bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Decontamination of the Digestive Tract in Invasively Ventilated Patients in an Intensive Care Unit: A protocol for a Systematic Review and Meta-Analysis
Authors: Hammond Naomi E , Myburgh John , Di Tanna Gian Luca , Garside Tessa , Vlok Ruan , Mahendran Sajeev , Adigbli Derick , Finfer Simon , Goodman Fiona , Guyatt Gordon , Venkatesh Balasubramanian , Seppelt Ian , Delaney Anthony 
Published: March 2022

AbstractIntroductionThe use of Selective Decontamination of the Digestive Tract (SDD) as a preventative infection-control strategy in invasively ventilated patients in the intensive care unit (ICU) remains low despite numerous randomised controlled trials (RCTs) consistently reporting reductions in interval mortality rates and shorter durations of mechanical ventilation. The Selective Decontamination of the Digestive Tract in the Intensive Care Unit (SuDDICU) cluster cross-over RCT, that includes over 5500 participants randomised to receive a standardised commercial grade SDD interventions or standard care, will be reported in 2022 and will add substantive weight to previous RCT data assessing the effect of SDD on interval mortality compared to standard care. We will conduct an updated systematic review and prospective aggregate data meta-analysis of previous conducted and published RCTs, developed using a protocol and statistical analysis plan completed prior to the completion of the SuDDICU RCT and including the SuDDICU data to present the most current evidence available to guide clinical practice.Methods and analysisWe will include RCTs that compare the effect on hospital mortality and other patient-centred outcomes of treatment with SDD compared to standard care in invasively ventilated adults in the ICU. We will perform a search that includes the electronic databases MEDLINE and EMBASE and clinical trial registries. Two reviewers will independently screen titles and abstracts, perform full article reviews and extract study data, with discrepancies resolved by a third reviewer. We will report study characteristics and quantify risk of bias. We will perform random effects Bayesian meta-analyses to provide pooled estimates that SDD improves outcomes, whenever it is feasible to do so. We will evaluate overall certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation framework.ConclusionThis updated systematic review and prospective meta-analysis will provide clinicians with an expedited assessment of the totality of current evidence about the effect on mortality of using SDD in mechanically ventilated ICU patients.
Studies of a siderophore-producing cyclization domain: A refined proposal of substrate binding
Authors: Gnann Andrew D. , Xia Yuan , Soule Jess , Barthélemy Clara , Mawani Jayata , Musoke Sarah Nzikoba , Castellano Brian , Brignole Edward , Frueh Dominique , Dowling Daniel P. 
Published: March 2022

AbstractNonribosomal peptide synthetase (NRPS) heterocyclization (Cy) domains generate biologically important ox-/thiazoline modifications in natural products, including in production of compounds targeting disease or siderophores that are important for bacterial pathogenicity. Cy domains share the NRPS condensation domain fold but catalyze consecutive condensation and cyclodehydration reactions via an unknown mechanism. To further understanding of Cy domain catalysis, we report the crystal structure of the second Cy domain (Cy2) of yersiniabactin synthetase from the causative agent of the plague, Yersinia pestis. We find the high-resolution structure of Cy2 adopts a conformation enabling exploration of binding the extended, thiazoline-containing cyclodehydration intermediate for catalysis and the acceptor carrier protein to which it is tethered. We also report complementary electrostatic interfaces between Cy2 and its donor carrier protein that mediate donor binding. Lastly, we explore domain flexibility through the normal mode approximation and identify small-molecule fragment binding sites to inform antibiotic design targeting Cy function. Our results suggest how carrier protein binding may influence global conformation, with consequences for active site catalytic states and inhibitor development.
Efficient compartmentalization in insect bacteriomes protects symbiotic bacteria from host immune system
Authors: Ferrarini Mariana Galvão , Dell’Aglio Elisa , Vallier Agnès , Balmand Séverine , Vincent-Monégat Carole , Hughes Sandrine , Gillet Benjamin , Parisot Nicolas , Zaidman-Rémy Anna , Vieira Cristina , Heddi Abdelaziz , Rebollo Rita 
Published: March 2022

