bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of NADPH oxidase blocks NETosis and reduces thrombosis in heparin-induced thrombocytopenia
Authors: Leung Halina H. L. , Perdomo Jose , Ahmadi Zohra , Yan Feng , McKenzie Steven E. , Chong Beng H. 
Published: September 2021

Abstract
Heparin-induced thrombocytopenia (HIT) is associated with severe and potentially lethal thrombotic complications. NETosis was recently shown to be an important driver of thrombosis in HIT. We investigated the role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their contributions to thrombus development in HIT. We showed that neutrophil activation by HIT immune complexes induced ROS-dependent NETosis. Analysis of thrombi formed in a microfluidics system showed ROS production in both platelets and neutrophils, and abundant neutrophil extracellular traps (NETs) and ROS distributed throughout the clot. Neutrophil-targeted ROS inhibition was sufficient to block HIT-induced NETosis and thrombosis using human blood. Inhibition of NOX2 with diphenyleneiodonium chloride or GSK2795039 abrogated HIT-induced thrombi in vivo using FcγRIIa+/hPF4+-transgenic mice. Thrombocytopenia in mice remained unaffected by ROS inhibition. Increased ROS production in activated neutrophils was also confirmed using fresh blood from patients with active HIT. Our findings show that ROS and NOX2 play a crucial role in NETosis and thrombosis in HIT. This enhances our understanding of the processes driving thrombosis in HIT and identifies NOX2 as a potential new therapeutic target for antithrombotic treatment of HIT.
Heterogeneous modulation of Bcl-2 family members and drug efflux mediate MCL-1 inhibitor resistance in multiple myeloma
Authors: Bolomsky Arnold , Miettinen Juho J. , Malyutina Alina , Besse Andrej , Huber Julia , Fellinger Stefanie , Breid Helene , Parsons Alun , Klavins Kristaps , Hannich J. Thomas , Kubicek Stefan , Caers Jo , Hübl Wolfgang , Schreder Martin , Zojer Niklas , Driessen Christoph , Tang Jing , Besse Lenka , Heckman Caroline A. , Ludwig Heinz 
Published: September 2021

AbstractAntiapoptotic Bcl-2 family members have recently (re)emerged as key drug targets in cancer, with a tissue- and tumor-specific activity profile of available BH3 mimetics. In multiple myeloma, MCL-1 has been described as a major gatekeeper of apoptosis. This discovery has led to the rapid establishment of clinical trials evaluating the impact of various MCL-1 inhibitors. However, our understanding about the clinical impact and optimal use of MCL-1 inhibitors is still limited. We therefore explored mechanisms of acquired MCL-1 inhibitor resistance and optimization strategies in myeloma. Our findings indicated heterogeneous paths to resistance involving baseline Bcl-2 family alterations of proapoptotic (BAK, BAX, and BIM) and antiapoptotic (Bcl-2 and MCL-1) proteins. These manifestations depend on the BH3 profile of parental cells that guide the enhanced formation of Bcl-2:BIM and/or the dynamic (ie, treatment-induced) formation of Bcl-xL:BIM and Bcl-xL:BAK complexes. Accordingly, an unbiased high-throughput drug-screening approach (n = 528) indicated alternative BH3 mimetics as top combination partners for MCL-1 inhibitors in sensitive and resistant cells (Bcl-xL&gt;Bcl-2 inhibition), whereas established drug classes were mainly antagonistic (eg, antimitotic agents). We also revealed reduced activity of MCL-1 inhibitors in the presence of stromal support as a drug-class effect that was overcome by concurrent Bcl-xL or Bcl-2 inhibition. Finally, we demonstrated heterogeneous Bcl-2 family deregulation and MCL-1 inhibitor cross-resistance in carfilzomib-resistant cells, a phenomenon linked to the MDR1-driven drug efflux of MCL-1 inhibitors. The implications of our findings for clinical practice emphasize the need for patient-adapted treatment protocols, with the tracking of tumor- and/or clone-specific adaptations in response to MCL-1 inhibition.
Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms
Authors: Elbracht Miriam , Meyer Robert , Kricheldorf Kim , Gezer Deniz , Thomas Eggermann , Betz Beate , Kurth Ingo , Teichmann Lino L. , Brümmendorf Tim H. , Germing Ulrich , Isfort Susanne , Koschmieder Steffen 
Published: September 2021

