bluuebunny/crossref_metadata_2025_split huggingface dataset:
Routine Versus On-Demand Blood Sampling in Critically Ill Patients: A Systematic Review*
Authors: Hjortsø Carl J. S. , Møller Morten H. , Perner Anders , Brøchner Anne C. 
Published: March 2023

OBJECTIVES:
We aimed to provide an overview of the current evidence on routine versus on-demand blood sampling in critical care. We assessed the reported proportion of patients exposed to daily routine blood sampling, the tests performed, characteristics associated with more frequent blood sampling, and the reported benefits and harms of routine blood sampling compared with on-demand sampling.

DATA SOURCES:
We systematically searched the Cochrane Library, the Excerpta Medica Database, and the Medical Literature Analysis and Retrieval System Online for studies assessing routine versus on-demand blood testing in critically ill patients from inception to September 2022.

STUDY SELECTION:
Abstracts and full texts were assessed independently and in duplicate by two reviewers.

STUDY EXTRACTION:
Data were extracted independently and in duplicate by two reviewers using predefined extraction forms.

DATA SYNTHESIS:
Of 12,212 records screened, 298 full-text articles were assessed for eligibility. We included 70 studies; 50 nonrandomized interventional studies and 20 observational studies. Exposure to routine blood testing was 52–100% (very low certainty of evidence). Blood testing seemed to occur more frequently in medical intensive care settings with a median of 18 blood tests per patient day (interquartile range, 10–33) (very low certainty of evidence). Mixed biochemistry seemed to be the most frequently performed blood tests across all settings (five tests per patient day; interquartile range, 2–10) (very low certainty of evidence). Reductions in routine blood testing seemed to be associated with reduced transfusion rates and costs without apparent adverse patient outcomes (low certainty of evidence).

CONCLUSIONS:
In this systematic review, routine blood testing in critically ill patients was common and varied considerably. A reduction in routine blood testing appeared to be associated with reduced transfusion rates and costs without adverse effects, but the evidence was very uncertain.
Statistical modeling and analysis of multiplexed imaging data
Authors: Bost Pierre , Casanova Ruben , Mor Uria , Bodenmiller Bernd 
Published: March 2023

AbstractThe rapid development of multiplexed imaging technologies has enabled the spatial cartography of various healthy and tumor tissues. However, the lack of adequate statistical models has hampered the use of multiplexed imaging to efficiently compare tissue composition across sample groups, for instance between healthy and tumor tissue samples. Here, we developed two statistical models that accurately describe the distribution of cell counts observed in a given field of view in an imaging experiment. The parameters of these distributions are directly linked to the field of view size and also to properties of the studied cell type such as cellular density and spatial aggregation. Using these models, we identified statistical tests that have improved statistical power for differential abundance testing of tissue composition compared to the commonly used rank-based test. Our analysis revealed that spatial aggregation is the main determinant of statistical power and that to have sufficient power to detect differences in cell counts when cells are highly aggregated may require sampling of hundreds of fields of view. To overcome this challenge, we provide a new stratified sampling strategy that might significantly reduce the number of required samples.
Elevated CD153 Expression on Aged T Follicular Helper Cells is Vital for B cell Responses
Authors: Thomas Alyssa L. , Wayman Joseph A. , Almanan Maha , Bejjani Anthony T. , Miraldi Emily R. , Chougnet Claire A. , Hildeman David A. 
Published: March 2023

AbstractOur recent data showed that an aberrant IL-10-producing T follicular helper population (Tfh10) accumulates dramatically with age and is associated with age-related declines in vaccine responsiveness. Through single cell gene expression and chromatin accessibility analysis of IL-10+and IL-10−memory CD4+ T cells from young and aged mice, we identified increased expression of CD153 on aged Tfh and Tfh10 cells. Mechanistically, we linked inflammaging (increased IL-6 levels) to elevated CD153 expression of Tfh cells through c-Maf. Surprisingly, blockade of CD153 in aged mice significantly reduced their vaccine-driven antibody response, which was associated with decreased expression of ICOS on antigen-specific Tfh cells. Combined, these data show that an IL-6/c-Maf/CD153 circuit is critical for maintaining ICOS expression. Thus, although overall Tfh-mediated B cell responses are reduced in the context of vaccines and aging, our data suggest that elevated expression of CD153 on Tfh cells potentiates the remaining Tfh function in aged mice.
Control of meiotic entry by dual inhibition of a key mitotic transcription factor
Authors: Su Amanda J. , Yendluri Siri C. , Ünal Elçin 
Published: March 2023

