Sene Seynabou D. , Pouye Mariama N. , Faye Awa Thioub , Nunez Vanessa , Diagne Cheikh Tidiane , Sadio Bacary Djilocalisse , Shapiro Lawrence , Faye Ousmane , Mbengue Alassane , Bei Amy K.
Published: March 2022

The recent stall in the global reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been under-prioritized in the evaluation of malaria vaccine candidates. This study uses genomic approaches to evaluate genetic diversity in next generation malaria vaccine candidate PfRh5. We used targeted deep amplicon sequencing to identify non-synonymous Single Nucleotide Polymorphisms (SNPs) in PfRH5 (Reticulocyte-Binding Protein Homologue 5) in 189 P. falciparum positive samples from Southern Senegal and identified 74 novel SNPs. We evaluated the population prevalence of these SNPs as well as the frequency in individual samples and found that only a single SNP, C203Y, was present at every site. Many SNPs were unique to the individual sampled, with over 90% of SNPs being found in just one infected individual. In addition to population prevalence, we assessed individual level SNP frequencies which revealed that some SNPs were dominant (frequency of greater than 25% in a polygenomic sample) whereas most were rare, present at 2% or less of total reads mapped to the reference at the given position. Structural modeling uncovered 3 novel SNPs occurring under epitopes bound by inhibitory monoclonal antibodies, potentially impacting immune evasion, while other SNPs were predicted to impact PfRh5 structure or interactions with the receptor or binding partners. Our data demonstrate that PfRh5 exhibits greater genetic diversity than previously described, with the caveat that most of the uncovered SNPs are at a low overall frequency in the individual and prevalence in the population. The structural studies reveal that novel SNPs could have functional implications on PfRh5 receptor binding, complex formation, or immune evasion, supporting continued efforts to validate PfRh5 as an effective malaria vaccine target and development of a PfRh5 vaccine.
A SARS-CoV-2 negative antigen rapid diagnostic in RT-qPCR positive samples correlates with a low likelihood of infectious viruses in the nasopharynx
Authors: Corrêa Isadora Alonso , Faffe Débora Souza , Galliez Rafael Mello , Gonçalves Cássia Cristina Alves , Araújo Maia Richard , da Silva Gustavo Peixoto , Rebello Moreira Filipe Romero , Mariani Diana , Campos Mariana Freire , de Carvalho Leitão Isabela , de Souza Marcos Romário , Cunha Marcela Sabino , dos Santos Nascimento Érica Ramos , de Jesus Ribeiro Liane , da Cruz Thais Felix Cordeiro , Policarpo Cintia , Gonzales Luis , Rodgers Mary A , Berg Michael , Vijesurier Roy , Cloherty Gavin A , Hackett John , da Costa Ferreira Orlando , Castiñeiras Terezinha Marta Pereira Pinto , Tanuri Amilcar , da Costa Luciana Jesus
Published: March 2022

SARS-CoV-2 transmission occurs even among fully vaccinated individuals; thus, prompt identification of infected patients is central to control viral circulation. Antigen rapid diagnostic tests (Ag-RDT) are highly specific, but sensitivity is variable.Discordant RT-qPCR vs Ag-RDT results are reported, raising the question of whether negative Ag-RDT in positive RT-qPCR samples could imply the absence of infectious viruses. To study the relationship between a negative Ag-RDT results with virological, molecular, and serological parameters, we selected a cross sectional and a follow-up dataset and analyzed virus culture, subgenomic RNA quantification, and sequencing to determine infectious viruses and mutations. We demonstrated that a positive SARS-CoV-2 Ag-RDT result correlates with the presence of infectious virus in nasopharyngeal samples. A decrease in sgRNA detection together with an expected increase in detectable anti-S and anti-N IgGs was verified in negative Ag-RDT / positive RT-qPCR samples. The data clearly demonstrates the less likelihood of a negative Ag-RDT sample to harbor infectious SARS-CoV-2 and consequently with a lower transmissible potential.
A Meta-Analytic Investigation of Grey Matter Differences in Anorexia Nervosa and Autism Spectrum Disorder
Authors: Sader Michelle , Williams Justin H. G. , Waiter Gordon D.
Published: March 2022