Abstract
The molecular causes of myeloproliferative neoplasms (MPNs) have not yet been fully elucidated. Approximately 7% to 8% of the patients carry predisposing genetic germline variants that lead to driver mutations, which enhance JAK-STAT signaling. To identify additional predisposing genetic germline variants, we performed whole-exome sequencing in 5 families, each with parent-child or sibling pairs affected by MPNs and carrying the somatic JAK2 V617F mutation. In 4 families, we detected rare germline variants in known tumor predisposition genes of the DNA repair pathway, including the highly penetrant BRCA1 and BRCA2 genes. The identification of an underlying hereditary tumor predisposition is of major relevance for the individual patients as well as for their families in the context of therapeutic options and preventive care. Two patients with essential thrombocythemia or polycythemia vera experienced progression to acute myeloid leukemia, which may suggest a high risk of leukemic transformation in these familial MPNs. Our study demonstrates the relevance of genetic germline diagnostics in elucidating the causes of MPNs and suggests novel therapeutic options (eg, PARP inhibitors) in MPNs. Furthermore, we uncover a broader tumor spectrum upon the detection of a germline mutation in genes of the DNA repair pathway.
Altered microbiota-host metabolic cross talk preceding neutropenic fever in patients with acute leukemia
Authors: Rashidi Armin , Ebadi Maryam , Rehman Tauseef Ur , Elhusseini Heba , Nalluri Harika , Kaiser Thomas , Ramamoorthy Sivapriya , Holtan Shernan G. , Khoruts Alexander , Weisdorf Daniel J. , Staley Christopher 
Published: September 2021

AbstractDespite antibiotic prophylaxis, most patients with acute leukemia receiving mucotoxic chemotherapy develop neutropenic fever (NF), many cases of which remain without a documented etiology. Antibiotics disrupt the gut microbiota, with adverse clinical consequences, such as Clostridioides difficile infection. A better understanding of NF pathogenesis could inform the development of novel therapeutics without deleterious effects on the microbiota. We hypothesized that metabolites absorbed from the gut to the bloodstream modulate pyrogenic and inflammatory pathways. Longitudinal profiling of the gut microbiota in 2 cohorts of patients with acute leukemia showed that Akkermansia expansion in the gut was associated with an increased risk for NF. As a prototype mucolytic genus, Akkermansia may influence the absorption of luminal metabolites; thus, its association with NF supported our metabolomics hypothesis. Longitudinal profiling of the serum metabolome identified a signature associated with gut Akkermansia and 1 with NF. Importantly, these 2 signatures overlapped in metabolites in the γ-glutamyl cycle, suggesting oxidative stress as a mediator involved in Akkermansia-related NF. In addition, the level of gut microbial–derived indole compounds increased after Akkermansia expansion and decreased before NF, suggesting their role in mediating the anti-inflammatory effects of Akkermansia, as seen predominantly in healthy individuals. These results suggest that Akkermansia regulates microbiota-host metabolic cross talk by modulating the mucosal interface. The clinical context, including factors influencing microbiota composition, determines the type of metabolites absorbed through the gut barrier and their net effect on the host. Our findings identify novel aspects of NF pathogenesis that could be targets for precision therapeutics. This trial was registered at www.clinicaltrials.gov as #NCT03316456.
Flatness of the Meckel cave may cause primary trigeminal neuralgia: a radiomics-based study
Authors: Lin Jinzhi , Zhang Yong , Li Wuming , Yan Jianhao , Ke Yiquan 
Published: September 2021

Abstract
Background
Neurovascular contact (NVC) is the main cause of primary trigeminal neuralgia (PTN); however, cases of PTN without NVC are still observed. In this study, the Meckel cave (MC) morphology in PTN were analyzed by radiomics and compared to healthy controls (HCs) to explore the cause of PTN.

Methods
We studied the 3.0T MRI data of 115 patients with PTN and 46 HCs. Bilateral MC was modeled using the 3D Slicer software, and the morphological characteristics of MC were analyzed using the radiomics method.

