bluuebunny/crossref_metadata_2025 huggingface dataset:
Attitudes Toward Human Papillomavirus Self-Sampling in Regularly Screened Women in Edmonton, Canada: A Cross-Sectional Study
Authors: Kraut Roni Y. , Manca Donna , Lofters Aisha , Hoffart Kaili , Khan Uzma , Liu Stephanie , Rehmani Jasmine , Babenko Oksana
Published: June 2021

Objective/Purpose

The aim of the study was to determine the level of interest in human papillomavirus (HPV) self-sampling as a method of cervical cancer screening in a population of women affiliated with a primary care clinic.

Materials and Methods

A survey was given to women (N = 182) between the ages of 25 and 69 years attending a family medicine clinic in Edmonton, Canada. Primary outcome measures include (1) the percentage of women who feel that HPV self-sampling should be available and (2) the percentage of women who would prefer HPV self-sampling to the Pap test. Secondary outcomes include the percentage of women aware of HPV self-sampling and factors associated with a preference for HPV self-sampling using logistic regression.

Results

Most women (84%) were up-to-date on Pap testing, and most (85%) had had postsecondary education (either completed or in progress). The percentage of the women who moderately or strongly felt that HPV self-sampling should be available was 60%; the percentage of the women who would prefer HPV self-sampling was 24%. Only 7% of the women reported being previously aware of HPV self-sampling. The factor associated with a preference for HPV self-sampling was the Pap comfort score, with an odds ratio of 1.51 (95% CI = 1.05–2.16, p = .026).

Conclusions

In this population of well-educated women who were mostly up-to-date on cervical screening, there was a clear interest to have the option of HPV self-sampling. It is important for cancer screening programs to take this into account, given that women are the ultimate beneficiaries of these programs.
Longitudinally extensive transverse myelitis combined with tuberculosis meningitis
Authors: Van Tuan Nguyen , Van Tuan Bui , Ung Hoang Tien , Van Thang Hoang , Van Tong Hoang , Thao Pham Ngoc , Thang Ta Ba
Published: June 2021

Rationale:

Central nervous system tuberculosis accounts for 1% of all the tuberculosis (TB) cases, of which tuberculous spondylitis is the most common, followed by scleritis and meningitis. Meningitis associated with transverse myelitis due to tuberculosis is rare but has been reported with severe clinical manifestations, including tuberculous sepsis, symptoms of meningitis and spinal cord injury.

Patients concerns:

Case 1, a 23-year-old male patient presented with fever, accompanied by quadriplegia and difficulty to urinate. Cultured Koch's Bacillus in liquid environment, Acid-Fast bacilli test, polymerase chain reaction and Xpert MTB/RIF assay for tuberculosis in the cerebrospinal fluid were positive for tuberculosis. Magnetic resonance imaging (MRI) showed heterogeneous signal on T2-weighted (T2W) hyperintensity and fluid-attenuated inversion recovery (FLAIR) images, heterogeneous signal intensity in the spinal cord, unclear medullary border and an increase in D10 - D11 diameter with clear signal in the spinal edges. Case 2, a 20-year-old male patient, presented with fever, severe headache, vomiting and paraplegia. Cultured Koch's Bacillus in liquid environment, testing for acid-fast bacilli test, polymerase chain reaction and Xpert MTB/ RIF tuberculosis in cerebrospinal fluid and sputum was positive for tuberculosis. The MRI displayed hyperintensities on T2W and FLAIR images, a slight increase in the spinal diameter and unclear, heterogeneous signal along the medullary border.

Diagnoses:

The first patient was diagnosed as tuberculosis meningitis combined with longitudinally extensive transverse myelitis and the second patient was diagnosed with pulmonary tuberculosis, tuberculous meningitis and longitudinally extensive transverse myelitis.

Interventions:

The two patients were treated with IIIA regimen, rifampicin, pyrazinamide, streptomycin, ethambutol combined with aggressive phase steroids.

Outcomes:

Following the anti-tuberculous therapy, the fever and mental status was alleviated in case 1, but improvement in muscle power of the limbs and sphincter function improved only after physical rehabilitation training. Case 2 was started on physical rehabilitation during the anti-tuberculous therapy. Though he tested negative for tuberculosis after the medical therapy, the muscle power of the limb showed only marginal improvement after the rehabilitation.

Lessons:

Meningitis combined with longitudinally extensive transverse myelitis is often difficult to diagnose early because the patients have altered mental status. If the patient has clinical manifestations of lower limb paralysis or quadriplegic paralysis, it is necessary to have an MRI of the spine to determine co-existing transverse myelitis lesions. Low-dose corticosteroid therapy in patients with meningitis combined with transverse myelitis leads to poor nerve recovery.
Management of mitochondrial leukoencephalopathy-related ataxia and cognitive impairment in a primary health care setup
Authors: Vodička Staša , Zelko Erika
Published: June 2021

Rationale:

Ataxia is defined as an impaired coordination of voluntary muscle movement. In cases of slowly progressing ataxia in young people, we should first consider a genetic origin. Herein, we describe the case of a 25-year-old patient with severe and advanced neurological disease which was diagnosed and treated by a family medicine physician, leading to the discovery of a new form of hereditary ataxia.