AbstractBackgroundMany insects house symbiotic intracellular bacteria (endosymbionts) that provide them with essential nutrients, thus promoting usage of nutrient-poor habitats. Endosymbiont seclusion within host specialized cells, called bacteriocytes, often organized in a dedicated organ, the bacteriome, is crucial in protecting them from host immune defenses while avoiding chronic host immune activation. Previous evidence obtained in the cereal weevil Sitophilus oryzae has shown that bacteriome immunity is activated against invading pathogens, suggesting endosymbionts might be targeted and impacted by immune effectors during an immune challenge. To pinpoint any molecular determinants associated with such challenges, we conducted a dual transcriptomic analysis of S. oryzae’s bacteriome subjected to immunogenic peptidoglycan fragments.ResultsWe show that upon immune challenge the bacteriome actively participates in the innate immune response via an induction of antimicrobial peptides (AMPs). Surprisingly, endosymbionts do not undergo any transcriptomic changes, indicating that this potential threat goes unnoticed. Immunohistochemistry showed that TCT-induced AMPs are located outside the bacteriome, excluding direct contact with the endosymbionts.ConclusionsThis work demonstrates that endosymbiont protection during an immune challenge is mainly achieved by efficient confinement within bacteriomes, which provides physical separation between host systemic response and endosymbionts.
Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries
Authors: Carbery Anna , Skyner Rachael , von Delft Frank , Deane Charlotte M. 
Published: March 2022

AbstractCurrent fragment-based drug design relies on the efficient exploration of chemical space though the use of structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the same interactions on a target, and thus be functionally similar. Using 3D structures of many fragments bound to multiple targets, we examined if there exists a better strategy for selecting fragments for screening libraries. We show that structurally diverse fragments can be described as functionally redundant, often making the same interactions. Ranking fragments by the number of novel interactions they made, we show that functionally diverse selections of fragments substantially increase the amount of information recovered for unseen targets compared to other methods of selection. Using these results, we design small functionally efficient libraries that are able to give significantly more information about new protein targets than similarly sized structurally diverse libraries. By covering more functional space (rather than chemical space), more diverse sets of drug leads can be generated, increasing the chances of fragment screens resulting in viable drug candidates.
A deep learning classification task for brain navigation during functional ultrasound imaging
Authors: Lambert Théo , Brunner Clément , Kil Dries , Wuyts Roel , D’Hondt Ellie , Montaldo Gabriel , Urban Alan 
Published: March 2022

AbstractPositioning and navigation are essential components of neuroimaging as they improve the quality and reliability of data acquisition, leading to advances in diagnosis, treatment outcomes, and fundamental understanding of the brain. Functional ultrasound (fUS) imaging is an emerging technology providing high-resolution images of the brain vasculature, allowing for the monitoring of brain activity. However, as the technology is relatively new, there is no standardized tool for inferring the position in the brain from the vascular images. This study presents a deep learning-based framework designed to address this challenge. Our approach uses an image classification task coupled with a regression on the resulting probabilities to determine the position of a single image. We conducted experiments using a dataset of 51 rat brain scans to evaluate its performance. The training positions were extracted at intervals of 375 µm, resulting in a positioning error of 176 µm. Further GradCAM analysis revealed that the predictions were primarily driven by subcortical vascular structures. Finally, we assessed the robustness of our method in a cortical stroke where the brain vasculature is severely impaired. Remarkably, no specific increase in the number of misclassifications was observed, confirming the method’s reliability in challenging conditions. Overall, our framework provides accurate and flexible positioning, not relying on a pre-registered reference but on conserved vascular patterns.
Integrated single-cell and spatial transcriptomic analyses unravel the heterogeneity of the prostate tumor microenvironment
Authors: Hirz Taghreed , Mei Shenglin , Sarkar Hirak , Kfoury Youmna , Wu Shulin , Verhoeven Bronte M. , Subtelny Alexander O. , Zlatev Dimitar V. , Wszolek Matthew W. , Salari Keyan , Murray Evan , Chen Fei , Macosko Evan Z. , Wu Chin-Lee , Scadden David T. , Dahl Douglas M. , Baryawno Ninib , Saylor Philip J. , Kharchenko Peter V. , Sykes David B. 
Published: March 2022