Results
The right side incidence rate in the PTN group was higher than the left side incidence. By analyzing the flatness feature of MC, we observed that the affected side of the PTN was lower than that of the unaffected side, the right MC of the PTN and HC was lower than that of the left MC, the MC of the affected side of the left and right PTN without bilateral NVC was lower than that of the unaffected side.

Conclusions
By providing a method to analyze the morphology of the MC, we found that there is an asymmetry in the morphology of bilateral MC in the PTN and HC groups. It can be inferred that the flatness of the MC may be a cause of PTN.
Impact of an end-of-fourth-year emergency medicine bootcamp
Authors: Lewis Jason J. , Grossestreuer Anne V. , Ullman Edward A. 
Published: September 2021

Abstract
Background
The final months of the fourth-year of medical school are variable in educational and clinical experience, and the effect on clinical knowledge and preparedness for residency is unclear. Specialty-specific “bootcamps” are a growing trend in medical education aimed at increasing clinical knowledge, procedural skills, and confidence prior to the start of residency.

Methods
We developed a 4-week Emergency Medicine (EM) bootcamp offered during the final month of medical school. At the conclusion of the course, participants evaluated its impact. EM residency-matched participants and non-participants were asked to self-evaluate their clinical knowledge, procedural skills and confidence 1 month into the start of residency. Program directors were surveyed to assess participants and non-participants across the same domains. A Fisher’s exact test was performed to test whether responses between participants and non-participants were statistically different.

Results
From 2015 to 2018, 22 students participated in the bootcamp. The majority reported improved confidence, competence, and procedural skills upon completion of the course. Self-assessed confidence was significantly higher in EM-matched participants 1 month into residency compared to EM-matched non-participants (p = 0.009). Self-assessed clinical knowledge and procedural skill competency was higher in participants than non-participants but did not reach statistical significance. Program directors rated EM-matched participants higher in all domains but this difference was also not statistically significant.

Conclusions
Participation in an EM bootcamp increases self-confidence at the start of residency among EM-matched residents. EM bootcamps and other specialty-specific courses at the end of medical school may ease the transition from student to clinician and may improve clinical knowledge and procedural skills.
Velo-Predictor: an ensemble learning pipeline for RNA velocity prediction
Authors: Wang Xin , Zheng Jie 
Published: September 2021

AbstractBackgroundRNA velocity is a novel and powerful concept which enables the inference of dynamical cell state changes from seemingly static single-cell RNA sequencing (scRNA-seq) data. However, accurate estimation of RNA velocity is still a challenging problem, and the underlying kinetic mechanisms of transcriptional and splicing regulations are not fully clear. Moreover, scRNA-seq data tend to be sparse compared with possible cell states, and a given dataset of estimated RNA velocities needs imputation for some cell states not yet covered.ResultsWe formulate RNA velocity prediction as a supervised learning problem of classification for the first time, where a cell state space is divided into equal-sized segments by directions as classes, and the estimated RNA velocity vectors are considered as ground truth. We propose Velo-Predictor, an ensemble learning pipeline for predicting RNA velocities from scRNA-seq data. We test different models on two real datasets, Velo-Predictor exhibits good performance, especially when XGBoost was used as the base predictor. Parameter analysis and visualization also show that the method is robust and able to make biologically meaningful predictions.ConclusionThe accurate result shows that Velo-Predictor can effectively simplify the procedure by learning a predictive model from gene expression data, which could help to construct a continous landscape and give biologists an intuitive picture about the trend of cellular dynamics.
Insights into 6S RNA in lactic acid bacteria (LAB)
Authors: Cataldo Pablo Gabriel , Klemm Paul , Thüring Marietta , Saavedra Lucila , Hebert Elvira Maria , Hartmann Roland K. , Lechner Marcus 
Published: September 2021

Abstract
Background
6S RNA is a regulator of cellular transcription that tunes the metabolism of cells. This small non-coding RNA is found in nearly all bacteria and among the most abundant transcripts. Lactic acid bacteria (LAB) constitute a group of microorganisms with strong biotechnological relevance, often exploited as starter cultures for industrial products through fermentation. Some strains are used as probiotics while others represent potential pathogens. Occasional reports of 6S RNA within this group already indicate striking metabolic implications. A conceivable idea is that LAB with 6S RNA defects may metabolize nutrients faster, as inferred from studies of Echerichia coli. This may accelerate fermentation processes with the potential to reduce production costs. Similarly, elevated levels of secondary metabolites might be produced. Evidence for this possibility comes from preliminary findings regarding the production of surfactin in Bacillus subtilis, which has functions similar to those of bacteriocins. The prerequisite for its potential biotechnological utility is a general characterization of 6S RNA in LAB.

