bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk Factors for Adverse Outcomes with Outpatient Parenteral Antimicrobial Therapy
Authors: Wang Alexander J. , Elnakieb Yaser , Bae Esther , Monogue Marguerite , Cutrell James B. , Lehmann Christoph U. , Yen Christina , Medford Richard J. 
Published: April 2023

ABSTRACTObjectivesOutpatient parenteral antimicrobial therapy (OPAT) use has increased significantly as it provides safe and reliable administration of long-term antimicrobials for severe infections. Benefits of OPAT include fewer antibiotic or line-related complications, increased patient satisfaction, shorter hospitalizations, and lower costs. Although OPAT programs carefully screen patients for eligibility and safety prior to enrollment, complications can occur. There is a paucity of studies identifying predictors of clinical outcomes in OPAT patients. Here, we seek to identify baseline predictors of OPAT outcomes utilizing machine learning methodologies.MethodsWe used electronic health record data from patients treated with OPAT between February 2019 and June 2022 at a large academic tertiary care hospital in Dallas, Texas. Three primary outcomes were examined: 1) clinical improvement at 30 days without evidence of reinfection; 2) patient actively being followed at 30 days; and 3) occurrence of any adverse event while on OPAT. Potential predictors were determineda priori, including demographic and clinical characteristics, OPAT setting, intravenous line type, and antimicrobials administered. Three classifiers were used to predict each outcome: logistic regression, random forest, and extreme gradient boosting (XGBoost). Model performance was measured using AUC, F1, and accuracy scores.ResultsWe included 664 unique patients in the study, of whom 57% were male. At 30 days, clinical improvement was present in 78% of patients. Two-thirds of patients (67%) were actively followed at 30 days, and 30% experienced an adverse event while on OPAT. The XGBoost model performed best for predicting treatment success (average AUC = 0.873), with significant predictors including ID consultation and the use of vancomycin. The logistic regression model was best for predicting adverse outcomes (average AUC = 0.710). Risk factors for adverse outcomes included management in the home setting and the use of vancomycin, daptomycin, or piperacillin-tazobactam.ConclusionOutcomes of patients undergoing OPAT can be predicted with the use of easily-obtainable clinical and demographic factors. Patients requiring certain antimicrobial therapies, such as vancomycin or daptomycin, may derive less benefit from early hospital discharge and OPAT.
Enhanced Classification Performance using Deep Learning Based Segmentation for Pulmonary Embolism Detection in CT Angiography
Authors: Kahraman Ali Teymur , Fröding Tomas , Toumpanakis Dimitris , Gustafsson Christian Jamtheim , Sjöblom Tobias 
Published: April 2023

AbstractPurposeTo develop a deep learning-based algorithm that automatically and accurately classifies patients as either having pulmonary emboli or not in CT pulmonary angiography (CTPA) examinations.Materials and MethodsFor model development, 700 CTPA examinations from 652 patients performed at a single institution were used, of which 149 examinations contained 1497 PE traced by radiologists. The nnU-Net deep learning-based segmentation framework was trained using 5-fold cross-validation. To enhance classification, we applied logical rules based on PE volume and probability thresholds. External model evaluation was performed in 770 and 34 CTPAs from two independent datasets.ResultsA total of 1483 CTPA examinations were evaluated. In internal cross-validation and test set, the trained model correctly classified 123 of 128 examinations as positive for PE (sensitivity 96.1%; 95% C.I. 91-98%;P< .05) and 521 of 551 as negative (specificity 94.6%; 95% C.I. 92-96%;P< .05). In the first external test dataset, the trained model correctly classified 31 of 32 examinations as positive (sensitivity 96.9%; 95% C.I. 84-99%;P< .05) and 2 of 2 as negative (specificity 100%; 95% C.I. 34-100%;P< .05). In the second external test dataset, the trained model correctly classified 379 of 385 examinations as positive (sensitivity 98.4%; 95% C.I. 97-99%;P< .05) and 346 of 385 as negative (specificity 89.9%; 95% C.I. 86-93%;P< .05).ConclusionOur automatic pipeline achieved beyond state-of-the-art diagnostic performance of PE in CTPA using nnU-Net for segmentation and volume- and probability-based post-processing for classification.HighlightsAn nnU-Net segmentation framework was applied to patient-level classification in CTPA examinations.The proposed algorithm can enable prioritization of patients with PE for rapid review in emergency radiology.The proposed algorithm showed outstanding performance on both internal and two publicly available external testing datasets (AUC, 98.3%; n=1355).
Epidemiology of scrub typhus and other rickettsial infections (2018-22) in the hyper-endemic setting of Mizoram, North-East India
Authors: Vanramliana  , Pautu Lalfakzuala , Lalmalsawma Pachuau , Rosangkima Gabriel , Sarma Devojit Kumar , Hunropuia  , Malvi Yogesh , Kodali Naveen Kumar , Amarthaluri Christiana , Balasubramani K , Nina Praveen Balabaskaran 
Published: April 2023

