bluuebunny/crossref_metadata_2025 huggingface dataset:
Crisis Scenarios for Simulation-Based Nontechnical Skills Training for Cardiac Surgery Teams
Authors: Kemper Tom , van Haperen Maartje , Eberl Susanne , Winkelman Toon , van Deventer San-Mari , Waller Elbert , Preckel Benedikt
Published: March 2023

Background

Nontechnical skills in cardiac surgery are vital in ensuring patient safety in the operating room (OR). To train these skills in a simulation-based scenario, a collection of commonly accepted crisis scenarios is needed to serve as a framework for a simulation-based training program.

Objective

The objective of this study was to identify and reach consensus on a collection of relevant crisis scenarios in cardiac surgery suitable for simulation-based team training focusing on nontechnical skills.

Methods

Using the Delphi method, a national assessment was performed among cardiac surgeons, cardiac anesthesiologists, clinical perfusionists, and cardiac OR nurses in the Netherlands. In the first Delphi round, potential crisis scenarios for simulation-based team training in cardiac surgery were identified. In the second round, the identified scenarios were rated using a 5-point Likert scale. Finally, based on consensus (two-thirds majority), scenarios were prioritized and explored for feasibility.

Results

One hundred fourteen experts participated in the study (26 cardiac anesthesiologists, 24 cardiac surgeons, 25 clinical perfusionists, and 39 OR nurses), representing all 16 cardiac surgical centers in the Netherlands. In the first round, 237 scenarios were identified. After eliminating duplicates and grouping similar scenarios, 44 scenarios were scored in round 2, which finally resulted in 13 relevant crisis scenarios with an expert consensus higher than 67%.

Conclusions

Thirteen crisis scenarios relevant to simulation-based team training were identified by an expert panel consisting of all members of the cardiac surgical team. Further research is needed to evaluate the educational value of the respective scenarios.
N-acetyl-5-methoxykynuramine enhance object location and working memory performances via modulating CaMKII, ERK and CREB phosphorylation
Authors: Iwashita Hikaru , Sano Masahiro , Kawaguchi Mari , Chiba Atsuhiko
Published: March 2023

Objectives

Melatonin (MEL) has been reported to enhance cognitive performance. Recently, we have demonstrated that a MEL metaboliteN-acetyl-5-methoxykynuramine (AMK) promoted the formation of long-term object recognition memory more potently than MEL. Here, we examined the effects of 1 mg/kg MEL and AMK on both object location memory and spatial working memory. We also investigated the effects of the same dose of these drugs on relative phosphorylation/activation levels of memory-related proteins in the hippocampus (HP), the perirhinal cortex (PRC) and the medial prefrontal cortex (mPFC).

Methods

Object location memory and spatial working memory were assessed using the object location task and the Y-maze spontaneous alternation task, respectively. Relative phosphorylation/activation levels of memory-related proteins were assessed using western blot analysis.

Results

AMK, as well as MEL, enhanced object location memory and spatial working memory. AMK increased the phosphorylation of cAMP-response element-binding protein (CREB) in both the HP and the mPFC 2 h after the treatment. AMK also increased the phosphorylation of extracellular signal-regulated kinases (ERKs) but decreased that of Ca2+/calmodulin-dependent protein kinases II (CaMKIIs) in the PRC and the mPFC 30 min after the treatment. MEL increased CREB phosphorylation in the HP 2 h after the treatment, whereas no detectable changes in the other proteins examined were observed.

Conclusion

These results suggested the possibility that AMK exerts stronger memory-enhancing effects than MEL by more remarkably altering the activation of memory-related proteins such as ERKs, CaMKIIs and CREB in broader brain regions, including the HP, mPFC and PRC, compared to MEL.
I see you, you see me: the impact of social presence on social interaction processes in autistic and non-autistic people
Authors: Freeth Megan , Morgan Emma J.
Published: March 2023

Environments that require social interaction are complex, challenging and sometimes experienced as overwhelming by autistic people. However, all too often theories relating to social interaction processes are created, and interventions are proposed, on the basis of data collected from studies that do not involve genuine social encounters nor do they consider the perception of social presence to be a potentially influential factor. In this review, we begin by considering why face-to-face interaction research is important in this field. We then discuss how the perception of social agency and social presence can influence conclusions about social interaction processes. We then outline some insights gained from face-to-face interaction research conducted with both autistic and non-autistic people. We finish by considering the impact of social presence on cognitive processes more broadly, including theory of mind. Overall, we demonstrate that choice of stimuli in studies assessing social interaction processes has the potential to substantially alter conclusions drawn. Ecological validity matters and social presence, in particular, is a critical factor that fundamentally impacts social interaction processes in both autistic and non-autistic people.

This article is part of a discussion meeting issue ‘Face2face: advancing the science of social interaction’.
Gesture, spatial cognition and the evolution of language
Authors: Levinson Stephen C.
Published: March 2023

Human communication displays a striking contrast between the diversity of languages and the universality of the principles underlying their use in conversation. Despite the importance of this interactional base, it is not obvious that it heavily imprints the structure of languages. However, a deep-time perspective suggests that early hominin communication was gestural, in line with all the other Hominidae. This gestural phase of early language development seems to have left its traces in the way in which spatial concepts, implemented in the hippocampus, provide organizing principles at the heart of grammar.