Results
We provide a genomic annotation of 6S RNA throughout the Lactobacillales order. It laid the foundation for a bioinformatic characterization of common 6S RNA features. This covers secondary structures, synteny, phylogeny, and product RNA start sites. The canonical 6S RNA structure is formed by a central bulge flanked by helical arms and a template site for product RNA synthesis. 6S RNA exhibits strong syntenic conservation. It is usually flanked by the replication-associated recombination protein A and the universal stress protein A. A catabolite responsive element was identified in over a third of all 6S RNA genes. It is known to modulate gene expression based on the available carbon sources. The presence of antisense transcripts could not be verified as a general trait of LAB 6S RNAs.

Conclusions
Despite a large number of species and the heterogeneity of LAB, the stress regulator 6S RNA is well-conserved both from a structural as well as a syntenic perspective. This is the first approach to describe 6S RNAs and short 6S RNA-derived transcripts beyond a single species, spanning a large taxonomic group covering multiple families. It yields universal insights into this regulator and complements the findings derived from other bacterial model organisms.
Up-regulation of apoptotic- and cell survival-related gene pathways following exposures of western corn rootworm to B. thuringiensis crystalline pesticidal proteins in transgenic maize roots
Authors: Coates Brad S. , Deleury Emeline , Gassmann Aaron J. , Hibbard Bruce E. , Meinke Lance J. , Miller Nicholas J. , Petzold-Maxwell Jennifer , French B. Wade , Sappington Thomas W. , Siegfried Blair D. , Guillemaud Thomas 
Published: September 2021

Abstract
Background
Resistance of pest insect species to insecticides, including B. thuringiensis (Bt) pesticidal proteins expressed by transgenic plants, is a threat to global food security. Despite the western corn rootworm, Diabrotica virgifera virgifera, being a major pest of maize and having populations showing increasing levels of resistance to hybrids expressing Bt pesticidal proteins, the cell mechanisms leading to mortality are not fully understood.

Results
Twenty unique RNA-seq libraries from the Bt susceptible D. v. virgifera inbred line Ped12, representing all growth stages and a range of different adult and larval exposures, were assembled into a reference transcriptome. Ten-day exposures of Ped12 larvae to transgenic Bt Cry3Bb1 and Gpp34/Tpp35Ab1 maize roots showed significant differential expression of 1055 and 1374 transcripts, respectively, compared to cohorts on non-Bt maize. Among these, 696 were differentially expressed in both Cry3Bb1 and Gpp34/Tpp35Ab1 maize exposures. Differentially-expressed transcripts encoded protein domains putatively involved in detoxification, metabolism, binding, and transport, were, in part, shared among transcripts that changed significantly following exposures to the entomopathogens Heterorhabditis bacteriophora and Metarhizium anisopliae. Differentially expressed transcripts in common between Bt and entomopathogen treatments encode proteins in general stress response pathways, including putative Bt binding receptors from the ATP binding cassette transporter superfamily. Putative caspases, pro- and anti-apoptotic factors, as well as endoplasmic reticulum (ER) stress-response factors were identified among transcripts uniquely up-regulated following exposure to either Bt protein.

Conclusions
Our study suggests that the up-regulation of genes involved in ER stress management and apoptotic progression may be important in determining cell fate following exposure of susceptible D. v. virgifera larvae to Bt maize roots. This study provides novel insights into insect response to Bt intoxication, and a possible framework for future investigations of resistance mechanisms.
Genome-wide association studies for canine hip dysplasia in single and multiple populations – implications and potential novel risk loci
Authors: Wang Shizhi , Strandberg Erling , Arvelius Per , Clements Dylan N. , Wiener Pamela , Friedrich Juliane 
Published: September 2021