Patient concerns:

In 2016, a 25-year-old professional driver arrived at our family medicine office with a gait disorder that he had been struggling with for the past 5 years. During clinical examination, gait ataxia was evident. In 2018, the patient returned to our family medicine office, with difficulty in speaking and could no longer retain urine. During the examination, he was not oriented in time and space, no longer recognized the staff, and responded only in a few words. Clinically, we observed postural and action tremors, bradykinesia, and increased muscle tone.

Diagnoses:

The patient was sent to a neurologist for further management. There, a magnetic resonance imaging scan of the head was prescribed, leading to a diagnosis of adrenoleukodystrophy; however, genetic testing and biochemical analysis performed in 2016 did not confirm that. With additional testing in 2018, we confirmed a hereditary mitochondrial leukoencephalopathy (the identified version c.2884C>T in the AARS2 gene has not been previously reported as a pathogen in relation to human diseases).

Interventions:

Unfortunately, no specific treatment is available, therefore, the reluctance of neurologists to provide treatment is understandable. Family medicine doctors are long-term companions to patients and are sometimes the only support for them and their families when it comes to such an incurable disease.

Outcomes:

Currently, the patient only needs palliative care. The diagnostic path was completed but no specific therapy is in view.

Lessons:

Our case shows a 25-year-old patient with severe and advanced neurological disease diagnosed and treated by a family medicine physician. Family doctors play an important role due to their long-term relationship with the patient and the comprehensive care they provide, even in cases where the disease is severe, and the prognosis is unfavorable.
A Systematic Review and Meta-analysis of the Medical Error Rate in Iran: 2005-2019
Authors: Khammarnia M. , Ansari-Moghaddam A. R. , Setoodehzadeh Fatemeh , Rezaei K. , Clark C. C. T. , Peyvand M.
Published: June 2021

Background and Objectives:

Medical errors (MEs) are one of the main factors affecting the quality of hospital services and reducing patient safety in health care systems, especially in developing countries. The aim of this study was to determine the rate of ME in Iran.

Methods:

This is a systematic literature review and meta-analysis of extracted data. The databases MEDLINE, EMBASE, Scopus, Cochrane, SID, Magiran, and Medlib were searched in Persian and English, using a combination of medical subject heading terms (“Medical Error” [Mesh] OR “Medication error” [Mesh] OR “Hospital Error” AND (“Iran” [Mesh]) for observational and interventional studies that reported ME rate in Iran from January 1995 to April 2019. We followed the STROBE checklist for the purpose of this review.

Results:

The search yielded a total of 435 records, of which 74 articles were included in the systematic review. The rate of MEs in Iran was determined as 0.35%. The rates of errors among physicians and nurses were 31% and 37%, respectively. The error rates during the medication process, including prescription, recording, and administration, were 31%, 27%, and 35%, respectively. Also, incidence of MEs in night shifts was higher than in any other shift (odds ratio [OR] = 38%; 95% confidence interval [CI]: 31%-45%). Moreover, newer nurses were responsible for more errors within hospitals than other nurses (OR = 57%; 95% CI: 41%-80%). The rate of reported error after the Health Transformation Plan was higher than before the Health Transformation Plan (OR = 40%; CI: 33%-49% vs OR = 30%; CI: 25%-35%).

Conclusion:

This systematic review has demonstrated the high ME rate in Iranian hospitals. Based on the error rate attributed solely to night shifts, more attention to the holistic treatment process is required. Errors can be decreased through a variety of strategies, such as training clinical and support staff regarding safe practices and updating and adapting systems and technologies.
SARS-CoV-2 specific memory B-cells from individuals with diverse disease severities recognize SARS-CoV-2 variants of concern
Authors: Lyski Zoe L. , Brunton Amanda E. , Strnad Matt I. , Sullivan Peter E. , Siegel Sarah A.R. , Tafesse Fikadu G. , Slifka Mark K. , Messer William B.
Published: June 2021

In this investigation we examined the magnitude, breadth, and durability of SARS-CoV-2 specific antibodies in two distinct B-cell compartments: long-lived plasma cell-derived antibodies in the plasma, and peripheral memory B-cells along with their associated antibody profiles elicited afterin vitrostimulation. We found that magnitude varied amongst individuals, but was the highest in hospitalized subjects. Variants of concern (VoC) -RBD-reactive antibodies were found in the plasma of 72% of samples in this investigation, and VoC-RBD-reactive memory B-cells were found in all but 1 subject at a single time-point. This finding, that VoC-RBD-reactive MBCs are present in the peripheral blood of all subjects including those that experienced asymptomatic or mild disease, provides a reason for optimism regarding the capacity of vaccination, prior infection, and/or both, to limit disease severity and transmission of variants of concern as they continue to arise and circulate.
Relationship Between Patient Sex and Serum Tumor Necrosis Factor Antagonist Drug and Anti-Drug Antibody Concentrations in Inflammatory Bowel Disease; A Nationwide Cohort Study
Authors: Shehab Mohammad , Alasfour Hajer , Abdullah Israa , Alhendi Ghadeer , Alhadab Anwar , Alfadhli Ahmad , Ziyab Ali H. , Battat Robert
Published: June 2021

Background

Anti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease

Methods

A nationwide multicenter retrospective cohort study was conducted by evaluating patients’ charts from July 2018 until September 2021. The effect of patient sex on anti-drug antibodies and serum drug concentration in patients with IBD across 7 hospitals was investigated. A subgroup analysis also investigated the effect of anti-TNF combination therapy. Geometric means were calculated, and multiple linear regression was used to estimate the adjusted ratio of geometric means (RoGM) and their 95% confidence intervals (CI).