Recent research reports Anorexia Nervosa (AN) to be highly dependent upon neurobiological function. Some behaviours, particularly concerning food selectivity are found in populations with both Autism Spectrum Disorder (ASD) and AN, and there is a proportionally elevated number of anorexic patients exhibiting symptoms of ASD. We performed a systematic review of structural MRI literature with the aim of identifying common structural neural correlates common to both AN and ASD. Across 46 ASD publications, a meta-analysis of volumetric differences between ASD and healthy controls revealed no consistently affected brain regions. Meta-analysis of 23 AN publications revealed increased volume within the orbitofrontal cortex and medial temporal lobe, and adult-only AN literature revealed differences within the genu of the anterior cingulate cortex. The changes are consistent with alterations in flexible reward-related learning and episodic memory reported in neuropsychological studies. There was no structural overlap between ASD and AN. Findings suggest no consistent neuroanatomical abnormality associated with ASD, and evidence is lacking to suggest that reported behavioural similarities between those with AN and ASD are due to neuroanatomical structural similarities.
TUNNEL WIDENING OF ACL RECONSTRUCTION AUGMENTED BY AN PLATELET RICH OSTEOCONDUCTIVE-OSTEOINDUCTIVE ALLOGRAFT COMPOUND: A RANDOMIZED BLIND-ANALYSIS PILOT STUDY
Authors: Solomon Ruth , Hommen Jan Pieter , Travascio Francesco
Published: March 2022

Background

The anterior cruciate ligament (ACL) is a commonly injured ligament in the knee. Bone tunnel widening is a known phenomenon after soft-tissue ACL reconstruction and etiology and clinical relevance have not been fully elucidated. Osteoconductive compounds are biomaterials providing an appropriate scaffold for bone formation such as demineralized bone matrix. Osteoinductive materials contain growth factors stimulating bone lineage cells and bone growth. A possible application of osteoinductive/osteoconductive (OIC) material is in ACL surgery.

Questions/Purposes

We hypothesized that OIC placed in ACL bone tunnels: 1) reduces tunnel widening, 2) improves graft maturation and 3) reduces tunnel ganglion cyst formation. To test this hypothesis, this study evaluated the osteogenic effects of demineralized bone matrix (DBM) and platelet rich plasma (PRP) on tunnel widening, graft maturation, and ganglion cyst formation.

Study Design

Randomized controlled clinical trial pilot study.

Methods

A total of 26 patients electing ACL reconstruction surgery were randomized between OIC and control group. Measurements of tunnel expansion and graft-tunnel incorporation were conducted via quantitative image analysis of MRI scans performed at six months after surgery for both groups.

Results

No patients had adverse post-operative reactions or infections. The use of OIC significantly reduced tunnel widening (p < 0.05) and improved graft maturation (p < 0.05). Patients treated with OIC presented with a significantly lower prevalence of ganglion cyst compared to the control group (p < 0.05).

Conclusion

The use of OIC has measurable effects on the reduction of tunnel widening, improved graft maturation and decreased size of ganglion cyst after ACL reconstruction.

Clinical Relevance

This study explored the utilization of biologics to minimize bone tunnel widening in ACL reconstruction surgery.
SARS-CoV-2 infections in infants in Haiti 2020-2021; evidence from a serological cohort
Authors: Louis Rigan , Pu Ruiyu , Logan Tracey D , Trimmer-Smith Luke , Chamblain Richard , Gallagher Adriana , De Rochars Valery Madsen Beau , Nelson Eric , Cummings Derek AT , Long Maureen T , Morris J. Glenn
Published: March 2022

Between February 2019 and March 2021, 388 dried blood spot samples were obtained from 257 children <30 months of age who were part of a longitudinal maternal/infant cohort in Haiti. Among the children followed, 16.7% became seropositive; sampling date was the only covariate associated with the hazard of seroconversion.
Regional medical inter-institutional cooperation in medical provider network constructed using patient claims data from Japan
Authors: Ohki Yu , Ikeda Yuichi , Kunisawa Susumu , Imanaka Yuichi
Published: March 2022