SummaryThe treatment of primary prostate cancer delicately balances an active surveillance approach for low-risk disease with multimodal treatment including surgery, radiation therapy, and hormonal therapy for high-risk disease. Recurrence and development of metastatic disease remains a clinical problem, without a clear understanding of what drives immune escape and tumor progression. Here, we sought to comprehensively describe the tumor microenvironment of localized prostate cancer contrasting this with adjacent normal samples and healthy controls. We performed single-cell RNA sequencing and high-resolution spatial transcriptomic analysis. This revealed tumor context dependent changes in gene expression. Our data point towards an immune suppressive tumor microenvironment associated with suppressive myeloid populations and exhausted T-cells, in addition to high stromal angiogenic activity. We inferred cell-to-cell relationships at an unprecedented scale for ligand-receptor interactions within undissociated tissue sections. Our work provides a highly detailed and comprehensive resource of the prostate tumor microenvironment as well as tumor-stromal cell interactions.HighlightsCharacterization of prostate cancer by combined scRNA-seq and spatial transcriptomic analysisPrimary prostate cancer establishes a suppressive immune microenvironmentThe prostate tumor microenvironment exhibits a high angiogenic gene expression patternA new computational analysis pipeline to deconvolute context-specific differential gene expression
Mapping the Cell-Membrane Proteome to the Cancer Hallmarks
Authors: Lazar Iulia M. , Karcini Arba , Haueis Joshua R. S. 
Published: March 2022

AbstractThe hallmarks of biological processes that underlie the development of cancer have been long recognized, yet, existing therapeutic treatments cannot prevent cancer from continuing to be one of the leading causes of death worldwide. This work was aimed at exploring the extent to which the cell-membrane proteins are implicated in triggering cancer hallmark processes, and assessing the ability to pinpoint novel therapeutic targets through a combined membrane proteome/cancer hallmark perspective. By using GO annotations, a database of human proteins associated broadly with ten cancer hallmarks was created. Cell-membrane cellular subfractions of SKBR3/HER2+ breast cancer cells used as a model system were analyzed by high resolution mass spectrometry, and high-quality proteins (FDR<3 %) identified by at least two unique peptides were mapped to the cancer hallmark database. Over 1100 experimentally detected cell-membrane or cell-membrane associated proteins, representing ~8 % of the human cell-membrane proteome, were mapped to the hallmark database. Representative membrane constituents such as receptors, CDs, adhesion and transport proteins were distributed over the entire genome and present in every hallmark category. Sustained proliferative signaling/cell cycle, adhesion/tissue invasion, and evasion of immune destruction emerged as prevalent hallmarks represented by the membrane proteins. Construction of protein-protein interaction networks uncovered a high level of connectivity between the hallmark members, with some receptor (EGFR, ERBB2, FGFR, MTOR, CSF1R), antigen (CD44), and adhesion (MUC1) proteins being implicated in most hallmark categories. An illustrative subset of 116 hallmark proteins that included 44 oncogenes, 28 tumor suppressors, and 38 approved drug targets was subjected to a more in-depth analysis. The existing drug targets were implicated mainly in signaling processes. Network centrality analysis revealed that nodes with high degree, rather than betweenness, represent a good resource for informing the selection of putative novel drug targets. Through heavy involvement in supporting cancer hallmark processes, we show that the functionally diverse and networked landscape of cancer cell-membrane proteins fosters unique opportunities for guiding the development of novel therapeutic interventions, including multi-agent, immuno-oncology and precision medicine applications.
Disrupting the plastid-hosted iron-sulfur cluster biogenesis pathway in Toxoplasma gondii has pleiotropic effects irreversibly impacting parasite viability
Authors: Renaud Eléa A. , Pamukcu Sarah , Cerutti Aude , Berry Laurence , Lemaire-Vieille Catherine , Yamaryo-Botté Yoshiki , Botté Cyrille Y. , Besteiro Sébastien 
Published: March 2022