Results

In the total study sample (n = 1093), males receiving infliximab had higher anti-drug antibody concentrations (38.3 vs. 22.3 AU/ml; aRoGM = 1.72, 95% CI: 1.30-2.27, p-value <0.001) compared to females. Additionally, infliximab serum drug concentrations among males were lower compared to females (2.6 vs. 4.1 ug/ml; aRoGM = 0.62, 95% CI: 0.44-0.88, p-value = 0.007). In the subgroup analysis (n = 359), male compared to female patients on combination therapy with infliximab and immunomodulators had similar anti-drug antibody concentrations (30.2 vs. 21.9 AU/ml; aRoGM = 1.38, 95% CI: 0.79-2.40, p-value = 0.254). There was no difference in the anti-drug antibody and serum drug concentrations among males and females on adalimumab.

Conclusion

In patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed.
Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients
Authors: Eddins Devon J. , Yang Junkai , Kosters Astrid , Giacalone Vincent D. , Pechuan Ximo , Chandler Joshua D. , Eum Jinyoung , Babcock Benjamin R. , Dobosh Brian S. , Hernández Mindy R. , Abdulkhader Fathma , Collins Genoah L. , Ramonell Richard P. , Moussion Christine , Orlova Darya Y. , Sanz Ignacio , Lee F. Eun-Hyung , Tirouvanziam Rabindra M. , Ghosn Eliver E.B.
Published: June 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing COVID-19 pandemic have caused ∼40 million cases and over 648,000 deaths in the United States alone. Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African-American (AA) patients in some areas, yet targeted studies within this demographic are scant. Multi-omics single-cell analyses of immune profiles from airways and matching blood samples of Black/AA patients revealed low viral load, yet pronounced and persistent pulmonary neutrophilia with advanced features of cytokine release syndrome and acute respiratory distress syndrome (ARDS), including exacerbated production of IL-8, IL-1β, IL-6, and CCL3/4 along with elevated levels of neutrophil elastase and myeloperoxidase. Circulating S100A12+/IFITM2+mature neutrophils are recruited via the IL-8/CXCR2 axis, which emerges as a potential therapeutic target to reduce pathogenic neutrophilia and constrain ARDS in severe COVID-19.

Graphical Abstract

The lung pathology due to severe COVID-19 is marked by a perpetual pathogenic neutrophilia, leading to acute respiratory distress syndrome (ARDS) even in the absence of viral burden. Circulating mature neutrophils are recruited to the airways via IL-8 (CXCL8)/CXCR2 chemotaxis. Recently migrated neutrophils further differentiate into a transcriptionally active and hyperinflammatory state, with an exacerbated expression of IL-8 (CXCL8), IL-1β (IL1B),CCL3, CCL4, neutrophil elastase (NE), and myeloperoxidase (MPO) activity. Airway neutrophils and recruited inflammatory monocytes further increase their production of IL-8 (CXCL8), perpetuating lung neutrophilia in a feedforward loop. MdCs and T cells produce IL-1β and TNF, driving neutrophils reprogramming and survival.
CD4+T cell lymphopenia and dysfunction in severe COVID-19 disease is autocrine TNF-α/TNFRI-dependent
Authors: Popescu Iulia , Snyder Mark E. , Iasella Carlo J. , Hannan Stefanie J. , Koshy Ritchie , Burke Robin , Das Antu , Brown Mark J. , Lyons Emily J. , Lieber Sophia C. , Chen Xiaoping , Sembrat John C. , An Xiaojing , Linstrum Kelsey , Kitsios Georgios , Konstantinidis Ioannis , Saul Melissa , Kass Daniel J. , Alder Jonathan K. , Chen Bill B. , Lendermon Elizabeth A. , Kilaru Silpa , Johnson Bruce , Morrell Matthew R. , Pilewski Joseph M. , Kiss Joseph E. , Wells Alan H. , Morris Alison , McVerry Bryan J. , McMahon Deborah K. , Triulzi Darrell J. , Chen Kong , Sanchez Pablo G. , McDyer John F.
Published: June 2021

Lymphopenia is common in severe COVID-19 disease, yet the mechanisms are poorly understood. In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+lymphopenia predominated, with lower CD4+/CD8+ratios in severe COVID-19 compared to recovered, mild disease (p<0.0001). In severe disease, immunodominant CD4+T cell responses to Spike-1(S1) produced increasedin vitroTNF-α, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-α+T cell responses inversely correlated with absolute CD4+counts from severe COVID-19 patients (n=76; R=-0.744, P<0.0001). TNF-α blockade including infliximab or anti-TNFRI antibodies strikingly rescued S1-specific CD4+proliferation and abrogated S1-AICD in severe COVID-19 patients (P<0.001). Single-cell RNAseq demonstrated downregulation of Type-1 cytokines and NFκB signaling in S1-stimulated CD4+cells with infliximab treatment. Lung CD4+T cells in severe COVID-19 were reduced and produced higher TNF-α versus PBMC. Together, our findings show COVID-19-associated CD4+lymphopenia and dysfunction is autocrine TNF-α/TNFRI-dependent and therapies targeting TNF-α may be beneficial in severe COVID-19.