The aging world population requires a sustainable and high-quality healthcare system. To examine the efficiency of medical cooperation, medical provider and physician networks were constructed using patient claims data. Previous studies have shown that these networks contain information on medical cooperation. However, the usage patterns of multiple medical providers in a series of medical services have not been considered. In addition, these studies used only general network features to represent medical cooperation, but their expressive ability was low. To overcome these limitations, we analyzed the medical provider network to examine its overall contribution to the quality of healthcare provided by cooperation between medical providers in a series of medical services. This study focused on: i) the method of feature extraction from the network, ii) incorporation of the usage pattern of medical providers, and iii) expressive ability of the statistical model. Femoral neck fractures were selected as the target disease. To build the medical provider networks, we analyzed the patient claims data from a single prefecture in Japan between January 1, 2014 and December 31, 2019. We considered four types of models: a model using node strength and linear regression to a model using feature representation by node2vec and regression tree ensemble, which is a machine learning method. The results showed that a stronger medical provider reduces the duration of hospital stay. The overall contribution of the medical cooperation to the duration of hospital stay extracted from the medical provider network using node2vec is approximately 20%, which is approximately 20 times higher than the model using strength.
Maternal Antibody Response and Transplacental Transfer Following SARS-CoV-2 Infection or Vaccination in Pregnancy
Authors: Otero Sebastian , Miller Emily S. , Sunderraj Ashwin , Shanes Elisheva D. , Sakowicz Allison , Goldstein Jeffery A. , Mithal Leena B.
Published: March 2022

Background

Pregnant persons are at increased risk of severe COVID-19 and adverse obstetric outcomes. Understanding maternal antibody response and transplacental transfer after SARS-CoV-2 infection and COVID-19 vaccination is important to inform public health recommendations.

Methods

This prospective observational cohort study included 351 birthing individuals who had SARS-CoV-2 infection or COVID-19 vaccination during pregnancy. IgG and IgM to SARS-CoV-2 S1 receptor binding domain were measured in maternal and cord blood. Antibody levels and transplacental transfer ratios were compared across 1) disease severity for those with SARS-CoV-2 infection and 2) infection versus vaccination.

Findings

There were 252 individuals with SARS-CoV-2 infection and 99 who received COVID-19 vaccination during pregnancy. Birthing people with more severe SARS-CoV-2 infection category had higher maternal and cord blood IgG levels (p=0.0001, p=0.0001). Median IgG transfer ratio was 0.87-1.2. Maternal and cord blood IgG were higher after vaccination than infection (p=0.001, p=0.001). Transfer ratio was higher after 90 days in the vaccinated group (p<0.001). Modeling showed higher amplitude and half-life of maternal IgG following vaccination (p<0.0001). There were no significant differences by fetal sex.

Interpretation

COVID-19 vaccination in pregnancy leads to higher and longer lasting maternal IgG levels, higher cord blood IgG, and higher transfer ratio after 90 days compared to SARS-CoV-2 infection. Greater infection severity leads to higher maternal and cord blood antibodies. Maternal IgG decreases over time following both vaccination and infection, reinforcing the importance of vaccination, even after infection, and vaccine boosters for pregnant patients.
A multi-scale fusion CNN model based on adaptive transfer learning for multi-class MI-classification in BCI system
Authors: Roy Arunabha M.
Published: March 2022