Abstract
Background
Association mapping studies of quantitative trait loci (QTL) for canine hip dysplasia (CHD) can contribute to the understanding of the genetic background of this common and debilitating disease and might contribute to its genetic improvement. The power of association studies for CHD is limited by relatively small sample numbers for CHD records within countries, suggesting potential benefits of joining data across countries. However, this is complicated due to the use of different scoring systems across countries. In this study, we incorporated routinely assessed CHD records and genotype data of German Shepherd dogs from two countries (UK and Sweden) to perform genome-wide association studies (GWAS) within populations using different variations of CHD phenotypes. As phenotypes, dogs were either classified into cases and controls based on the Fédération Cynologique Internationale (FCI) five-level grading of the worst hip or the FCI grade was treated as an ordinal trait. In a subsequent meta-analysis, we added publicly available data from a Finnish population and performed the GWAS across all populations. Genetic associations for the CHD phenotypes were evaluated in a linear mixed model using 62,089 SNPs.

Results
Multiple SNPs with genome-wide significant and suggestive associations were detected in single-population GWAS and the meta-analysis. Few of these SNPs overlapped between populations or between single-population GWAS and the meta-analysis, suggesting that many CHD-related QTL are population-specific. More significant or suggestive SNPs were identified when FCI grades were used as phenotypes in comparison to the case-control approach. MED13 (Chr 9) and PLEKHA7 (Chr 21) emerged as novel positional candidate genes associated with hip dysplasia.

Conclusions
Our findings confirm the complex genetic nature of hip dysplasia in dogs, with multiple loci associated with the trait, most of which are population-specific. Routinely assessed CHD information collected across countries provide an opportunity to increase sample sizes and statistical power for association studies. While the lack of standardisation of CHD assessment schemes across countries poses a challenge, we showed that conversion of traits can be utilised to overcome this obstacle.
Transcriptome analysis provides genome annotation and expression profiles in the central nervous system of Lymnaea stagnalis at different ages
Authors: Rosato Martina , Hoelscher Brittany , Lin Zhenguo , Agwu Chidera , Xu Fenglian 
Published: September 2021

Abstract
Background
The pond snail, Lymnaea stagnalis (L. stagnalis), has served as a valuable model organism for neurobiology studies due to its simple and easily accessible central nervous system (CNS). L. stagnalis has been widely used to study neuronal networks and recently gained popularity for study of aging and neurodegenerative diseases. However, previous transcriptome studies of L. stagnalis CNS have been exclusively carried out on adult L. stagnalis only. As part of our ongoing effort studying L. stagnalis neuronal growth and connectivity at various developmental stages, we provide the first age-specific transcriptome analysis and gene annotation of young (3 months), adult (6 months), and old (18 months) L. stagnalis CNS.

Results
Using the above three age cohorts, our study generated 55–69 millions of 150 bp paired-end RNA sequencing reads using the Illumina NovaSeq 6000 platform. Of these reads, ~ 74% were successfully mapped to the reference genome of L. stagnalis. Our reference-based transcriptome assembly predicted 42,478 gene loci, of which 37,661 genes encode coding sequences (CDS) of at least 100 codons. In addition, we provide gene annotations using Blast2GO and functional annotations using Pfam for ~ 95% of these sequences, contributing to the largest number of annotated genes in L. stagnalis CNS so far. Moreover, among 242 previously cloned L. stagnalis genes, we were able to match ~ 87% of them in our transcriptome assembly, indicating a high percentage of gene coverage. The expressional differences for innexins, FMRFamide, and molluscan insulin peptide genes were validated by real-time qPCR. Lastly, our transcriptomic analyses revealed distinct, age-specific gene clusters, differentially expressed genes, and enriched pathways in young, adult, and old CNS. More specifically, our data show significant changes in expression of critical genes involved in transcription factors, metabolisms (e.g. cytochrome P450), extracellular matrix constituent, and signaling receptor and transduction (e.g. receptors for acetylcholine, N-Methyl-D-aspartic acid, and serotonin), as well as stress- and disease-related genes in young compared to either adult or old snails.

Conclusions
Together, these datasets are the largest and most updated L. stagnalis CNS transcriptomes, which will serve as a resource for future molecular studies and functional annotation of transcripts and genes in L. stagnalis.