One Sentence Summary

Autocrine TNF-α/TNFRI regulates CD4+T cell lymphopenia and dysfunction in severe COVID-19 disease.
Single cell clonal analysis identifies an AID-dependent pathway of plasma cell differentiation
Authors: Gómez-Escolar Carmen , Serrano-Navarro Alvaro , Benguria Alberto , Dopazo Ana , Sánchez-Cabo Fátima , Ramiro Almudena R
Published: June 2021

Germinal centers (GC) are microstructures where B cells that have been activated by antigen can improve the affinity of their B cell receptors and differentiate into memory B cells (MBCs) or antibody secreting plasma cells. Activation Induced Deaminase (AID) initiates antibody diversification in GCs by somatic hypermutation and class switch recombination. Here we have addressed the role of AID in the terminal differentiation of GC B cells by combining single cell transcriptome and immunoglobulin clonal analysis in a mouse model that traces AID-experienced cells. We identified 8 transcriptional clusters that include dark zone and light zone GC subsets, plasmablasts/plasma cells (PB), 4 subsets of MBCs and a novel prePB subset, which shares the strongest clonal relationships with PBs. Mice lacking AID have various alterations in the size and expression profiles of these transcriptional clusters. We find that AID deficiency leads to a reduced proportion of prePB cells and severely impairs transitions between the prePB and the PB subsets. Thus, AID shapes the differentiation fate of GC B cells by enabling PB generation from a prePB state.
The Foundational data initiative for Parkinson’s disease (FOUNDIN-PD): enabling efficient translation from genetic maps to mechanism
Authors: Bressan Elisangela , Reed Xylena , Bansal Vikas , Hutchins Elizabeth , Cobb Melanie M. , Webb Michelle G , Alsop Eric , Grenn Francis P. , Illarionova Anastasia , Savytska Natalia , Violich Ivo , Broeer Stefanie , Fernandes Noémia , Sivakumar Ramiyapriya , Beilina Alexandra , Billingsley Kimberley , Berghausen Joos , Pantazis Caroline B. , Pitz Vanessa , Patel Dhairya , Daida Kensuke , Meechoovet Bessie , Reiman Rebecca , Courtright-Lim Amanda , Logemann Amber , Antone Jerry , Barch Mariya , Kitchen Robert , Li Yan , Dalgard Clifton L. ,   The American Genome Center, Rizzu Patrizia , Hernandez Dena G , Hjelm Brooke E. , Nalls Mike , Gibbs J. Raphael , Finkbeiner Steven , Cookson Mark R , Van Keuren-Jensen Kendall , Craig David W , Singleton Andrew B , Heutink Peter , Blauwendraat Cornelis
Published: June 2021

The FOUNdational Data INitiative for Parkinson’s Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson’s disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson’s Progression Markers Initiative study including participants with PD carrying monogenic PD (SNCA) variants, variants with intermediate effects and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modelling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser (https://www.foundinpd.org) as a resource for understanding the molecular pathogenesis of PD.
Scalable Bayesian GPFA with automatic relevance determination and discrete noise models
Authors: Jensen Kristopher T. , Kao Ta-Chu , Stone Jasmine T. , Hennequin Guillaume
Published: June 2021

Latent variable models are ubiquitous in the exploratory analysis of neural population recordings, where they allow researchers to summarize the activity of large populations of neurons in lower dimensional ‘latent’ spaces. Existing methods can generally be categorized into (i) Bayesian methods that facilitate flexible incorporation of prior knowledge and uncertainty estimation, but which typically do not scale to large datasets; and (ii) highly parameterized methods without explicit priors that scale better but often struggle in the low-data regime. Here, we bridge this gap by developing a fully Bayesian yet scalable version of Gaussian process factor analysis (bGPFA), which models neural data as arising from a set of inferred latent processes with a prior that encourages smoothness over time. Additionally, bGPFA uses automatic relevance determination to infer the dimensionality of neural activity directly from the training data during optimization. To enable the analysis of continuous recordings without trial structure, we introduce a novel variational inference strategy that scales near-linearly in time and also allows for non-Gaussian noise models appropriate for electrophysiological recordings. We apply bGPFA to continuous recordings spanning 30 minutes with over 14 million data points from primate motor and somatosensory cortices during a self-paced reaching task. We show that neural activity progresses from an initial state at target onset to a reach-specific preparatory state well before movement onset. The distance between these initial and preparatory latent states is predictive of reaction times across reaches, suggesting that such preparatory dynamics have behavioral relevance despite the lack of externally imposed delay periods. Additionally, bGPFA discovers latent processes that evolve over slow timescales on the order of several seconds and contain complementary information about reaction time. These timescales are longer than those revealed by methods which focus on individual movement epochs and may reflect fluctuations in e.g. task engagement.
Novel temporal and spatial patterns of metastatic colonization from rapid-autopsy tumor biopsies
Authors: Huang Xiaomeng , Qiao Yi , Brady Samuel W. , Factor Rachel E. , Downs-Kelly Erinn , Farrell Andrew , McQuerry Jasmine A. , Shrestha Gajendra , Jenkins David , Johnson W. Evan , Cohen Adam L. , Bild Andrea H. , Marth Gabor T.
Published: June 2021

Background

Metastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult, and thus poorly understood.