Deep learning-based brain-computer interface (BCI) in motor imagery (MI) has emerged as a powerful method for establishing direct communication between the brain and external electronic devices. However, due to inter-subject variability, inherent complex properties, and low signal-to-noise ratio (SNR) in electroencephalogram (EEG) signal are major challenges that significantly hinders the accuracy of the MI classifier. To overcome this, the present work proposes an efficient transfer learning-based multi-scale feature fused CNN (MSFFCNN) which can capture the distinguishable features of various non-overlapping canonical frequency bands of EEG signals from different convolutional scales for multi-class MI classification. In order to account for inter-subject variability from different subjects, the current work presents 4 different model variants including subject-independent and subject-adaptive classification models considering different adaptation configurations to exploit the full learning capacity of the classifier. Each adaptation configuration has been fine-tuned in an extensively trained pre-trained model and the performance of the classifier has been studied for vast range of learning rates and degrees of adaptation which illustrates the advantages of using an adaptive transfer learning-based model. The model achieves an average classification accuracy of 94.06% (±2.29%) and kappa value of 0.88 outperforming several baseline and current state-of-the-art EEG-based MI classification models with fewer training samples. The present research provides an effective and efficient transfer learning-based end-to-end MI classification framework for designing a high-performance robust MI-BCI system.
Toxicological Analysis of Poly-Lactide Co-Glycolide Microparticles, Chitosan Nanoparticles and Poly(Anhydride) Nanoparticles in Vero Cell
Authors: Hazarika Dipankar , Borah Durlabh Prasad , Boruah Jayanta Sarma , Begum Yasmin , Sultana Anisha , Tamuly Shantanu , Nath Rita , Chowdhury Devasish , Dutta Biswajit , Borah Probodh , Kalita Dhruba Jyoti
Published: March 2022

The present study was carried out to evaluate in-vitro toxicity associated with chitosan nanoparticles, poly(anhydride) nanoparticles and poly-lactide co-glycolide (PLG) microparticle in Vero cell line. The cytotoxicity of all three micro/nano-particles was assessed using different concentration. For each concentration, the confluent monolayer was treated for a period of 36-48 hours and studied for morphological alteration, live and death count etc. after the treatment. It was observed that the different concentrations of chitosan nanoparticles and Gantrez® nanoparticles did not have significant effect on the cell viability as evident from the non-significant difference between the OD540 of formazan product formed from MTT in treated and untreated cells. The concentration of chitosan nanoparticles and Gantrez® nanoparticles up to 1000 μg/ml did not have any influence in cellular metabolic activities and viability. However, a reduction in the cellular viability and metabolic activities were observed when PLG microparticles were used at 1000 μg/ml. At concentrations below 1000 μg/ml, all the nanoparticles/microparticles were found to be safe in terms of cytotoxicity.
Generalized Method of Moments improves parameter estimation in biochemical signaling models of time-stamped single-cell snapshot data
Authors: John Wu , Stewart William CL , Ciriyam Jayaprakash , Jayajit Das
Published: March 2022

Motivation

Ordinary differential equations are commonly used to model the sub-cellular dynamics of average values of proteins and mRNAs. New single-cell technologies provide cell-to-cell differences in protein/mRNA abundances that allow for the evaluation of higher order moments. However, using this additional information to improve parameter estimation can be challenging since the magnitudes of single-cell abundances can vary widely between proteins/mRNA.

Results

We employ Generalized Method of Moments (GMM) and Particle Swarm Optimization to address the above challenges in mechanistic modeling of signaling kinetics data. Using synthetic data from linear and non-linear models, we show that the proposed method improves parameter estimation and enables construction of approximate confidence intervals. Furthermore, our approach exploits parallel computation to scale with increasing data size and dimensions. We apply our software CyGMM to estimate parameters in a linear ODE model for publicly available longitudinal single-cell cytometry data for CD8+ T cells. Our results demonstrate substantial improvements for modeling data from single-cell cytometry and RNA-seq experiments.

Availability

We also make freely available our estimation software CyGMM written in C++ on github (https://github.com/jhnwu3/CyGMM).