SUMMARYThe mitosis to meiosis transition requires dynamic changes in gene expression, but whether and how the mitotic transcriptional machinery is regulated during this transition is unknown. In budding yeast, SBF and MBF transcription factors initiate the mitotic gene expression program. Here, we report two mechanisms that work together to restrict SBF activity during meiotic entry: repression of the SBF-specific Swi4 subunit through LUTI-based regulation and inhibition of SBF by Whi5, a functional homolog of the Rb tumor suppressor. We find that untimely SBF activation causes downregulation of early meiotic genes and delays meiotic entry. These defects are largely driven by the SBF-target G1 cyclins, which block the interaction between the central meiotic regulator Ime1 and its cofactor Ume6. Our study provides insight into the role ofSWI4LUTIin establishing the meiotic transcriptional program and demonstrates how the LUTI-based regulation is integrated into a larger regulatory network to ensure timely SBF activity.HIGHLIGHTSSBF subunit Swi4 is downregulated at meiotic entry by the LUTI-based mechanismSWI4LUTIand Whi5 work together to inhibit SBF at meiotic entrySBF and Ime1 TFs antagonize each other, ensuring mutually exclusive cell statesSBF-target G1 cyclins block meiosis by preventing Ime1-Ume6 interaction
Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to control local Peyer’s patch development
Authors: Howley Kelsey , Berthelette Alyssa , Ceglia Simona , Kang Joonsoo , Reboldi Andrea 
Published: March 2023

AbstractLymphoid tissue inducer (LTi) cells develop during intrauterine life and rely on developmental programs to initiate the organogenesis of secondary lymphoid organs (SLOs). This evolutionary conserved process endows the fetus with the ability to orchestrate the immune response after birth and to react to the triggers present in the environment. While it is established that LTi function can be shaped by maternal-derived cues and is critical to prepare the neonate with a functional scaffold to mount immune response, the cellular mechanisms that control anatomically distinct SLO organogenesis remain unclear.We discovered that LTi cells forming Peyer’s patches, gut-specific SLOs, require the coordinated action of two migratory G protein coupled receptors (GPCR) GPR183 and CCR6. These two GPCRs are uniformly expressed on LTi cells across SLOs, but their deficiency specifically impacts Peyer’s patch formation, even when restricted to fetal window. The unique CCR6 ligand is CCL20, while the ligand for GPR183 is the cholesterol metabolite 7α,25-Dihydroxycholesterol (7α,25-HC), whose production is controlled by the enzyme cholesterol 25-hydroxylase (CH25H). We identified a fetal stromal cell subset that expresses CH25H and attracts LTi cells in the nascent Peyer’s patch anlagen. GPR183 ligand concentration can be modulated by the cholesterol content in the maternal diet and impacts LTi cell maturation in vitro and in vivo, highlighting a link between maternal nutrients and intestinal SLO organogenesis.Our findings revealed that in the fetal intestine, cholesterol metabolite sensing by GPR183 in LTi cells for Peyer’s patch formation is dominant in the duodenum, the site of cholesterol absorption in the adult. This anatomic requirement suggests that embryonic, long-lived non-hematopoietic cells might exploit adult metabolic functions to ensure highly specialized SLO development in utero.
Efficacy of neurofeedback training for improving attentional performance in healthy adults: A systematic review and meta-analysis
Authors: Kimura Ikko , Noyama Hiroki , Onagawa Ryoji , Takemi Mitsuaki , Osu Rieko , Kawahara Jun-ichiro 
Published: March 2023