This article is part of a discussion meeting issue ‘Face2face: advancing the science of social interaction’.
COVID-19 PCR: frequency of internal control inhibition in the clinical practice
Authors: Pasqualotto Alessandro C , Seus Amanda L.
Published: March 2023

Introduction: Diagnosis of COVID-19 is best performed with real-time PCR (qPCR), the most sensitive method for detection and quantification of viral RNA. Using the CDC protocol, for e ach sample tested for the virus, three qPCR tests are performed, targeting the viral genes N1, and N2, in addition to the internal control gene RNase P. Samples in which internal control fail to amplify should be labelled ‘invalid’. Methods: Thus, this study aims to determine the frequency of inhibition of the RNase P gene used as an internal control in qPCR tests for SARS-CoV-2 in a reference hospital in Southern Brazil during COVID-19 pandemic (01/FEB/2021 to 31/MAR/2021) Results: A total 10,311 samples were available for analysis. Mean Ct value for the RNAse P gene was 26.65 and the standard deviation was 3.18. A total of 252 samples were inhibited (2.4%) during the study period: amongst these, 77 (30.5%) showed late amplifications (beyond 2 standard deviations from mean Ct value), and 175 (69.4%) revealed no fluorescence at all for the RNase P gene. Conclusions: In conclusion, this study shows a low percentage of inhibition using RNase P as an internal control in COVID-19 PCR reactions using the CDC protocol. Thus, proving the effectiveness of this protocol for identification of SARS-CoV-2 in clinical samples. Re-extracting was efficacious for samples that showed little or no fluorescence for the RNase P gene. Keywords: SARS-CoV-2; Covid-19; qPCR; Inhibition; Internal control
Evidence for some antimicrobial properties of English churchyard lichens.
Authors: Taylor J A , Fourie T , Powell M , Chianella I
Published: March 2023

The emergence of multidrug resistant bacteria has driven the need for novel antibiotics. Our investigations have focussed on lichens as they naturally produce a wide range of unique and very effective defence chemicals. The aim of this study was to evaluate some of the antimicrobial properties of ten common British churchyard lichens. The lichen material was sampled from 10 species, namely Caloplaca flavescens, Diploicia canescens, Cladonia fimbriata, Psilolechia lucida, Lecanora campestris subsp. Campestris, Lecanora sulphurea, Pertusaria amara f.amara, Lepraria incana, Porpidia tuberculosa  and
 Xanthoria calcicola. Crude acetone extracts of these lichens were tested against 6 bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonela typhimurium, Listeria monocytogenes and Lactobacillus acidophilus) and two fungi (Trichophyton interdigitale and Aspergillus flavus) by using the disc diffusion susceptibility test method. Extracts of Diploicia canescens, Psilolechia lucida, Lecanora sulphurea,Pertusaria amara and Lepraria incana showed clear inhibition of the Gram positive bacteria tested (S. aureus, L. monocytogenes, L. Plantarum). Diploicia  canescens,  Pertusaria  amara and Lepraria incana extracts also inhibited  the dermatophyte fungi tested.  Lepraria incana’s extract was the only sample tested here that showed activity against any of the Gram negative bacteria tested and that was inhibition of Pseudomnas aeruginosa. Overall, our results showed that crude extracts of Diploicia canescens and Pertusaria amara had the most potent antimicrobial activity of all the extracts tested against the organisms in these studies. This finding is in agreement with published findings elsewhere. The activity of the Porpidia tuberculosa margin material being different from that of the main colony material was an interesting and new finding
In-vitro assessment of Thyme oil (Thymus vulgaris) as antifungal agent against Phyllosticta citricarpa
Authors: Magunga Bheki Thapelo , Malebo Ntsoaki Joyce
Published: March 2023

Abstract: The spread of Citrus black spot (CBS) is a major concern in the citrus industry because the disease threatens fruit marketability and citrus tree health. Furthermore, there is a public concern about the safety and side effects of synthetic fungicides currently being used to control citrus black spot. Synthetic fungicides are reported to have carcinogenic effects on humans and are also toxic to the environment, however this depends on the structure of the active ingredient and the dose present. Furthermore, microorganisms tend to develop resistance to most synthetic fungicides. This problem has prompted research into the identification of new ways with broad activity in treatment of microbial disease in plants such as the use of essential oils.
The purpose of the study was to investigate the use of Thyme oil (Thymus vulgaris) as an alternative antifungal against Citrus Black Spot (CBS). Thyme oil was characterised using GC/MS. Thymol (32.1%) and ρ-Cymene (20.4%), were identified, as major compounds. Furthermore, the minimum inhibitory concentration (MIC) of essential oils against the test organism was 25 (µg/ml). The antifungal activity of Thyme oil, Thyme hydrosol and antifungal anti-mitochondrials was tested in vitro against Phyllosticta citricarpa using the agar diffusion bioassay. Comparative antifungal activity was observed between antifungal anti-mitochondrial, Thyme oil and hydrosol as indicated by an inhibition zone, minimal growth and maximum growth zone towards the edge of the plate. We propose that Thyme oil, like antifungal anti-mitochondrials, inhibits fungal growth by targeting structures with increased mitochondrial activity. This was further confirmed by Scanning Electron Microscopy (SEM) and XTT colorimetric assay. This indicates that Thyme oil and hydrosol can be used as potential alternative antifungal agents against Citrus Black Spot (CBS).
Circulating PACAP levels are associated with increased amygdala-default mode network resting-state connectivity in posttraumatic stress disorder
Authors: Clancy KJ , Devignes Q , Kumar P , May V , Hammack SE , Akman E , Casteen EJ , Pernia CD , Jobson SA , Lewis MW , Daskalakis NP , Carlezon WA , Ressler KJ , Rauch SL , Rosso IM
Published: March 2023

The pituitary adenylate cyclase-activating polypeptide (PACAP) system is implicated in posttraumatic stress disorder (PTSD) and related amygdala-mediated arousal and threat reactivity. PTSD is characterized by increased amygdala reactivity to threat and, more recently, aberrant intrinsic connectivity of the amygdala with large-scale resting state networks, specifically the default mode network (DMN). While the influence of PACAP on amygdala reactivity has been described, its association with intrinsic amygdala connectivity remains unknown. To fill this gap, we examined functional connectivity of resting-state functional magnetic resonance imaging (fMRI) in eighty-nine trauma-exposed adults (69 female) screened for PTSD symptoms to examine the association between blood-borne (circulating) PACAP levels and amygdala-DMN connectivity. Higher circulating PACAP levels were associated with increased amygdala connectivity with posterior DMN regions, including the posterior cingulate cortex/precuneus (PCC/Precun) and left angular gyrus (lANG). Consistent with prior work, this effect was seen in female, but not male, participants and the centromedial, but not basolateral, subregions of the amygdala. Clinical association analyses linked amygdala-PCC/Precun connectivity to anxious arousal symptoms, specifically exaggerated startle response. Taken together, our findings converge with previously demonstrated effects of PACAP on amygdala activity in PTSD-related processes and offer novel evidence for an association between PACAP and intrinsic amygdala connectivity patterns in PTSD. Moreover, these data provide preliminary evidence to motivate future work ascertaining the sex- and subregion-specificity of these effects. Such findings may enable novel mechanistic insights into neural circuit dysfunction in PTSD and how the PACAP system confers risk through a disruption of intrinsic resting-state network dynamics.
Baseline inflammatory status affects the prognostic impact of statins in patients with peripheral arterial disease
Authors: Jujo Kentaro , Ueshima Daisuke , Abe Takuro , Shimazaki Kensuke , Fujimoto Yo , Tanaka Tomofumi , Murata Teppei , Miyazaki Toru , Matsumoto Michiaki , Tokuyama Hideo , Shimura Tsukasa , Funada Ryuichi , Murata Naotaka , Higashitani Michiaki
Published: March 2023

Background

Statins bring favorable effects on the clinical prognosis of patients with atherosclerotic disease partly through their anti-inflammatory properties. However, this effect has not been fully verified in patients with peripheral arterial disease (PAD). We aimed to test whether statins exert different prognostic effects depending on the degrees of inflammation in patients with PAD.

Methods

This study was a sub-analysis of a multicenter prospective cohort of 2,321 consecutive patients with PAD who received endovascular therapy (EVT). After excluding patients without information on C-reactive protein (CRP) levels at the time of index EVT, 1,974 patients (1,021 statin users and 953 non-users) were ultimately analyzed. Enrolled patients were classified into four groups depending on CRP levels: low CRP (<0.1 mg/dL), intermediate-low CRP (0.1–0.3 mg/dL), intermediate-high CRP (0.3–1.0 mg/dL), and high CRP (>1.0 mg/dL). A composite of death, stroke, myocardial infarction, and major amputation as the primary endpoint was compared between statin users and non-users in each CRP category.

Results

Overall, statin users showed a significantly lower event rate than non-users (log-rank, p<0.001). However, statin therapy was associated with significantly lower event rates only in the intermediate-high- and high-CRP categories (p=0.02 and p=0.008, respectively). Multivariable Cox regression analysis revealed that statin use was independently associated with the primary endpoint only in the high-CRP category (adjusted hazard ratio: 0.64 [95% confidence interval: 0.41–0.98]).

Conclusion

Statins may exert favorable prognostic effects in patients with PAD and highly elevated CRP levels but not in those with low to moderate CRP levels.

Condensed abstract

This multicenter retrospective study compared the prognostic effects of statins among patients with peripheral arterial disease (PAD) presenting diverse baseline C-reactive protein (CRP) levels [low CRP (<0.1 mg/dL), intermediate-low CRP (0.1–0.3 mg/dL), intermediate-high CRP (0.3–1.0 mg/dL), and high CRP (>1.0 mg/dL)]. Multivariable analysis showed that statin use was independently associated with a lower rate of death, stroke, myocardial infarction, and major amputation only in the high-CRP category. This suggests that statins may have favorable prognostic effects in patients with PAD and active inflammation.
Impact of Anemia on Outcomes and Resource Utilization in Patients with Myocardial Infarction: A National Database Analysis
Authors: Jhand Aravdeep S. , Abusnina Waiel , Tak Hyo Jung , Ahmed Arslan , Ismayl Mahmoud , Altin S. Elissa , Sherwood Matthew W. , Alexander John H. , Rao Sunil V. , Abbott J. Dawn , Carson Jeffrey L. , Goldsweig Andrew M.
Published: March 2023

Background

Although anemia is common in patients with myocardial infarction (MI), management remains controversial. We quantified the association of anemia with in-hospital outcomes and resource utilization in patients admitted with MI using a large national database.

Methods

All hospitalizations with a primary diagnosis code for acute MI in the National Inpatient Sample (NIS) between 2014 and 2018 were identified. Among these hospitalizations, patients with anemia were identified using a secondary diagnosis code. Data on demographic and clinical variables were collected. Outcomes of interest included in-hospital adverse events, length of stay (LOS), and total cost. Multivariable logistic regression and generalized linear models were used to evaluate the relationship between anemia and outcomes.

Results

Among 1,113,181 MI hospitalizations, 254,816 (22.8%) included concomitant anemia. Anemic patients were older and more likely to be women. After adjustment for demographics and comorbidities, anemia was associated with higher mortality (7.1 vs. 4.3%; odds ratio 1.09; 95% confidence interval [CI] 1.07-1.12, p<0.001). Anemia was also associated with a mean of 2.71 days longer LOS (average marginal effects [AME] 2.71; 95% CI 2.68-2.73, p<0.05), and higher total costs (mean cost $9,703 higher; AME $9703, 95% CI $9,577-$9,829, p<0.05). Anemic patients who received blood transfusions had higher mortality as compared with those who did not (8.2% vs. 7.0, p<0.001).

Conclusion

In MI patients, anemia was associated with higher in-hospital mortality, adverse events, total cost, and length of stay. Transfusion was associated with increased mortality, and its role in MI requires further research.
Balanced nitrogen-iron nutrition boosts grain yield and nitrogen use efficiency in rice and wheat
Authors: Wu Jie , Song Ying , Wang Jing-Xian , Wan Guang-Yu , Zhang Zi-Sheng , Xia Jin-Qiu , Sun Liang-Qi , Lu Jie , Ma Chuan-Xi , Yu Lin-Hui , Xiang Cheng-Bin
Published: March 2023

Nutrients must be balanced for optimal plant growth. However, the potential significance of balanced nitrogen-iron (N-Fe) for improving crop yield and nitrogen use efficiency (NUE) has never been addressed. Here, we show that balanced N-Fe substantially increases tiller number and boosts yield and NUE in rice and wheat. NIN-like protein 4 plays a pivotal role in maintaining the N-Fe balance by coordinately regulating the expression of multiple genes in N and Fe metabolism and signaling. Moreover, we show that foliar spraying of balanced N-Fe at the tillering stage can effectively increase rice tillers, yield and NUE in the field, which can be reproduced with wheat. Our findings provide guidelines for innovative fertilization to reduce N fertilizer input and promote yield, thus benefitting environment-friendly and sustainable agriculture worldwide.
Lorazepam stimulates IL-6 production and is associated with poor survival outcomes in pancreatic cancer
Authors: Cornwell Abigail C. , Tisdale Arwen A. , Venkat Swati , Maraszek Kathryn E. , Alahmari Abdulrahman A. , George Anthony , Attwood Kristopher , George Madison , Rempinski Donald , Franco-Barraza Janusz , Parker Mark D. , Gomez Eduardo Cortes , Fountzilas Christos , Cukierman Edna , Steele Nina G. , Feigin Michael E.
Published: March 2023

Purpose

This research investigates the association between benzodiazepines (BZDs) and cancer patient survival outcomes. Due to the high prevalence of BZD use in pancreatic cancer patients, we evaluated the effect of commonly prescribed BZDs on the pancreatic cancer tumor microenvironment and cancer-associated fibroblast (CAF) signaling.

Experimental Design

Multivariate Cox regression modeling was used to retrospectively measure associations between Roswell Park cancer patient survival outcomes and BZD prescription records. Immunohistochemistry, H&E, Masson’s trichrome,in situhybridization, and RNA sequencing were used to evaluate the impact of lorazepam (LOR) on the PDAC tumor microenvironment, using murine pancreatic cancer models. ELISA and qPCR were used to determine the impact of BZDs on IL-6 expression/secretion by human immortalized pancreatic CAFs. PRESTO-Tango assays, reanalysis of PDAC single cell sequencing/TCGA datasets, and GPR68 CRISPRi knockdown CAF cells were used to mechanistically determine the impact of BZDs on CAF-specific GPR68 signaling.

Results

LOR is associated with worse progression-free survival (PFS) while alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, IL-6 expression/secretion in CAFs, and ischemic necrosis. LOR promotes inflammatory signaling and IL-6 secretion by CAFs through activation of GPR68. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs significantly increase GPR68 activation under acidic conditions. LOR increases IL-6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP, and other GPR68 non-activator BZDs decrease IL-6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs.

Conclusion

We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.
Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia
Authors: Guardiola-Ripoll Maria , Almodóvar-Payá Carmen , Arias-Magnasco Angelo , Latorre-Guardia Mariona , Papiol Sergi , Canales-Rodríguez Erick J , García-León María Ángeles , Fuentes-Claramonte Paola , Salavert Josep , Tristany Josep , Torres Llanos , Rodríguez-Cano Elena , Salvador Raymond , Pomarol-Clotet Edith , Fatjó-Vilas Mar
Published: March 2023

Schizophrenia (SZ) is hypothesised to represent a costly trade-off in the evolution of the neurodevelopmental ontogenetic mechanisms associated with human-specific cognitive capacities. Human Accelerated Regions (HARs) are evolutionary conserved genomic regions that have accumulated human-specific sequence changes. These evolutionary markers function as neurodevelopmental transcription enhancers and have been associated with the brain’s cortical expansion and connectivity, the processing of neural information, and the risk for SZ. We sought to investigate whether HARs’ polygenic load influenced neuroanatomical measures.

Our sample consisted of 128 patients with SZ and 115 healthy controls with high-resolution structural T1 MRI and genome-wide genotyping data. We extracted the cortical thickness (CT) and surface area (SA) for the 34 Desikan-Killiany regions per hemisphere. We calculated four polygenic risk scores (PRS): SZ genetic load (Global PRSSZ), HARs’ specific variability (HARs PRSSZ), HARs’ variability associated with transcriptional regulatory elements uniquely active in the foetal brain (FB-HARs PRSSZ) and in the adult brain (AB-HARs PRSSZ). Through linear regression analyses, we explored whether these four PRSs modulated CT and SA within diagnostic groups and the PRSs and diagnostic interaction on the cortical measures.

Results indicate that FB-HARs PRSSZinfluenced patients’ right SA on the lateral orbitofrontal cortex, the superior temporal cortex, the pars triangularis and the paracentral lobule and that a higher SZ risk load in FB-HARs is associated with lower SA values.

These findings evidence the involvement of the HARs-foetal gene regulatory activity in SA architecture and the evolutionary component of this regulation in SZ. These data emphasise the importance of HARs in the transcriptional regulatory machinery from early neurodevelopment and their role as the bridging point between the neurodevelopmental and evolutionary hypotheses in SZ.
Rare Comorbidity between Inflammatory Bowel Disease and Primary Biliary Cholangitis: Evidence from Causality, Shared Genetic Architecture and Transcriptomics
Authors: Huang Wentao , Jiang Rui , Zeng Ruijie , Ma Yuying , Zhang Lijun , Tong Shuangshuang , Lyu Yanlin , Wang Jiaxuan , Leung Felix W , Sha Weihong , Chen Hao
Published: March 2023

Background

Clinical studies have found comorbidity between Inflammatory Bowel Disease (IBD) and primary sclerosing cholangitis (PSC). Primary biliary cholangitis (PBC) is another autoimmune liver disease but the coexistence of IBD and PBC is rare. Whether there exists comorbidity between IBD and PBC and potential mechanism remains unclear.

Methods

We assessed the casual effect between PBC and IBD, i.e., Crohn Disease (CD) and Ulcerative Colitis (UC) independently based on genome-wide association studies (GWAS) summary statistics. By leveraging data from GWAS data, Bulk tissue RNA sequencing (bulk RNA-seq) data, and Single-cell RNA sequencing (scRNA-seq) dataset, we investigated the shared genetic architecture between IBDs and PBC. The transcriptomic expressions of shared genes were explored in patients with IBD (intestinal biopsies) and PBC (peripheral CD4+T cells).

Result

We found a bidirectional causal relationship for PBC and IBDs using Mendelian randomization. The IBDs had been considered as the protective factors on PBC (0.87[95% confidence interval (CI): 0.81-0.93],P= 8.72e-5, vice versa (0.91[95% CI: 0.81-0.93],P= 2.65e-09). We find a consistent negative genetic correlation between PBC and IBD (LDSC:rg= -0.2245,P= 2.89e-5). Cross-trait analysis yielded 9 shared risk SNPs and 7 nearest genes. In transcriptome analysis, we observed significant (P< 0.05) differences expression in intestinal biopsies (PGAP3andDENND1B) and in peripheral CD4+T cells (PTPN11andPNMT). We identified shared tissue-specific heritability enrichment for PBC and IBD (including CD not UC) in lung, spleen and cells EBV-transformed lymphocytes and identified shared cell type-level enrichment for IBD, CD and PBC in type 1 dendritic cells, natural killer cells, CD8+cytotoxic T lymphocytes in lung and activated CD8+T cell in spleen.

Conclusion

Our study indicates that IBD and PBC are protective factors for each other and shared genetic architecture may contribute to the negative genetic correlation. These findings may explain the rare comorbidity between IBD and PBC.
Local genetic correlation analysis links depression with molecular and brain imaging endophenotypes
Authors: Werme J. , Tissink E.P. , de Lange S.C. , van den Heuvel M.P. , Posthuma D. , de Leeuw C.A.
Published: March 2023

Major depressive disorder (MDD) is a heritable psychiatric disorder which is considered one of the leading causes of disability world-wide. Improved understanding of its genetic component could inform novel treatment developments, but so far, gaining functional insights from genome-wide association studies has been difficult. In this study, we sought to generate hypotheses about plausible mechanisms through which genetic variants could influence MDD using a novel approach. Considering the cisregions of protein coding genes as the loci of interest, we applied local genetic correlation analysis to study the genetic relationship between MDD and a range of brain, endocrine, and immune related endophenotypes across several modalities (tissue specific gene expression and splicing, regional brain volumes, and brain network connectivity). We identify significant genetic relations between MDD and endophenotypes within the cis-regions of multiple genes, and perform endophenotype specific enrichment analyses of the top associated genes. Our results offer potential mechanisms through which MDD related variants in these genomic regions could act, and convergent evidence from multiple endophenotypes implicateFLOT1as a gene which may exhibit wide-ranging pleiotropic effects and be particularly interesting for functional follow-up. Here, we have illustrated how local genetic correlation analysis applied to lower level endophenotypes has the power to prioritise genes and functional paths which warrant further investigation for their possible role in MDD aetiology.
A Novel Collaborative Learning Model for Teeth and Fillings in Radiographs
Authors: Bumann Erin Ealba , Al-Qarni Saeed , Chandrashekar Geetha , Sabzian Roya , Bohaty Brenda , Lee Yugyung
Published: March 2023

It is critical for dentists to identify and differentiate primary and permanent teeth, fillings, dental restorations and areas with pathological findings when reviewing dental radiographs to ensure that an accurate diagnosis is made and the optimal treatment can be planned. Unfortunately, dental radiographs are sometimes read incorrectly due to human error or low-quality images. While secondary or group review can help catch errors, many dentists work in practice alone and/or do not have time to review all of their patients’ radiographs with another dentist. Artificial intelligence may facilitate the accurate interpretation of radiographs. To help support the review of panoramic radiographs, we developed a novel collaborative learning model that simultaneously identifies and differentiates primary and permanent teeth and detects fillings. We used publicly accessible dental panoramic radiographic images and images obtained from the University of Missouri-Kansas City School of Dentistry to develop and optimize two high-performance classifiers: (1) a system for tooth segmentation that can differentiate primary and permanent teeth and (2) a system to detect dental fillings. By utilizing these high-performance classifiers, we created models that can identify primary and permanent teeth, as well as their associated dental fillings. We also designed a novel method for collaborative learning that utilizes these two classifiers to enhance recognition performance. Our model improves upon the existing machine learning models to simultaneously identify and differentiate primary and permanent teeth, and to identify any associated fillings.
Functional host-specific adaptation of the intestinal microbiome in hominids
Authors: Rühlemann MC , Bang C , Gogarten JF , Hermes BM , Groussin M , Waschina S , Poyet M , Ulrich M , Akoua-Koffi C , Deschner T , Muyembe-Tamfum JJ , Robbins MM , Surbeck M , Wittig RM , Zuberbühler K , Baines JF , Leendertz FH , Franke A
Published: March 2023

Fine-scale knowledge of the changes in composition and function of the human gut microbiome compared that of our closest relatives is critical for understanding the evolutionary processes underlying its developmental trajectory. To infer taxonomic and functional changes in the gut microbiome across hominids at different timescales, we performed high-resolution metagenomic-based analyses of the fecal microbiome from over two hundred samples including diverse human populations, as well as wild-living chimpanzees, bonobos, and gorillas. We find human-associated taxa depleted within non-human apes and patterns of host-specific gut microbiota, suggesting the widespread acquisition of novel microbial clades along the evolutionary divergence of hosts. In contrast, we reveal multiple lines of evidence for a pervasive loss of diversity in humans populations in correlation with a high Human Development Index, including evolutionarily conserved clades. Similarly, patterns of co-phylogeny are found to be disrupted in humans. Together with identifying individual microbial taxa and functional adaptations that correlate to host phylogeny, these findings offer new and exciting insights into specific candidates playing a role in the diverging trajectories of the gut microbiome of hominids, demonstrating that repeated horizontal gene transfer and gene loss, as well as the adaptation to transient microaerobic conditions appear to have played a role in the evolution of the human gut microbiome.
Fast and accurate DNASeq Variant Calling workflow composed of LUSH toolkit
Authors: Wang Taifu , Zhang Youjin , Wang Haoling , Zheng Qiwen , Yang Jiaobo , Zhang Tiefeng , Sun Geng , Liu Weicong , Yin Longhui , He Xinqiu , You Rui , Wang Chu , Liu Zhencheng , Liu Zhijian , Wang Jin’an , Jin Xiangqian , He Zengquan
Published: March 2023

Background

Whole genome sequencing (WGS) is becoming increasingly prevalent for molecular diagnosis, staging and prognosis because of its declining costs and the ability to detect nearly all genes associated with a patient’s disease. The currently widely accepted variant calling pipeline, GATK, is limited in terms of its computational speed and efficiency, which cannot meet the growing analysis needs.

Methods

In this study, we propose a fast and accurate DNASeq variant calling workflow that is purely composed of tools from LUSH toolkit. The LUSH pipeline is highly optimized for the WGS pipeline based on SOAPnuke, BWA and GATK which can be deployed on any general-purpose CPU-based computing system. We validated the accuracy, speed and scalability of the LUSH pipeline on several standard WGS datasets.

Results

Our test results show that the LUSH pipeline and the GATK pipeline are highly consistent in terms of accuracy, achieving over 99% precision and recall on NA12878. For speed, the LUSH pipeline completes 30x WGS data in 1.6 hours, which is about 17x faster than the GATK pipeline. From BAM to VCF, LUSH_HC even takes only 12 minutes, about 76x faster than GATK. Moreover, the LUSH pipeline shows favorable scalability in terms of thread and sequencing depth.

Conclusion

The LUSH pipeline provides far superior computational speed to GATK while maintaining a high level of accuracy comparable to that of GATK, which greatly facilitates bedside analysis of acute patients, large-scale cohort data analysis, and variant calling in crop breeding programs.
Shotgun metagenomics unravels higher antibiotic resistome profile in Bangladeshi gut microbiome
Authors: Bhattacharjee Arittra , Jamal Tabassum Binte , Ahammad Ishtiaque , Chowdhury Zeshan Mahmud , Rahman Anisur , Dewan Gourab , Talukder Shiny , Hossain Mohammad Uzzal , Das Keshob Chandra , Keya Chaman Ara , Salimullah Md
Published: March 2023

Antibiotic resistance management is a challenging task in Low and Middle-Income Countries (LMICs) such as Bangladesh. Improper regulation and uncontrolled spreading of Antibiotic Resistant Genes (ARGs) from LIMCs pose a great threat to global public health. The human gut microbiome is a massive reservoir of Antibiotic Resistant Genes (ARGs). In this study, we unraveled the ARGs in the gut microbiome of the Bangladeshi population and compared them with several other countries around the world. Here, 31 fecal samples from different ethnic groups living in Bangladesh namely Bengali (n=9), Chakma (n=6), Khyang (n=5), Marma (n=6), and Tripura (n=5) were collected. Shotgun metagenomic sequencing method was implemented for revealing the ARGs. The resistome profiling was executed on three levels-the total microbiome, the plasmidome, and the virome. In all three levels, samples from Bangladeshi cohorts showed higher ARG profiles compared to foreign samples. On average, the number of ARGs in the Bangladeshi samples ranged between 75.11 and 88. Among them, class C beta-lactamases, quinolone resistance genes, and tetracycline efflux pumps were relatively more abundant. Additionally, the MexPQ-OpmE drug resistance pathway was found to be more prevalent. Findings from our study suggest that the spread of antibiotic resistance within the Bangladeshi population is being facilitated by the gut microbiome especially via the mobilome. Therefore, strict regulation on antibiotic usage is necessary to halt the spread of ARGs.
First insights into theAurelia auritatranscriptome response upon manipulation of its microbiome
Authors: Weiland-Bräuer Nancy , Koutsouveli Vasiliki , Langfeldt Daniela , Schmitz Ruth A.
Published: March 2023

The associated diverse microbiome contributes to the overall fitness ofAurelia aurita, particularly to asexual reproduction. However, howA. auritamaintains this specific microbiome or reacts to manipulations is unknown. In this report, the response ofA. auritato manipulations of its native microbiome was studied by a transcriptomics approach. Microbiome-manipulated polyps were generated by antibiotic treatment and challenging polyps with a non-native, native, and potentially pathogenic bacterium. Total RNA extraction followed by RNAseq resulted in over 155 million reads used for ade novoassembly. The transcriptome analysis showed that the antibiotic-induced change and resulting reduction of the microbiome significantly affected the host transcriptome, e.g., genes involved in processes related to immune response and defense mechanisms were highly upregulated. Similarly, manipulating the microbiome by challenging the polyp with a high load of bacteria (2 × 107cells/polyp) resulted in induced transcription of apoptosis-, defense-, and immune response genes. A second focus was on host-derived quorum sensing interference as a potential defense strategy. Quorum Quenching (QQ) activities and the respective encoding QQ-ORFs ofA. auritawere identified by functional screening a cDNA-based expression library generated inEscherichia coli. Corresponding sequences were identified in the transcriptome assembly. Moreover, gene expression analysis revealed differential expression of QQ genes depending on the treatment, strongly suggesting QQ as an additional defense strategy. Overall, this study allows first insights intoA. aurita’sresponse to manipulating its microbiome, thus paving the way for an in-depth analysis of the basal immune system and additional fundamental defense strategies.
Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes
Authors: Gonçalves Luciana Mateus , Fahd Qadir Mirza Muhammad , Boulina Maria , Makhmutova Madina , Almaça Joana
Published: March 2023

Pancreatic islets are endocrine organs that depend on their microvasculature to function properly. Along with endothelial cells, pericytes comprise the islet microvascular network. These mural cells are crucial for microvascular stability and function, but it is not known if/how they are affected during the development of type 1 diabetes (T1D). Here we investigated islet pericyte density, phenotype and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (Aab+; all GADA+) and recent onset T1D cases. Our data show that islet pericyte and capillary responses to vasoactive stimuli are impaired early on in T1D. Microvascular dysfunction is associated with a switch in the phenotype of islet pericytes towards pro-fibrotic myofibroblasts. Using publicly available RNAseq data, we further found that transcriptional alterations related to endothelin-1 signaling, vascular and ECM remodeling are hallmarks of single Aab+ donor pancreata. Our data show that islet pericyte/microvascular dysfunction is present at early stages of islet autoimmunity.

Highlights

Changes in islet pericyte coverage and phenotype occur during T1D progression.

Vascular responses to vasoactive stimuli are impaired in islets from Aab+ and T1D donors.

Endothelin-1 action and receptor expression are altered in vascular cells from Aab+ and T1D donors.

Strong vascular remodeling occurs in the pancreas of Aab+ and T1D donors.
Impact of Post-Translational Modification on MHC Peptide Binding and TCR Engagement
Authors: Kelly Joey J. , Bloodworth Nathaniel , Shao Qianqian , Shabanowitz Jeffery , Hunt Donald , Meiler Jens , Pires Marcos M.
Published: March 2023

The human major histocompatibility complex (MHC) plays a crucial role in the presentation of peptidic fragments from proteins; these peptides can be derived from self-proteins or from non-human antigens, such as those produced by viruses or bacteria. To prevent cytotoxicity against healthy cells, thymocytes expressing T cell receptors (TCRs) that recognize self-peptides are removed from circulation in a process called negative selection. However, post-translational modifications (PTMs) are largely excluded from negative selection; this feature opens the door to the possibility that PTMs directly contribute to the development of autoreactive T cells and subsequent autoimmune diseases. Despite it being well-established that PTMs are prevalent in peptides presented on MHCs, the exact mechanisms by which PTMs influence the antigen presentation machinery remains poorly understood. In our work, we introduce chemical modifications mirroring PTMs onto peptides to systematically investigate their impact on MHC binding and TCR recognition. Our findings reveal the numerous ways PTMs alter antigen presentation, which could have implications for tumor neoantigen presentation.
Sleep Deprivation, Sleep Fragmentation and Social Jet Lag increase temperature preference inDrosophila
Authors: Roach S Tanner , Ford Melanie C , Simhambhatla Vikram , Loutrianakis Vasilios , Farah Hamza , Li Zhaoyi , Periandri Erica M. , Abdalla Dina , Huang Irene , Kalra Arjan , Shaw Paul J.
Published: March 2023

Despite the fact that sleep deprivation substantially affects the way animals regulate their body temperature, the specific mechanisms behind this phenomenon are not well understood. In both mammals and flies, neural circuits regulating sleep and thermoregulation overlap, suggesting an interdependence that may be relevant for sleep function. To investigate this relationship further, we exposed flies to 12 h of sleep deprivation, or 48 h of sleep fragmentation and evaluated temperature preference in a thermal gradient. Flies exposed to 12 h of sleep deprivation chose warmer temperatures after sleep deprivation. Importantly, sleep fragmentation, which prevents flies from entering deeper stages of sleep, but does not activate sleep homeostatic mechanisms nor induce impairments in short-term memory also resulted in flies choosing warmer temperatures. To identify the underlying neuronal circuits, we used RNAi to knock down the receptor forPigment dispersing factor, a peptide that influences circadian rhythms, temperature preference and sleep. Expressing UAS-PdfrRNAiin subsets of clock neurons prevented sleep fragmentation from increasing temperature preference. Finally, we evaluated temperature preference after flies had undergone a social jet lag protocol which is known to disrupt clock neurons. In this protocol, flies experience a 3 h light phase delay on Friday followed by a 3 h light advance on Sunday evening. Flies exposed to social jet lag exhibited an increase in temperature preference which persisted for several days. Our findings identify specific clock neurons that are modulated by sleep disruption to increase temperature preference. Moreover, our data indicate that temperature preference may be a more sensitive indicator of sleep disruption than learning and memory.
Multimodal neural correlates of childhood psychopathology
Authors: Royer Jessica , Kebets Valeria , Piguet Camille , Chen Jianzhong , Ooi Leon Qi Rong , Kirschner Matthias , Siffredi Vanessa , Misic Bratislav , Yeo B.T. Thomas , Bernhardt Boris C.
Published: March 2023

Abstract

Complex structural and functional changes occurring in typical and atypical development necessitate multidimensional approaches to better understand the risk of developing psychopathology. Here, we simultaneously examined structural and functional brain network patterns in relation to dimensions of psychopathology in the Adolescent Brain Cognitive Development dataset. Several components were identified, recapitulating the psychopathology hierarchy, with the general psychopathology (p) factor explaining most covariance with multimodal imaging features, while the internalizing, externalizing, and neurodevelopmental dimensions were each associated with distinct morphological and functional connectivity signatures. Connectivity signatures associated with thepfactor and neurodevelopmental dimensions followed the sensory-to-transmodal axis of cortical organization, which is related to the emergence of complex cognition and risk for psychopathology. Results were consistent in two separate data subsamples, supporting generalizability, and robust to variations in analytical parameters. Our findings help in better understanding biological mechanisms underpinning dimensions of psychopathology, and could provide brain-based vulnerability markers.
Identification of novel buffering mechanisms in aortic arch artery development and congenital heart disease
Authors: Ramirez AnnJosette , Vyzas Christina A. , Zhao Huaning , Eng Kevin , Degenhardt Karl , Astrof Sophie
Published: March 2023

Rationale

The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease (CHD) arising from defective morphogenesis of pharyngeal arch arteries (PAA) and their derivatives.

Objective

To uncover mechanisms underlying the robustness of PAA morphogenesis.

Methods and Results

The second heart field (SHF) gives rise to the PAA endothelium. Here, we show that the number of SHF-derived ECs is regulated byVEGFR2andTbx1. Remarkably, when SHF-derived EC number is decreased, PAA development can be rescued by the compensatory endothelium. Blocking such compensatory response leads to embryonic demise. To determine the source of compensating ECs and mechanisms regulating their recruitment, we investigated three-dimensional EC connectivity, EC fate, and gene expression. Our studies demonstrate that the expression of VEGFR2 by the SHF is required for the differentiation of SHF-derived cells into PAA ECs. The deletion of one VEGFR2 allele (VEGFR2SHF-HET) reduces SHF contribution to the PAA endothelium, while the deletion of both alleles (VEGFR2SHF-KO) abolishes it. The decrease in SHF-derived ECs in VEGFR2SHF-HETand VEGFR2SHF-KOembryos is complemented by the recruitment of ECs from the nearby veins. Compensatory ECs contribute to PAA derivatives, giving rise to the endothelium of the aortic arch and the ductus in VEGFR2SHF-KOmutants. Blocking the compensatory response in VEGFR2SHF-KOmutants results in embryonic lethality shortly after mid-gestation. The compensatory ECs are absent inTbx1+/-embryos, a model for 22q11 deletion syndrome, leading to unpredictable arch artery morphogenesis and CHD.Tbx1regulates the recruitment of the compensatory endothelium in an SHF-non-cell-autonomous manner.

Conclusions

Our studies uncover a novel buffering mechanism underlying the resiliency of PAA development and remodeling.

Nonstandard Abbreviations and Acronyms in Alphabetical Order

CHD – congenital heart disease; ECs – endothelial cells; IAA-B – interrupted aortic arch type B; PAA – pharyngeal arch arteries; RERSA – retro-esophageal right subclavian artery; SHF – second heart field; VEGFR2 – Vascular endothelial growth factor receptor 2.