Contact

jayajit@gmail.com

Supplementary information

Supplementary data are available at Bioinformatics online.
A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family via up-regulation of the PI3K-Akt signaling pathway
Authors: Xu Liangpu , Wang Xinrui , Li Jia , Chen Lingji , Wang Haiwei , Xu Shiyi , Zhang Yanhong , Li Wei , Yao Pengcheng , Tan Meihua , Zhou Si , Chen Meihuan , Pan Yali , Chen Xuemei , Chen Xiaolan , Liu Yunliang , Lin Na , Huang Hailong , Cao Hua
Published: March 2022

Background

The fimbrin protein family contains a variety of proteins, of which Plastin1 (PLS1) is an important member. The latest researches show that variations in the coding region of PLS1 gene is related to the development of deafness.

However, it remains unknown about the molecular mechanism of deafness caused by PLS1 gene variants.

Methods

whole exome sequencing was performed on the affected family members and healthy ones to identify the pathogenic variants, followed by sanger sequencing. Minigene assay was conducted to investigate the impact of the variant on PLS1 mRNA splicing. The pathogenicity of the variant was further investigated in zebrafish. RNA-sequencing (RNA-seq) was done for analyzing the dysregulated downstream signaling pathways caused by knockdown of PLS1 expression.

Results

We identified a novel variant PLS1 c.981+1G>A in a large Chinese family with hearing loss and demonstrated that the variant is responsible for the occurrence of hearing loss by inducing Exon8 skipping or deletion of Exon8 (47bp). The variant caused abnormal inner ear phenotypes, characterized by decreased mean otolith distance, anterior otolith diameter, posterior otolith diameter, and cochlear diameter, swimming speed and distance in zebrafish. Furthermore, silencing PLS1 expression significantly upregulated genes in the PI3K-Akt signaling pathway, including Col6a3, Spp1, Itgb3 and Hgf.

Conclusions

PLS1 c.981+1G>A is a novel pathogenic variant for hearing loss by inducing Exon8 skipping or deletion of Exon8 (47bp). Up-regulation of the PI3K-Akt signaling pathway plays an important role in the pathogenesis of PLS-1 gene.
Fragment-Based Ligand Generation Guided By Geometric Deep Learning On Protein-Ligand Structure
Authors: Powers Alexander S. , Yu Helen H. , Suriana Patricia , Dror Ron O.
Published: March 2022

Abstract

Computationally-aided design of novel molecules has the potential to accelerate drug discovery. Several recent generative models aimed to create new molecules for specific protein targets. However, a rate limiting step in drug development is molecule optimization, which can take several years due to the challenge of optimizing multiple molecular properties at once. We developed a method to solve a specific molecular optimization problem in silico: expanding a small, fragment-like starting molecule bound to a protein pocket into a larger molecule that matches that physiochemical properties of known drugs. Using data-efficient E(3) equivariant based neural networks and a 3D atomic point cloud representation, our model learns how to attach new molecular fragments to a growing structure by recognizing realistic intermediates generated en route to a final ligand. This approach always generates chemically valid molecules and incorporates all relevant 3D spatial information from the protein pocket. This framework produces promising molecules as assessed by multiple properties that address binding affinity, ease of synthesis, and solubility. Overall, we demonstrate the feasibility of 3D molecular structure expansion conditioned on protein pockets while maintaining desirable drug-like physiochemical properties and developed a tool that could accelerate the work of medicinal chemists.
Single-nucleotide substitution determines pollen production in Japanese cedar
Authors: Kakui Hiroyuki , Ujino-Ihara Tokuko , Hasegawa Yoichi , Tsurisaki Eriko , Futamura Norihiro , Iwai Junji , Higuchi Yuumi , Fujino Takeshi , Suzuki Yutaka , Kasahara Masahiro , Yamaguchi Katsushi , Shigenobu Shuji , Otani Masahiro , Nakano Masaru , Ueno Saneyoshi , Moriguchi Yoshinari
Published: March 2022