AbstractIn the last decade, there has been an emergence of scrub typhus in many parts of India. In Mizoram, North-East India, there has been a steep increase in scrub typhus and other rickettsial infections in the last 5 years. As part of the public health response, the Mizoram Government has integrated screening (by rapid immunochromatographic test and/or Weil-Felix test) and line listing of scrub typhus and other rickettsial infections across all its health settings, a first in India. From 2018-22 (study period), 22914 cases were reported; of these, 19651 were positive for scrub typhus. Aizawl district is the worst affected, with 10580 cases (46.17%). The average incidence rate of rickettsial infections is 3.54 cases per 1000 persons-year, and the case fatality rate is 0.35. Patients with eschar (aOR=2.5, p<0.05), construction workers (aOR=17.9, p<0.05), and children aged 10 and below (aOR=5.4, p<0.05) have higher odds of death due to rickettsial infections.
Keystone competitor creates spatial patterns of biodiversity
Authors: Ennis Katherine K. , Perfecto Ivette , Vandermeer John 
Published: April 2023

AbstractConventional ecological theory on competition and competitive exclusion states that competition should limit diversity. However, diversity of all species is more common than competitive exclusion would suggest, especially in the tropics. Here, we use theoretical and field approaches to examine the relationship between a keystone ant competitor (Azteca sericeasur) and the richness of a ground-foraging ant community in a spatially explicit context. Theoretically, we demonstrate that a fixed keystone competitor can increase species diversity. In addition, we sampled the ground-foraging ant community in three differentially managed coffee habitats and found – with the exception of plots in the most intensified coffee habitat – a consistently higher species richness near to the keystone competitor and lower richness with increasing distance. These patterns show that keystone competitors may contribute to the maintenance of local species richness.
hipFG: High-throughput harmonization and integration pipeline for functional genomics data
Authors: Cifello Jeffrey , Kuksa Pavel P. , Saravanan Naveensri , Valladares Otto , Leung Yuk Yee , Wang Li-San 
Published: April 2023

AbstractSummaryPreparing functional genomic (FG) data with diverse assay types and file formats for integration into analysis workflows that interpret genome-wide association and other studies is a significant and time-consuming challenge. Here we introduce hipFG, an automatically customized pipeline for efficient and scalable normalization of heterogenous FG data collections into standardized, indexed, rapidly searchable analysis-ready datasets while accounting for FG datatypes (e.g., chromatin interactions, genomic intervals, quantitative trait loci).Availability and ImplementationhipFG is freely available athttps://bitbucket.org/wanglab-upenn/hipFG. Docker container is available athttps://hub.docker.com/r/wanglab/hipfg.Contactlswang@pennmedicine.upenn.eduSupplementary informationSupplementary data are available as BioRxiv supplemental files.
Representation Learning to Effectively Integrate and Interpret Omics Data
Authors: Masarone Sara 
Published: April 2023

AbstractThe last decade has seen an increase in the amount of high throughput data available to researchers. While this has allowed scientists to explore various hypotheses and research questions, it has also highlighted the importance of data integration to facilitate knowledge extraction and discovery. Although many strategies have been developed over the last few years, integrating data whilst generating an interpretable embedding still remains challenging due to difficulty in regularisation, especially when using deep generative models. Thus, we introduce a framework called Regularised Multi-View Variational Autoencoder (RMV-VAE) to integrate different omics data types whilst allowing researchers to obtain more biologically meaningful embeddings.
Combined inactivation of RB and Hippo pathways converts differentiating photoreceptors into eye progenitor cells through derepression ofhomothorax
Authors: Rader Alexandra E. , Bayarmagnai Battuya , Frolov Maxim V. 
Published: April 2023

ABSTRACTThe RB and Hippo pathways interact to regulate cell proliferation and differentiation. However, their mechanism of interaction is not fully understood.Drosophilaphotoreceptors with inactivated RB and Hippo pathways specify normally but fail to maintain neuronal identity and dedifferentiate. We performed single-cell RNA-sequencing to elucidate the cause of dedifferentiation and the fate of these cells. We find that dedifferentiated cells adopt a progenitor-like fate due to inappropriate activation of the retinal differentiation suppressorhomothorax(hth) by Yki/Sd. This results in activation of the Yki/Hth transcriptional program, driving photoreceptor dedifferentiation. We show that Rbf physically interacts with Yki which, together with the GAGA factor, inhibitshthexpression. Thus, RB and Hippo pathways cooperate to maintain photoreceptor differentiation by preventing inappropriate expression ofhthin differentiating photoreceptors. Our work accentuates the importance of both RB and Hippo pathway activity for maintaining the state of terminal differentiation.
Stem cell growth directs region-specific cell fate decisions during intestinal nutrient adaptation
Authors: Mattila Jaakko , Viitanen Arto , Fabris Gaia , Korzelius Jerome , Hietakangas Ville 
Published: April 2023

ABSTRACTThe adult intestine is a regionalized organ, whose size and cellular composition is adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell type composition remains unclear. Here we show that nutrient adaptation involves region-specific control of intestinal cell size, number and differentiation. We uncovered that activation of mTOR complex 1 increases ISC size in a region-specific manner. This promotes Delta expression to direct cell fate towards the absorptive enteroblast lineage, while inhibiting secretory enteroendocrine cell differentiation. The observed coupling between nutrient sensing and cell fate enabled mitigation of aging-induced ISC misdifferentiation through intermittent fasting. In conclusion, ISC size acts as an early fate determinant allowing regional control of intestinal cell differentiation in response to nutrition with relevance to maintenance of tissue integrity during aging.HighlightsmTORC1 signaling regulates ISC size in a region-specific mannermTORC1 signaling is activated in the S and G2 phase of the ISC cell cycleISC size directs differentiation towards absorptive vs. secretory lineageIntermittent fasting mitigates aging induced deregulation of ISC differentiationGRAPHICAL ABSTRACT
Determining The Structure of the Bacterial Voltage-gated Sodium Channel NaChBac Embedded in Liposomes by Cryo Electron Tomography and Subtomogram Averaging
Authors: Chang Shih-Ying Scott , Dijkman Patricia M. , Wiessing Simon A. , Kudryashev Misha 
Published: April 2023

ABSTRACTVoltage-gated sodium channels shape action potentials that propagate signals along cells. When the membrane potential reaches a certain threshold, the channels open and allow sodium ions to flow through the membrane depolarizing it, followed by the deactivation of the channels. Opening and closing of the channels is important for cellular signalling and regulates various physiological processes in muscles, heart and brain. Mechanistic insights into the voltage-gated channels are difficult to achieve as the proteins are typically extracted from membranes for structural analysis which results in the loss of the transmembrane potential. Here, we report the structural analysis of a bacterial voltage-gated sodium channel, NaChBac, reconstituted in liposomes under an electrochemical gradient by cryo electron tomography and subtomogram averaging. We show that the small channel, most of the residues of which are embedded in a membrane, can be localized using a genetically fused GFP. GFP can aid the initial alignment to an average resulting in a correct structure, but does not help for the final refinement. At a moderate resolution of ∼16 Å the structure of NaChBac in an unrestricted membrane bilayer is 10% wider than the structure of a purified protein previously solved in nanodiscs, suggesting the potential movement of the peripheral voltage-sensing domains. Our structural analysis explores the limits of structural analysis of membrane proteins in membranes.HIGHLIGHTSStructural analysis of the bacterial voltage-gated sodium channel NaChBac in lipid vesicles under the resting membrane potential by cryo electron tomography and subtomogram averaging.Fused GFP allows identification of a 120-kDa mostly transmembrane protein in tomograms, and helps for the initial alignment but not for the final refinements.The map of NaChBac in liposomes at a resolution of 16.3 Å is ∼10% wider than the protein structure in a nanodisc.
Class I histone deacetylase complex: structure and functional correlates
Authors: Wang Xiao , Wang Yannan , Liu Simiao , Zhang Yi , Xu Ke , Ji Liting , Kornberg Roger D. , Zhang Heqiao 
Published: April 2023