AbstractLike many other apicomplexan parasites, Toxoplasma gondii contains a plastid harbouring key metabolic pathways, including the SUF pathway that is involved in the biosynthesis of iron-sulfur clusters. These cofactors are key for a variety of proteins involved in important metabolic reactions, potentially including plastidic pathways for the synthesis of isoprenoid and fatty acids. It was shown previously that impairing the NFS2 cysteine desulfurase, involved in the first step of the SUF pathway, leads to an irreversible killing of intracellular parasites. However, the metabolic impact of disrupting the pathway remained unexplored. We have generated another mutant of the pathway, deficient for the SUFC ATPase, and we have investigated in details the phenotypic consequences of TgNFS2 and TgSUFC depletion on parasite homeostasis. Our analysis confirms that Toxoplasma SUF mutants are severely and irreversibly impacted in growth: cell division and membrane homeostasis are particularly affected. Lipidomic analysis suggests a defect in apicoplast-generated fatty acids, along with a simultaneous increase in scavenging of host-derived lipids. However, addition of exogenous lipids did not allow full restauration of growth, suggesting other more important cellular functions were impacted in addition to fatty acid synthesis. For instance, we have shown that the SUF pathway is also key for generating isoprenoid-derived precursors necessary for the proper targeting of GPI-anchored proteins as well as for the parasite gliding motility. Thus, plastid-generated iron-sulfur clusters support the functions of proteins involved in several vital downstream cellular pathways, which implies the SUF machinery may be explored for discovering new potential anti-Toxoplasma targets.
Drivers of nematode diversity in forest soils across climatic zones
Authors: Shao Yuanhu , Wang Zuyan , Liu Tao , Kardol Paul , Ma Chengen , Hu Yonghong , Cui Yang , Zhao Cancan , Zhang Weixin , Guo Dali , Fu Shenglei 
Published: March 2022

AbstractNematodes are the most abundant multi-cellular animals in soil, influencing key processes and functions in terrestrial ecosystems. Yet, little is known about the drivers of nematode abundance and diversity in forest soils across climatic zones. This is despite forests cover approximately 30% of the earth’s land surface, provide many crucial ecosystem services but strongly vary in hydrothermal conditions and associated ecosystem properties across climatic zones.Here, we collected nematode samples from 13 forests across a latitudinal gradient. We divided this gradient in temperate, warm-temperate, and tropical climatic zones. Using boosted regression trees, we showed that across the gradient, nematode abundance and diversity were mainly influenced by soil organic carbon. However, within climatic zones, other factors were more important in driving nematode alpha-diversity, nematode biomass and the abundance of different trophic groups: mean annual temperature and total soil phosphorus in temperate zones, soil pH in warm-temperate zones, and mean annual precipitation in tropical zones. Additionally, nematode beta-diversity was higher in temperate than in warm-temperate and tropical zones, and we did not find significant differences among climatic zones in nematode gamma diversity.Together, our findings indicate a latitudinal shift in the main climatic variables controlling soil nematode communities and demonstrate that the drivers of soil nematode diversity in forested ecosystems are affected by the spatial scale and climatic conditions considered. This implies that high resolution studies are needed to accurately predict how soil functions respond if climate conditions move beyond the coping range of soil organisms. Our results also emphasize the importance of studying the area-diversity relationship of soil organisms under different climatic conditions.
VolumesJ: A new method and tool for volumetric estimation of brain structures after serial sectioning
Authors: Ferreiro Elisabete , Rodríguez-Iglesias Noelia , Cardoso João , Valero Jorge 
Published: March 2022

AbstractVolume estimations are crucial for many neuroscience studies, allowing the evaluation of changes in the size of brain areas that may have relevant functional consequences. Classical histological methods and modern human brain imaging techniques rely on obtaining physical or digital sections, with a known thickness, of the organ to be analyzed. This “slicing” strategy is associated with an ineludible loss of information about the three-dimensional organization of the analyzed structures, especially affecting the precision of volumetric measurements. To overcome this problem, several methods have been developed. One of the most commonly used approaches for volume estimation is the classical Cavalieri’s method.Within this book chapter, we provide first an overview of Cavalieri’s method and propose a new one, named the Truncated Cone Shape (TCS) method, for the estimation of volumes from tissue sections. Second, we compare the accuracy of both methods using computer-generated objects of different shapes and sizes. We conclude that, more frequently, the TCS method provides a better estimate of real volumes than Cavalieri’s method. And third, we describe a protocol to estimate volumes using a self-developed and freely available tool for ImageJ: VolumestJ (https://github.com/Jorvalgl/VolumestJ). This new tool helps to implement both Cavalieri’s and TCS methods using digital images of tissue sections. We consider that VolumestJ will facilitate the labor of researchers interested in volume estimations.
Dependence on a variable residue limits the breadth of an HIV MPER neutralizing antibody, despite convergent evolution with broadly neutralizing antibodies
Authors: Scheepers Cathrine , Kgagudi Prudence , Mzindle Nonkululeko , Gray Elin S. , Moyo-Gwete Thandeka , Lambson Bronwen E. , Oosthuysen Brent , Mabvakure Batsirai , Garrett Nigel J. , Abdool Karim Salim S. , Morris Lynn , Moore Penny L. 
Published: March 2022

ABSTRACTBroadly neutralizing antibodies (bNAbs) that target the membrane-proximal external region (MPER) of HIV gp41 envelope, such as 4E10 and VRC42.01, can neutralize >95% of viruses. These two MPER-directed monoclonal antibodies share germline antibody genes (IGHV1-69 and IGKV3-20) and form a bNAb epitope class. Furthermore, convergent evolution within these two lineages towards a 111.2GW111.3 motif in the CDRH3 is known to enhance neutralization potency. We have previously isolated an MPER neutralizing antibody, CAP206-CH12, that uses these same germline heavy and light chain genes but lacks breadth (neutralizing only 6% of heterologous viruses). Longitudinal sequencing of the CAP206-CH12 lineage over three years revealed similar convergent evolution towards 111.2GW111.3 among some lineage members. Mutagenesis of CAP206-CH12 from 111.2GL111.3 to 111.2GW111.3 modestly improved neutralization breadth (by 9%) and potency (3-fold), but did not reach the levels of breadth and potency of VRC42.01 and 4E10. To explore the lack of potency/breadth, viral mutagenesis was performed to map the CAP206-CH12 epitope. This indicated that CAP206-CH12 is dependent on D674, a highly variable residue at the solvent-exposed elbow of MPER. In contrast, VRC42.01 and 4E10 were dependent on highly conserved residues (W672, F673, T676, and W680) facing the hydrophobic patch of the MPER. Therefore, while CAP206-CH12, VRC42.01, and 4E10 share germline genes and show some evidence of convergent evolution, their dependence on different amino acids, which impacts orientation of binding to the MPER, result in differences in breadth and potency. These data have implications for the design of HIV vaccines directed at the MPER epitope.Author SummaryGermline-targeting immunogens are a promising HIV vaccine design strategy. This approach is reliant on the identification of broadly neutralizing antibody (bNAb) classes, which use the same germline antibody genes to target the same viral epitopes. Here, we compare three HIV Envelope MPER-directed antibodies (4E10, VRC42.01 and CAP206-CH12) that despite having shared antibody genes, show distinct neutralization profiles. We show that CAP206-CH12 targets a single highly variable residue in the MPER, which results in low neutralization breadth. In contrast, the 4E10 and VRC42.01 mAbs are dependent on highly conserved residues in the MPER, resulting in exceptional neutralization breadth. Our data suggest that while shared germline genes within bNAb epitope classes are required, in some cases these are not sufficient to produce neutralization breadth, and MPER immunogens will need to trigger responses to conserved sites.