Pollinosis, also known as pollen allergy or hay fever, is a global problem caused by pollen produced by various plant species1–6. The wind-pollinated Japanese cedar (Cryptomeria japonica) is the largest contributor to severe pollinosis in Japan, where increasing proportions of people have been affected in recent decades7. TheMS4(MALE STERILITY 4) locus of Japanese cedar controls pollen production, and its homozygous mutants (ms4/ms4) show abnormal pollen development after the tetrad stage and produce no mature pollen. In this study, we narrowed down theMS4locus by fine mapping in Japanese cedar and foundTKPR1(TETRAKETIDE α-PYRONE REDUCTASE) gene in this region. Transformation experiments usingArabidopsis thalianashowed that single-nucleotide substitution ofCjTKPR1determines pollen production. Broad conservation of TKPR1 beyond plant division could lead to the creation of pollen-free plant not only for Japanese cedar but also for broader plant species.
Harnessing the power of technical and natural variation in 116 yeast datasets to benchmark long read assembly pipelines
Authors: Gettle Noah , Gallone Brigida , Verstrepen Kevin J. , Stelkens Rike
Published: March 2022

With increases in throughput and reductions in cost, long read sequencing has become the standard for most genome assembly projects and has opened up new avenues for large-scale genomic research. While more amenable to assembly than short-read sequence data, long-read datasets tend to have higher error rates. To address this problem numerous tools have been developed to correct reads before assembly and polish assembled contigs. Although, numerous studies have been conducted to assess or benchmark these tools, few capture the real variance in long read sequence data that might affect tool performance much less full pipeline performance. To address these shortcomings, we compiled a dataset containing long-read sequences of 116 different strains of brewers’ yeast, S. cerevisiae, gathered largely from public databases and evaluated different assembly-related tools as well as their interactions. We found that pre-assembly short-read error correction of long reads combined with post-assembly short-read polishing provided the best assemblies. We also found that correction/polishing steps with uncorrected long reads often lead to degradation of assembly quality. Finally, we show which tools and pipelines work best with different types of input data.
Diminished distractor filtering with increased perceptual load and sustained effort explains attention deficit in post-stroke fatigue
Authors: Kuppuswamy Annapoorna , Harris Anthony , De Doncker William , Alexander Adrian , Lavie Nilli
Published: March 2022

Objectives

Post-stroke fatigue (PSF) is a prevalent symptom associated with attention deficits. However, it is currently unclear what drives these. Here we applied Load Theory of Attention to investigate the role of perceptual load in the relationship between attention, distraction, and fatigue levels in PSF.

Methods

Thirty-two chronic stroke survivors performed a selective attention task under different perceptual load levels. Neural responses to targets and distractors were measured with frequency-tagged EEG responses.

Results

We showed that Fatigue Severity Scale-7 (FSS-7) scores are predictive of slower responses, irrespective of the task level of perceptual load. Although average distractor frequency (10Hz) power was reduced with higher perceptual load, the reduction in 10Hz power with increasing task load, was smaller in those with higher FSS-7 scores. Higher FSS-7 scores were also associated with increased 10Hz distractor response as time progressed, both within task-trials and across the experiment duration.

Conclusion

The results are consistent with previous reports of slower processing speed and sustained selective attention deficits. Importantly they demonstrate that higher fatigue severity is associated with a reduced ability to suppress neural response to irrelevant distractors stimuli when the task demands more attention due to its increased perceptual load. An account for attention deficit in PSF based on a distractor filtering deficit that emerges with increased perceptual load and sustained effort can explain a myriad of PSF symptoms (e.g. sensory perceptual overload, and difficulties to concentrate).

Key messages

What is already known on this topic

➢

Post-stroke fatigue involves mental fatigue which is exacerbated in cognitively demanding task, as well as difficulties in concentrating and sustaining attention on a task.