ABSTRACTSchizosaccharomyces pombeClr6S, a class I histone deacetylase complex, functions as a zinc-dependent enzyme to remove acetyl groups from lysine residues in histone tails. We report here the cryo-EM structures of Clr6S alone and in a complex with a nucleosome. The active center, revealed at near atomic resolution, includes features important for catalysis - a water molecule coordinated by zinc, the likely nucleophile for attack on the acetyl-lysine bond, and a loop that may position the substrate for catalysis. The cryo-EM map in the presence of a nucleosome reveals multiple Clr6S-nucleosome contacts, and a high degree of relative motion of Clr6S and the nucleosome. Such flexibility may be attributed to interaction at a site in the flexible histone tail, and is likely important for function of the deacetylase, which acts at multiple sites in other histone tails.
c-di-AMP determines the hierarchical organization of bacterial RCK proteins
Authors: Rocha Rita , Jorge João M. P. , Texeira-Duarte Celso M. , Figueiredo-Costa Inês R. , Herzberg Christina , Stülke Jörg , Morais-Cabral João H. 
Published: April 2023

AbstractRCK domains or proteins are important regulatory components of cation and K+channels and transporters both in eukaryotic and prokaryotic organisms. A lasting unanswered question about bacterial RCK proteins relates to the physiological role of the multiple, sometimes closely related, RCK genes encoded in the genome. We explored this question with the Ktr channels ofBacillus subtilisthat include two genes encoding RCK proteins (KtrA and KtrC) and two genes encoding their membrane protein partners (KtrB and KtrD). Using a combination ofin vivocharacterization andin vitrofunctional analysis, we determined that the two RCK proteins are neither physiologically redundant or functionally equivalent. Instead, KtrC is the physiologically dominant RCK protein due to its ability to mediate K+transport inactivation by c-di-AMP, a bacterial second messenger that is the master regulator of the K+machinery in many species, while KtrA assembled channels are very insensitive to the dinucleotide. Moreover, KtrC and KtrA can form heteromeric assemblies that can control the Ktr channel activity and are sensitive to c-di-AMP inhibition. In parallel, we showed that conditions with a large number of Ktr channels assembled with KtrA, or with RCK proteins that do not mediate c-di-AMP inhibition, are toxic to the cell. Altogether, we have demonstrated that c-di-AMP regulation of Ktr channels goes beyond affecting transcription and functional activity, it also determines the hierarchical organization of bacterial RCK proteins.
Human V-ATPase a-subunit isoforms bind specifically to distinct phosphoinositide phospholipids
Authors: Mitra Connie , Kane Patricia M. 
Published: April 2023

ABSTRACTV-ATPases are highly conserved multi-subunit enzymes that maintain the distinct pH of eukaryotic organelles. The integral membrane a-subunit is encoded by tissue and organelle specific isoforms, and its cytosolic N-terminal domain (aNT) modulates organelle specific regulation and targeting of V-ATPases. Organelle membranes have specific phosphatidylinositol phosphate (PIP) lipid enrichment linked to maintenance of organelle pH. In yeast, the aNT domains of the two a-subunit isoforms bind PIP lipids enriched in the organelle membranes where they reside; these interactions affect activity and regulatory properties of the V-ATPases containing each isoform. Humans have four a-subunit isoforms. We hypothesize that the aNT domains of the human isoforms will also bind to specific PIP lipids. The a1 and a2 isoforms of human V-ATPase a-subunits are localized to endolysosomes and Golgi, respectively. Bacterially expressed Hua1NT and Hua2NT bind specifically to endolysosomal PIP lipids PI(3)P and PI(3,5)P2 and Golgi enriched PI(4)P, respectively. Despite the lack of canonical PIP binding sites, potential binding sites in the HuaNT domains were identified by sequence comparisons and existing subunit structures and models. Mutations at a similar location in the distal loops of both HuaNT isoforms compromise binding to their cognate PIP lipids, suggesting that these loops encode PIP specificity of the a-subunit isoforms. These data also suggest a mechanism through which PIP lipid binding could stabilize and activate V-ATPases in distinct organelles.
Cell Type Specific CAG Repeat Expansions and Toxicity of Mutant Huntingtin in Human Striatum and Cerebellum
Authors: Mätlik Kert , Baffuto Matthew , Kus Laura , Deshmukh Amit Laxmikant , Davis David A. , Paul Matthew R. , Carroll Thomas S. , Caron Marie-Christine , Masson Jean-Yves , Pearson Christopher E. , Heintz Nathaniel 
Published: April 2023

SUMMARYBrain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington’s disease (HD). However, the relationships between CAG expansions, death of specific cell types, and molecular events associated with these processes are not established. Here we employed fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise in striatal medium spiny neurons (MSNs) and cholinergic interneurons, in cerebellar Purkinje neurons, and atmATXN3in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1 in a concentration-dependent manner. Our data indicate that ongoing CAG expansions are not sufficient for cell death, and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity.
Unveiling the Domain-Specific and RAS Isoform-Specific Details of BRAF Regulation
Authors: Trebino Tarah , Markusic Borna , Nan Haihan , Banerjee Shrhea , Wang Zhihong 
Published: April 2023

AbstractBRAF is a key member in the MAPK signaling pathway essential for cell growth, proliferation, and differentiation. Dysregulation or mutation of BRAF is often the underlying cause of various types of cancer. RAS, a small GTPase protein that acts upstream of BRAF, has been identified as a driver of up to one-third of all cancers. When BRAF interacts with RAS via the RAS binding domain (RBD) and membrane recruitment, BRAF undergoes a conformational change from an inactive, autoinhibited monomer to an active dimer and subsequently phosphorylates MEK to propagate the signal. Despite the central role of BRAF in cellular signaling, the exact order and magnitude of its activation steps has yet to be confirmed experimentally. By studying the inter- and intramolecular interactions of BRAF, we unveil the domain-specific and isoform-specific details of BRAF regulation. We employed pulldown assays, open surface plasmon resonance (OpenSPR), and hydrogen-deuterium exchange mass spectrometry (HDX-MS) to investigate the roles of the regulatory regions in BRAF activation and autoinhibition. Our results demonstrate that the BRAF specific region (BSR) and cysteine rich domain (CRD) play a crucial role in regulating the activity of BRAF. Moreover, we quantified the autoinhibitory binding affinities between the N-terminal domains and the kinase domain (KD) of BRAF and revealed the individual roles of the BRAF regulatory domains. Additionally, our findings provide evidence that the BSR negatively regulates BRAF activation in a RAS isoform-specific manner. Our findings also indicate that oncogenic BRAF-KDD594Gmutant has a lower affinity for the regulatory domains, implicating that pathogenic BRAF acts through decreased propensity for autoinhibition. Collectively, our study provides valuable insights into the activation mechanism of BRAF kinase and may help to guide the development of new therapeutic strategies for cancer treatment.
Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor induced colitis
Authors: van Eijs Mick J.M. , ter Linde José J.M. , Baars Matthijs J.D. , Amini Mojtaba , Laclé Miangela M. , Brand Eelco C. , Delemarre Eveline M. , Drylewicz Julia , Nierkens Stefan , Verheijden Rik J. , Oldenburg Bas , Vercoulen Yvonne , Suijkerbuijk Karijn P.M. , van Wijk Femke 
Published: April 2023

SummaryColitis is a prevalent adverse event associated with immune checkpoint inhibitor (ICI) therapy with similarities to inflammatory bowel disease. Incomplete mechanistic understanding of ICI-colitis curtails evidence-based treatment. Given the often-overlooked connection between tissue architecture and mucosal immune cell function, we here applied imaging mass cytometry (IMC) to gain spatial proteomic insight in ICI-colitis in comparison to ulcerative colitis (UC). Using a cell segmentation pipeline that simultaneously utilizes high-resolution nuclear imaging and high-multiplexity IMC, we show that CD8+T cells are significantly more abundant (and dominant) in anti-PD-1 +/-anti-CTLA-4-induced colitis compared to anti-CTLA-4-induced colitis and UC. We identified activated, cycling CD8+tissue-resident memory T (TRM) cells at the lamina propria-epithelial interface as drivers of cytotoxicity in ICI-colitis and UC. Moreover, we found that combined ICI-induced colitis featured highest granzyme B levels both in tissue and serum. Together, these data reinforce CD8+TRMcells as potentially targetable drivers of ICI-colitis.