Results

Via rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumor’s evolution at subclonal resolution. The most unique, previously not reported aspect of the tumor’s evolution we observed in this patient was the presence of “subclone incubators”, i.e. already metastatic sites where substantial tumor evolution occurred before colonization of additional sites and organs by subclones that evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g. abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion; subclones at this site were the source of all four subsequent metastatic waves; and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known driver or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patient’s metastases for effective clinical intervention.

Conclusions

Our analysis revealed the presence of substantial tumor evolution at metastatic incubator sites, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.
Bifidobacterium castoris strains isolated from wild mice show evidence of frequent host switching and diverse carbohydrate metabolism potential
Authors: Kujawska Magdalena , Raulo Aura , Baltrūnaitė Laima , Knowles Sarah CL , Hall Lindsay J
Published: June 2021

Members of the gut microbiota genus Bifidobacterium are widely distributed human and animal symbionts believed to exert beneficial effects on their hosts. However, in-depth genomic analyses of animal-associated species and strains are somewhat lacking, particularly in wild animal populations. Here, to examine patterns of host specificity and carbohydrate metabolism capacity, we sequenced whole genomes of Bifidobacterium isolated from wild-caught small mammals from two European countries (UK and Lithuania). Members of B. castoris, B. animalis and B. pseudolongum were detected in wild mice (Apodemus sylvaticus, A. agrarius and A. flavicollis), but not voles or shrews. B. castoris constituted the most commonly recovered Bifidobacterium (78% of all isolates), with the majority of strains only detected in a single population, although populations frequently harboured multiple co-circulating strains. Phylogenetic analysis revealed that the mouse-associated B. castoris clades were not specific to a particular location or host species, and their distribution across the host phylogeny was consistent with regular host shifts rather than host-microbe codiversification. Functional analysis suggested that mouse-derived B. castoris strains encoded an extensive arsenal of carbohydrate-active enzymes, including putative novel glycosyl hydrolases such as chitosanases that may act on chitin-derived substrates such as mushrooms or insects, along with genes encoding putative exopolysaccharides, some of which may have been acquired via horizontal gene transfer. Overall, these results provide a rare genome-level analysis of host specificity and genomic capacity among important gut symbionts of wild animals, and reveal that Bifidobacterium has a labile relationship with its host over evolutionary time scale.
Alpha-to-beta- and gamma-band activity reflect predictive coding in affective visual processing
Authors: Strube Andreas , Rose Michael , Fazeli Sepideh , Büchel Christian
Published: June 2021

Processing of negative affective pictures typically leads to desynchronization of alpha-to-beta frequencies (ERD) and synchronization of gamma frequencies (ERS). Given that in predictive coding higher frequencies have been associated with prediction errors, while lower frequencies have been linked to expectations, we tested the hypothesis that alpha-to-beta ERD and gamma ERS induced by aversive pictures are associated with expectations and prediction errors, respectively. We recorded EEG while volunteers were involved in a probabilistically cued affective picture task using three different negative valences to produce expectations and prediction errors. Our data show that alpha-to-beta band activity was related to the expected valence of the stimulus as predicted by a cue. The absolute mismatch of the expected and actual valence, which denotes an absolute prediction error was related to gamma band activity. This demonstrates that top-down predictions and bottom-up prediction errors are represented in specific spectral patterns associated with affective picture processing.
Deep Learning Approach to Genomic Breakage Study from Primary Sequence
Authors: Kim Pora , Tan Hua , Liu Jiajia , Yang Mengyuan , Zhou Xiaobo
Published: June 2021

Identifying the molecular mechanisms related to genomic breakage is an important goal of cancer mechanism studies. Among the diverse location of the breakpoints of structural variants, the fusion genes, which have the breakpoints in the gene bodies and typically identified from RNA-seq data, can provide a highlighted structural variant resource for studying the genomic breakages with expression and potential pathogenic impacts. In this study, we developed FusionAI which utilizes deep learning to predict gene fusion breakpoints based on primary sequences and let us identify fusion breakage code and genomic context. FusionAI leverages the known fusion breakpoints to provide a prediction model of the fusion genes from the primary genomic sequences via deep learning, thereby helping researchers a more accurate selection of fusion genes and better understand genomic breakage.

Highlights

FusionAI, a 9-layer deep neural network, predicts fusion gene breakpoints from a DNA sequence

FusonAI reduce the cost and effort for validating fusion genes by decreasing specificity

High feature importance scored regions were apart 100nt on average from the exon junction breakpoints

High feature importance scored regions overlapped with 44 different human genomic features

Transcription factor fusion genes are targeted by the GC-rich motif TFs

FusionAI gives less scores to the non-disease derived breakpoints
Adult fibroblasts retain organ-specific transcriptomic identity
Authors: Forte Elvira , Ramialison Mirana , Nim Hieu T. , Mara Madison , Cohn Rachel , Daigle Sandra L. , Boyd Sarah , Hinson J. Travis , Costa Mauro W. , Rosenthal Nadia A. , Furtado Milena B.
Published: June 2021

Organ fibroblasts are essential components of homeostatic and diseased tissues. They participate in sculpting the extracellular matrix, sensing the microenvironment and communicating with other resident cells. Recent studies have revealed transcriptomic heterogeneity among fibroblasts within and between organs. To dissect the basis of inter-organ heterogeneity, we compare the gene expression of fibroblasts from different tissues (tail, skin, lung, liver, heart, kidney, gonads) and show that they display distinct positional and organ-specific transcriptome signatures that reflect their embryonic origins. We demonstrate that fibroblasts’ expression of genes typically attributed to the surrounding parenchyma is established in embryonic development and largely maintained in culture, bioengineered tissues, and ectopic transplants. Targeted knockdown of key organ-specific transcription factors affects fibroblasts functions, with modulation of genes related to fibrosis and inflammation. Our data open novel opportunities for the treatment of fibrotic diseases in a more precise, organ-specific manner.
Molecular mechanism of quorum sensing inhibition in Streptococcus by the phage protein paratox
Authors: Rutbeek Nicole R. , Rezasoltani Hanieh , Patel Trushar R. , Khajehpour Mazdak , Prehna Gerd
Published: June 2021

Streptococcus pyogenes, or Group A Streptococcus, is a Gram-positive bacterium that can be both a human commensal and pathogen. Central to this dichotomy are temperate bacteriophages that incorporate into the bacterial genome as a prophage. These genetic elements encode both the phage proteins as well as toxins harmful to the human host. One such conserved phage protein paratox (Prx) is always found encoded adjacent to the toxin genes and this linkage is preserved during transduction. Within Streptococcus pyogenes, Prx functions to inhibit the quorum-sensing ComRS receptor-signal pair that is the master regulator of natural competence, or the ability to uptake endogenous DNA. Specifically, Prx directly binds and inhibits the receptor ComR by unknown mechanism. To understand how Prx inhibits ComR at the molecular level we pursued an X-ray crystal structure of Prx bound to ComR. The structural data supported by solution X-ray scattering data demonstrate that Prx induces a conformational change in ComR to directly access the DNA binding domain. Furthermore, electromobility shift assays and competition binding assays reveal that Prx effectively uncouples the inter-domain conformational change that is required for activation of ComR by the signaling molecule XIP. Although to our knowledge the molecular mechanism of quorum-sensing inhibition by Prx is unique, it is analogous to the mechanism employed by the phage protein Aqs1 in Pseudomonas aeruginosa. Together, this demonstrates an example of convergent evolution between Gram-positive and Gram-negative phages to inhibit quorum-sensing, and highlights the versatility of small phage proteins.
Reverse-Complement Equivariant Networks for DNA Sequences
Authors: Mallet Vincent , Vert Jean-Philippe
Published: June 2021

As DNA sequencing technologies keep improving in scale and cost, there is a growing need to develop machine learning models to analyze DNA sequences, e.g., to decipher regulatory signals from DNA fragments bound by a particular protein of interest. As a double helix made of two complementary strands, a DNA fragment can be sequenced as two equivalent, so-called Reverse Complement (RC) sequences of nucleotides. To take into account this inherent symmetry of the data in machine learning models can facilitate learning. In this sense, several authors have recently proposed particular RC-equivariant convolutional neural networks (CNNs). However, it remains unknown whether other RC-equivariant architectures exist, which could potentially increase the set of basic models adapted to DNA sequences for practitioners. Here, we close this gap by characterizing the set of all linear RC-equivariant layers, and show in particular that new architectures exist beyond the ones already explored. We further discuss RC-equivariant pointwise nonlinearities adapted to different architectures, as well as RC-equivariant embeddings of k-mers as an alternative to one-hot encoding of nucleotides. We show experimentally that the new architectures can outperform existing ones.
Nitrogen fixation in mesoscale eddies of the North Pacific Subtropical Gyre: patterns and mechanisms
Authors: Dugenne Mathilde , Gradoville Mary R. , Church Matthew J. , Barone Benedetto , Wilson Samuel T. , Sheyn Uri , Harke Matthew J. , Björkman Karin M. , Hawco Nicholas J. , Hynes Annette M. , Ribalet François , Karl David M. , Delong Edward F. , Dyhrman Sonya T. , Armbrust E. Virginia , John Seth , Eppley John M. , Harding Katie , Stewart Brittany , Cabello Ana M. , Turk-Kubo Kendra A. , Caffin Mathieu , White Angelicque E. , Zehr Jonathan P.
Published: June 2021

1.