➢

However previous research has not converged on a clear account of the nature of attention deficits in post-stroke fatigue, as well as on how these relate to the level of perceptual demand in a cognitive task

What this study adds

➢

The study suggests that attention deficits in post-stroke fatigue are attributed to a failure to attenuate neural responses to distractors with increased perceptual load in the task, as well as with increased demands on sustained attention with a longer task engagement

➢

This pattern points to a distractor filtering deficit that is magnified by perceptual load and sustained mental effort as main drivers of attention deficits in post-stroke fatigue

How this study might affect research, practice or policy

➢

This study enhances our understanding of attentional deficit in post-stroke fatigue, within an integrative account that explains mental fatigue symptomology
Plasmid characterization in bacterial isolates of public health relevance in a tertiary healthcare facility in Kilimanjaro, Tanzania
Authors: Sengeruan Lameck Pashet , van Zwetselaar Marco , Kumburu Happiness , Aarestrup Frank M. , Kreppel Katharina , Sauli Elingarami , Sonda Tolbert
Published: March 2022

Plasmids are infectious double stranded DNA molecules that are found within bacteria. Horizontal gene transfer promotes successful spread of different types of plasmids within or among bacteria species, making their detection an important task for guiding clinical treatment. We used whole genome sequenced data to determine the prevalence of plasmid replicons in clinical bacterial isolates, the presence of resistance and virulence genes in plasmids, and the relationship between resistance and virulence genes within each plasmid. All bacterial sequences were de novo assembled using Unicycler before extraction of plasmids. Assembly graphs were submitted to Gplas+plasflow for plasmid prediction. The predicted plasmid components were validated using PlasmidFinder.

A total of 159 (56.2%) out of 283 bacterial isolates were found to carry plasmids, with E. coli, K. pneumoniae and S. aureus being the most prevalent plasmid carriers. A total of 27 (87.1%) combined plasmids were found to carry both resistance and virulence genes compared to 4 (12.9%) single plasmids. No statistically significant correlation was found between the number of antimicrobial resistance and virulence genes in plasmids (r =-0.25, p > 0.05). Our findings show a relatively high proportion of plasmid-carrying isolates suggesting selection pressure due to antibiotic use in the hospital. Co-occurrence of antibiotic resistance and virulence genes in clinical isolates is a public health relevant problem needing attention.
The MAPK/ERK channel capacity exceeds 6 bit/hour
Authors: Nałęcz-Jawecki Paweł , Gagliardi Paolo Armando , Kochańczyk Marek , Dessauges Coralie , Pertz Olivier , Lipniacki Tomasz
Published: March 2022

Living cells utilize signaling pathways to sense, transduce, and process information. As the extracellular stimulation often has rich temporal characteristics which may govern dynamic cellular responses, it is important to quantify the rate of information flow through the signaling pathways. In this study, we used an epithelial cell line expressing a light-activatable FGF receptor and an ERK activity reporter to assess the ability of the MAPK/ERK pathway to transduce signal encoded in a sequence of pulses. By stimulating the cells with random light pulse trains, we demonstrated that the MAPK/ERK channel capacity is at least 6 bits per hour. The input reconstruction algorithm detects the light pulses with 1-min accuracy 5 min after their occurrence. The high information transmission rate may enable the pathway to coordinate multiple processes including cell movement and respond to rapidly varying stimuli such as chemoattracting gradients created by other cells.

Author summary

To respond to external stimulation, living cells need to transfer information from membrane receptors to downstream proteins that regulate physiological outcomes. In this study we used cells expressing a light-activatable receptor that transmits signals to MAPK/ERK transduction pathway, which regulates numerous physiological processes including proliferation, differentiation and cell motility. By stimulating these cells with various sequences of short light pulses we found that ERK, the last component of the considered signal transduction pathway, may receive at least 6 bits per hour. This bitrate allows 6 binary decisions per hour, enabling rapid responses to varied extracellular stimuli.
Distribution and frequency of salivary gland tumours: an international multicenter study
Authors: Alsanie Ibrahim , Rajab Shahad , Cottom Hannah , Adegun Oluyori , Agarwal Reshma , Jay Amrita , Graham Laura , James Jacqueline , Barrett A William , van Heerden Willie , de Vito Mariano , Canesso Alessandra , Adisa Akinyele Olumuyiwa , Akinshipo Abdul-Warith Olaitan , Ajayi Oluseyi Folake , Nwoga Mark Chukwuemeka , Okwuosa Chukwubuzor Udokwu , Omitola Olufemi Gbenga , Orikpete Efetobo Victor , Soluk-Tekkesin Merva , Bello Ibrahim , Qannam Ahmed , Gonzalez Wilfredo , de Oliveira Maria Eduard Perez , Santos-Silva Alan Roger , Vargas Pablo Agustin , Toh Eu-Wing , Khurram Syed Ali
Published: March 2022