AbstractThis systematic review and meta-analysis examined the NFT effects on attentional performance in healthy adults. Six databases were searched until June 2022 to identify parallel randomized controlled trials (RCTs) evaluating attentional improvements after NFT. Risk of bias was assessed using the Cochrane Collaboration tool. We identified 41 RCTs for qualitative synthesis and 15 RCTs (569 participants) for meta-analysis. The overall NFT effect on attentional performance was significant (standardized mean difference = 0.27, 95% confidence interval = 0.10–0.44). However, no significant pooled effect was found within the trials comparing its effect with sham NFT (8 RCTs). Additionally, variable effects were observed on individual subsets of attentional performance. Further sham-controlled RCTs are required to validate the improvement of attentional performance with NFT.
BRCA1secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance
Authors: Nesic Ksenija , Krais John J. , Vandenberg Cassandra J. , Wang Yifan , Patel Pooja , Cai Kathy Q. , Kwan Tanya , Lieschke Elizabeth , Ho Gwo-Yaw , Barker Holly E. , Bedo Justin , Casadei Silvia , Farrell Andrew , Radke Marc , Shield-Artin Kristy , Penington Jocelyn S. , Geissler Franziska , Kyran Elizabeth , Zhang Fan , Dobrovic Alexander , Olesen Inger , Kristeleit Rebecca , Oza Amit , Ratnayake Gayanie , Traficante Nadia ,   Australian Ovarian Cancer Study, DeFazio Anna , Bowtell David D. L. , Harding Thomas C. , Lin Kevin , Swisher Elizabeth M. , Kondrashova Olga , Scott Clare L. , Johnson Neil , Wakefield Matthew J. 
Published: March 2023

AbstractBRCA1splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out the mutation-containing exon, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers ofBRCA1exon skipping remain undetermined.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) withBRCA1exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi.BRCA1exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondaryBRCA1splice site mutations (SSMs), predictedin silicoto drive exon skipping. Predictions were confirmed using qRT-PCR, RNA sequencing, western blots andBRCA1minigene modelling. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.We demonstrate that SSMs driveBRCA1exon 11 skipping and PARPi resistance, and should be clinically monitored, along with frame-restoring secondary mutations.Statement of significanceFew PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene’s reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression ofBRCA1hypomorphs, which in turn promote PARPi resistance.
Distinct Transcriptomic Responses to Aβ plaques, Neurofibrillary Tangles, andAPOEin Alzheimer’s Disease
Authors: Das Sudeshna , Li Zhaozhi , Wachter Astrid , Alla Srinija , Noori Ayush , Abdourahman Aicha , Tamm Joseph A. , Woodbury Maya E. , Talanian Robert V. , Biber Knut , Karran Eric H. , Hyman Bradley T. , Serrano-Pozo Alberto 
Published: March 2023

ABSTRACTINTRODUCTIONOmics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer’s disease (AD) but the spatial relationships with plaques and tangles andAPOE-linked differences remain unclear.METHODSWe performed laser capture microdissection of Aβ plaques, the 50μm halo around them, tangles with the 50μm halo around them, and areas distant (>50μm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing.RESULTSAβ plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Aβ plaques had more differentially expressed genes than tangles. We identified a gradient Aβ plaque>peri-plaque>tangle>distant for these changes. ADAPOEε4 homozygotes had greater changes thanAPOEε3 across locations, especially within Aβ plaques.DISCUSSIONTranscriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Aβ plaques, and are exacerbated by theAPOEε4 allele.
Semi-rational evolution of a recombinant DNA polymerase for modified nucleotide incorporation efficiency
Authors: Zhai Lili , Wang Zi , Liu Fen , Xu Chongjun , Wang Jingjing , Han Hongyan , Xie Qingqing , Zhang Wenwei , Zheng Yue , Buell Alexander K. , Dong Yuliang 
Published: March 2023

AbstractEngineering improved B-family DNA polymerases to incorporate 3′-O-modified nucleotide reversible terminators is limited by an insufficient understanding of the structural determinants that define polymerization efficiency. To explore the key mechanism for unnatural nucleotide incorporation, we engineered a B-family DNA polymerase fromThermococcus Kodakaraenis(KOD pol) by using semi-rational design strategies. We first scanned the active pocket of KOD pol through site-directed saturation mutagenesis and combinatorial mutations and identified a variant Mut_C2 containing five mutation sites (D141A, E143A, L408I, Y409A, A485E) using a high-throughput microwell-based screening method. Mut_C2 demonstrated high catalytic efficiency in incorporating 3’-O-azidomethyl-dATP labeled with a Cy3 dye, whereas the wild-type KOD pol failed to incorporate it. Computational simulations were then conducted towards the DNA binding region of KOD pol to predict additional mutations with enhanced catalytic activity, which were subsequently experimentally verified. By a stepwise combinatorial mutagenesis approach, we obtained an eleven-mutation variant, named Mut_E10 by introducing additional mutations to the Mut_C2 variant. Mut_E10, which carried six specific mutations (S383T, Y384F, V389I, V589H, T676K, and V680M) within the DNA-binding region, demonstrated over 20-fold improvement in kinetic efficiency as compared to Mut_C2. In addition, Mut_E10 demonstrated satisfactory performance in two different sequencing platforms (BGISEQ-500 and MGISEQ-2000), indicating its potential for commercialization. Our study demonstrates that an effective enhancement in its catalytic efficiency towards modified nucleotides can be achieved efficiently through combinatorial mutagenesis of residues in the active site and DNA binding region of DNA polymerase. These findings contribute to a comprehensive understanding of the mechanisms that underlie the incorporation of modified nucleotides by DNA polymerase. The beneficial mutation sites, as well as the nucleotide incorporation mechanism identified in this study, can provide valuable guidance for the engineering of other B-family DNA polymerases.
The central renin angiotensin II system – a genetic pathway, functional decoding and selective target engagement characterization in humans
Authors: Xu Ting , Chen Zhiyi , Zhou Xinqi , Wang Lan , Zhou Feng , Yao Dezhong , Zhou Bo , Becker Benjamin 
Published: March 2023

AbstractThe brain renin angiotensin II system plays a pivotal role in cognition and neuropathology via the central angiotensin II type 1 receptor (AT1R), yet the lack of a biologically informed framework currently impedes translational and therapeutic progress. We combined imaging transcriptomic and meta-analyses with pharmaco-resting state fMRI employing a selective AT1R antagonist in a discovery-replication design (n=132 individuals). The AT1R was densely expressed in subcortical systems engaged in reward, motivation, stress, and memory. Pharmacological target engagement suppressed spontaneous neural activity in subcortical systems with high AT1R expression and enhanced functional network integration in cortico-basal ganglia-thalamo-cortical circuits. AT1R-regulation on functional network integration was further mediated by dopaminergic, opioid and corticotrophin-releasing hormone pathways. Overall, this work provides the first comprehensive characterization of the architecture and function of the brain renin angiotensin II system indicating that the central AT1R-mediates human cognition and behavior via regulating specific circuits and interacting with classical transmitter systems.
The importance of cellulolytic and xylanolytic activities ofBacillus subtilison dairy cow feed digestibility
Authors: Bontà Valeria , Battelli Marco , Rama Erlinda , Casanova Michela , Pasotti Lorenzo , Galassi Gianluca , Colombini Stefania , Calvio Cinzia 
Published: March 2023

AbstractA large body of literature has accumulated on the beneficial impact of the administration ofBacillito dairy cows, particularly on dry matter intake, lactation performances and milk composition. In this work we sought to establish whether the ability ofB. subtilisto secrete cellulase and xylanase enzymes could be involved in the positive effect exerted by these bacteria.Several feed ingredients were treated with twoB. subtilisstrains only differing for the amount of secreted cellulosolytic and xylanolytic enzymes, and feed quality was assessed. We found thatin vitrofibre digestibility correlated with the activity of those enzymes. Our results revealed thatB. subtiliscellulases and xylanases can effectively improve forage quality, providing a scientific rationale on the use ofBacillias forage supplements to improve animal productivity. Moreover, a particular care was taken in designing a sustainable and economically viableBacillus-based additive preparation process.
Activity-based tyrosine phosphatomics using F2Pmp probes
Authors: Niinae Tomoya , Ishihama Yasushi 
Published: March 2023

ABSTRACTWe showed that the F2Pmp probe binds to PTP in a sequence-dependent manner. In addition, this study is the first successful example of comprehensive enrichment of classical PTP at the protein level. Furthermore, we found that F2Pmp probe can enrich PTPs in a PTP activity dependent manner. Using the F2Pmp probe, the fluctuation of PTPN1 and PTPN2 activities were revealed. This enrichment approach using the F2Pmp probe could be a generic tool for activity-based tyrosine phosphatomics.
Kinome screening identifies integrated stress response kinase EIF2AK1 / HRI as a negative regulator of PINK1 mitophagy signaling
Authors: Singh Pawan K. , Agarwal Shalini , Volpi Ilaria , Wilhelm Léa P. , Becchi Giada , Keenlyside Andrew , Macartney Thomas , Toth Rachel , Rousseau Adrien , Masson Glenn R. , Ganley Ian G. , Muqit Miratul M. K. 
Published: March 2023

ABSTRACTLoss-of-function mutations of the PINK1 kinase cause familial early-onset Parkinson’s disease (PD). PINK1 is activated upon mitochondrial damage to phosphorylate Ubiquitin and Parkin to trigger removal of damaged mitochondria by autophagy (mitophagy). PINK1 also indirectly phosphorylates a subset of Rab GTPases including Rab8A. We have performed an siRNA screen targeting all human Ser/Thr kinases in HeLa cells and discovered that knockdown of the eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1), also known as heme-regulated inhibitor (HRI) kinase, a branch of the integrated stress response (ISR), selectively enhances mitochondrial depolarization-induced stabilization of PINK1 and increased phosphorylation of ubiquitin and Rab8A. We confirm our findings in multiple human cell lines, including SK-OV-3, U2OS and ARPE-19 cells. Knockdown of the upstream mitochondrial-cytosol relay component, DELE1, enhanced PINK1 stabilisation and activation similar to EIF2AK1 knockdown. Strikingly, we demonstrate that the small molecule ISR inhibitor, ISRIB, also enhances PINK1 activation and signaling under conditions of mitochondrial damage. Using themito-QC mitophagy reporter in human cells, we observe that EIF2AK1 knockdown or ISRIB treatment significantly enhances PINK1-dependent mitophagy but does not alter deferiprone-induced mitophagy. Our findings indicate that the DELE1-EIF2AK1 ISR signaling relay is a negative regulator of PINK1-dependent mitophagy and suggest that inhibitors of DELE1-EIF2AK1 and/or ISRIB analogues could have therapeutic benefits in PD and related disorders.
First insights into nasal microbiome in wine tasters
Authors: Duarte-Coimbra Sofia , Forcina Giovanni , Pérez-Pardal Lucía , Beja-Pereira Albano 
Published: March 2023

AbstractOver the last decades, the study of the microbiome has been receiving increasing attention as a major driver of individual health and wellbeing. The accumulation of knowledge on microbiomes sparked new research lines, from which the association between oral microbiome composition and taste perception is of great interest. Taste plays a paramount role in food and beverage choice as well as emotions. For wine tasters, the smell is also part of the tasting evaluation. However, the nasal microbiome is relatively unexplored. The relation between the microorganisms residing in the nostrils is still poorly known despite their leading role in flavor perception. Therefore, characterizing the composition of nasal microbiomes represents a fundamental prerequisite to elucidate their relationship with taste. To improve our understanding of the relationship between taste and the microorganism inhabiting the nostrils, the nasal microbiome of 5 wine tasters versus 5 non-tasters was analyzed through the sequencing of the V3-V4 region of the16S rRNAgene. The taxonomic composition of these nasal microbiomes was characterized, and the comparison of diversity indexes revealed no significant differences. However, the experimental group showed a lower number of identified taxa (171) when compared to the control group (287). Another interesting result was the higher presence of Krebs Cycle pathways in wine tasters, which could indicate the importance of the nostril bacterial community in alcohol oxidation. Regarding smoking habits, smokers presented a lower microbiome diversity. These preliminary results should be confirmed in a larger sample dataset of wine tasters and controls.