Mesoscale eddies have been shown to support elevated dinitrogen (N2) fixation rates (NFRs) and abundances of N2-fixing microorganisms (diazotrophs), but the mechanisms underlying these observations are not well understood. We explored relationships among NFRs and cyanobacterial diazotroph abundances in eddy pairs of opposite polarity sampled in the North Pacific Subtropical Gyre and compared our observations to seasonal trends from the Hawaii Ocean Time-series (HOT) program. Consistent with previous reports, we found that NFRs were anomalously high for this region (up to 3.7-fold above previous monthly HOT observations) in the centers of the sampled anticyclones, coinciding with elevated abundances ofCrocosphaerain the summertime. We then coupled our field-based observations, together with transcriptomic analyses of nutrient stress marker genes and ecological models, to evaluate potential mechanisms controlling diazotroph abundance and activity at the mesoscale. Specifically, we evaluated the role of biological (via estimates of growth and grazing rates) and physical controls on populations ofCrocosphaera,Trichodesmium,and diatom symbionts. Our results suggest that increasedCrocosphaeraabundances associated with summertime anticyclones resulted from the alleviation of phosphate limitation, allowing cells to grow at rates exceeding grazing losses. In contrast, distributions of larger, buoyant taxa (Trichodesmiumand diatom symbionts) appeared less affected by eddy-driven biological controls. Instead, they appeared driven by physical dynamics along frontal boundaries that separate cyclonic and anticyclonic eddies. Together, the interplay of eddy-specific changes in bottom-up control, top-down control, and the physical accumulation of cells likely explains the elevated diazotroph abundances and NFRs associated with anticyclones and eddy fronts.
Control over sampling boosts numerical evidence processing in human decisions from experience
Authors: Appelhoff Stefan , Hertwig Ralph , Spitzer Bernhard
Published: June 2021

When acquiring information about choice alternatives, decision makers may have varying levels of control over which and how much information they sample before making a choice. How does control over sampling affect the quality of experience-based decisions? Here, combining variants of a numerical sampling task with neural recordings, we show that control over when to stop sampling can enhance (i) behavioral choice accuracy, (ii) the build-up of parietal decision signals, and (iii) the encoding of numerical sample information in multivariate electroencephalogram (EEG) patterns. None of these effects were observed when participants could only control which alternatives to sample, but not when to stop sampling. Furthermore, levels of control had no effect on early sensory signals or on the extent to which sample information leaked from memory. The results indicate that freedom to stop sampling can amplify decisional evidence processing from the outset of information acquisition and lead to more accurate choices.
Identification of a motif in Trm732 required for 2’-O-methylation of the tRNA anticodon loop by Trm7
Authors: Funk Holly M. , DiVita Daisy J. , Sizemore Hannah E. , Wehrle Kendal , Weiner Catherine L. , Guy Adrian R. , Phizicky Eric M. , Guy Michael P.
Published: June 2021

Posttranscriptional tRNA modifications are essential for proper gene expression, and defects in the enzymes that perform tRNA modifications are associated with numerous human disorders. Throughout eukaryotes, 2’-O-methylation of residues 32 and 34 of the anticodon loop of tRNA is important for proper translation, and in humans, lack of these modifications results in non-syndromic X-linked intellectual disability. In yeast, the methyltransferase Trm7 forms a complex with Trm732 to 2’-O-methylate tRNA residue 32 and with Trm734 to 2’-O-methylate tRNA residue 34. Trm732 and Trm734 are required for the methylation activity of Trm7, but the role of these auxiliary proteins is not clear. Additionally, Trm732 and Trm734 homologs are implicated in biological processes not directly related to translation, suggesting that these proteins may have additional cellular functions. To identify critical amino acids in Trm732, we generated variants and tested their ability to function in yeast cells. We identified a conserved RRSAGLP motif in the conserved DUF2428 domain of Trm732 that is required for tRNA modification activity by both yeast Trm732 and its human homolog THADA. The identification of Trm732 variants that lack tRNA modification activity will help to determine if other biological functions ascribed to Trm732 and THADA are directly due to tRNA modification, or to secondary effects due to other functions of these proteins.
TUSX: an accessible toolbox for transcranial ultrasound simulation
Authors: Heimbuch Ian S. , Faas Guido C. , Iacoboni Marco , Charles Andrew C.
Published: June 2021

Abstract

Normally, the complicated nature of acoustic simulation makes it infeasible for most research groups doing individual transcranial ultrasound studies, hindering interpretation of results and complicating the determination of safety limits. We present here an open-source MATLAB toolbox to perform acoustic simulations using subject-specific medical images for transcranial ultrasound experiments. This toolbox, Transcranial Ultrasound Simulation Toolbox (TUSX), consists of an integrated processing pipeline that takes in structural MR or CT images, processes them for accurate simulation, and runs the simulations using k-Wave, an existing open-source acoustics package. We describe here the processing TUSX performs, along with its reasoning. We also validate its output using real-world pressure measurements in a water tank.
SALARECON connects the Atlantic salmon genome to growth and feed efficiency
Authors: Zakhartsev Maksim , Rotnes Filip , Gulla Marie , Øyås Ove , van Dam Jesse C. J. , Suarez-Diez Maria , Grammes Fabian , Hafþórsson Róbert Anton , van Helvoirt Wout , Koehorst Jasper J. , Schaap Peter J. , Jin Yang , Mydland Liv Torunn , Gjuvsland Arne B. , Sandve Simen R. , Martins dos Santos Vitor A. P. , Vik Jon Olav
Published: June 2021

Atlantic salmon (Salmo salar) is the most valuable farmed fish globally and there is much interest in optimizing its genetics and rearing conditions for growth and feed efficiency. Marine feed ingredients must be replaced to meet global demand, with challenges for fish health and sustainability. Metabolic models can address this by connecting genomes to metabolism, which converts nutrients in the feed to energy and biomass, but such models are currently not available for major aquaculture species such as salmon. We present SALARECON, a model focusing on energy, amino acid, and nucleotide metabolism that links the Atlantic salmon genome to metabolic fluxes and growth. It performs well in standardized tests and captures expected metabolic (in)capabilities. We show that it can explain observed hypoxic growth in terms of metabolic fluxes and apply it to aquaculture by simulating growth with commercial feed ingredients. Predicted limiting amino acids and feed efficiencies agree with data, and the model suggests that marine feed efficiency can be achieved by supplementing a few amino acids to plant- and insect-based feeds. SALARECON is a high-quality model that makes it possible to simulate Atlantic salmon metabolism and growth. It can be used to explain Atlantic salmon physiology and address key challenges in aquaculture such as development of sustainable feeds.

Author summary

Atlantic salmon aquaculture generates billions of euros annually, but faces challenges of sustainability. Salmon are carnivores by nature, and fish oil and fish meal have become scarce resources in fish feed production. Novel, sustainable feedstuffs are being trialed hand in hand with studies of the genetics of growth and feed efficiency. This calls for a mathematical-biological framework to integrate data with understanding of the effects of novel feeds on salmon physiology and its interplay with genetics. We have developed the SALARECON model of the core salmon metabolic reaction network, linking its genome to metabolic fluxes and growth. Computational analyses show good agreement with observed growth, amino acid limitations, and feed efficiencies, illustrating the potential for in silico studies of potential feed mixtures. In particular, in silico screening of possible diets will enable more efficient animal experiments with improved knowledge gain. We have adopted best practices for test-driven development, virtual experiments to assay metabolic capabilities, revision control, and FAIR data and model management. This facilitates fast, collaborative, reliable development of the model for future applications in sustainable production biology.
Characterization of the MIRO-independent mitochondrial association activity of TRAK proteins
Authors: Mitchell Lili , Reda Kathryn E. , Fatima Hijab , Vasquez Claudia E. , Quintero-Carmona Omar A.
Published: June 2021

Current models suggest that MIRO GTPases anchor cytoskeletal motors to the mitochondrial outer membrane (MOM). However, our previous findings indicate that the unconventional myosin, MYO19, interacts with MIRO weakly but that a MIRO-independent MOM-localizing domain interacts more tightly with the MOM. To test the model that MIRO proteins serve as weaker, initial recruiters of cytoskeletal motors to mitochondria, we examined interactions between TRAK proteins (microtubule motor-mitochondria adapter proteins) and the MOM via quantitative fluorescence microscopy and steady-state kinetic approaches. Using GFP-TRAK truncations expressed in MIRO1-2 double knockout mouse embryonic fibroblasts, we identified a MIRO-independent mitochondrial binding domain in the C-terminus of TRAK1 and TRAK2, sufficient for localization to the MOM--similar to what we observed for full length GFP-TRAK proteins. The MIRO-binding domains (MBD) of the TRAK proteins were only able to localize to mitochondria in the presence of ectopic expression of MIRO. Importantly, fluorescence recovery after photobleaching (FRAP) demonstrated that the steady-state kinetics of TRAKMBD/MIRO2 interaction were faster-exchanging than for either full-length TRAK or the TRAK C-terminal MOM-binding domain expressed alone. These data support the model that MIRO supports weak associations of cytoskeletal motors to the MOM, while MIRO-independent binding contributes significantly to tighter association of such motors to the MOM.
Digital PCR quantification of DNA, RNA and extracellular microRNA of mouse oocytes
Authors: Yang Joan Xiaohui , Zhao Xin Yuan , Bi Dexi , Wei Qing , Mattar Citra , Ling Pang Joy Yan , Lee Yie Hou
Published: June 2021

Despite numerous advances in in vitro fertilization (IVF) techniques since its first success in 1978, almost half of the patients treated remain childless. The multifactorial nature of IVF treatment means that success is dependent on variables, including the quality of oocytes. Therefore, new technologies are needed to objectively and quantitatively examine how each oocyte can be selected or optimized to achieve for the best possible outcomes for patients. Here, we report an optimized digital polymerase chain reaction (dPCR) for direct absolute quantification of nucleic acids within 3.5 h without the need for sample extraction or purification. Using individual oocytes, the developed method demonstrated absolute quantification with a linear dynamic range of 0.65 – 33 copies/µL (r2=0.999), high accuracy and excellent reproducibility of <10% relative standard deviation. The method then identified the variable expression of Gapdh (0.72-16.95 copies/oocyte), Hprt1 (1.05-19.05 copies/oocyte) and ATPase 6, (5.55-32358.15 copies/oocyte) in ovaries even from the same mouse. Finally, dPCR was used to validate extracellular microRNAs from oocytes incubated with a toxic unsaturated very-long chained ceramide. This study therefore shows the feasibility of dPCR for the rapid and sensitive absolute quantification of DNA/RNA and extracellular miRNA for the study of oocytes.