Background

Salivary gland tumours (SGT) are a relatively rare group of neoplasms with a wide range of histopathological appearance and clinical features. To date, most of the epidemiological studies on salivary gland tumours are limited for a variety of reason including being out of date, extrapolated from either a single centre or country studies, or investigating either major or minor glands only.

Methods

This study aimed to mitigate these shortcomings by analysing epidemiological data including demographic, anatomical location and histological diagnoses of SGT from multiple centres across the world. The analysed data included age, gender, location and histological diagnosis from fifteen centres covering the majority of the world health organisation (WHO) geographical regions between 2006 and 2019.

Results

A total of 5798 cases were analysed including 65% benign and 35% malignant tumours. A slight female predilection (54%) and peak incidence between the fourth and seventh decade for both benign and malignant tumours was observed. The majority (69%) of the SGT presented in major and 31% in the minor glands. The parotid gland was the most common location (70%) for benign and minor glands (46%) for malignant tumours. Pleomorphic adenoma (70%), and Warthin’s tumour (17%), were the most common benign tumours whereas mucoepidermoid carcinoma (25%) and adenoid cystic carcinoma (16%) were the most frequent malignant tumours.

Conclusions

This multicentre investigation presents the largest cohort study to date analysing salivary gland tumour data from tertiary centres scattered across the globe. These findings should serve as a baseline for future studies evaluating the epidemiological landscape of these tumours.
Standardization of cytological behavior of pollens in sorghum by Image analysis
Authors: Narkhede Gopal W. , Mehtre Shivaji P , Deshpande Santosh P
Published: March 2022

The development of iso-nuclear male sterile (A) and maintainer (B) line along with male fertile (R) lines, referred to as fertility restorers, helped in cost-effective seed production and deployment of hybrids. The pollen viability/fertility for maintenance (B-line) and restoration (R-line) remains a significant phenotyping hurdle in developing new lines. We carried out the present investigation to evaluate the pollen fertility status of Cytoplasmic Genetic Male Sterility (CGMS) based hybrids in sorghum. The experimental material consisted of 238 CGMS based hybrids developed from the crossing of individuals of (296B ×IS 188551) - based Recombinant Inbred Line (RIL) population (F7:F8) with male-sterile line (296A). The experiment was conducted in the rainy and post-rainy seasons during 2016 to evaluate pollen fertility. The authors illustrated the pollen fertility status by counting pollen counts using two methods: viz., visual counting by the naked eye, and image analysis using ImageJ (NIH, USA) software. We compared results between counts recorded visually and ImageJ reads for randomly selected 50 individuals each during the rainy and post-rainy seasons. The pollen counts from ImageJ were 95% efficient in detecting sterile vs. fertile counts. These results provide a better, efficient, and quick tool for characterizing the pollen behavior and also add value to the genetics studies by accounting for the quantitative variation encoded by multiple loci.
Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy
Authors: Yoshioka Nozomu , Kurose Masayuki , Yano Masato , Tran Dang Minh , Okuda Shujiro , Mori-Ochiai Yukiko , Horie Masao , Nagai Toshihiro , Nishino Ichizo , Shibata Shinsuke , Takebayashi Hirohide
Published: March 2022

Dystonin (DST), which encodes cytoskeletal linker proteins, express three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. DST mutations cause different disorders including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex; however, etiology of the muscle phenotype in DST-related diseases has been unclear. Because DST-b contains all of the DST-a-encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. To investigate the specific function of DST-b in striated muscles, we generated a Dst-b-specific mutant mouse model harboring a nonsense mutation. Dst-b mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in Dst-b mutation-induced cardiomyopathy. RNA sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. In silico analysis identified DST-b alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by DST-b mutations. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles.