bluuebunny/crossref_metadata_2025_split huggingface dataset:
The nucleoid protein HU positively regulates the expression of type VI secretion systems in
Enterobacter cloacae
Authors: Hernández-Martínez Gabriela , Ares Miguel A. , Rosales-Reyes Roberto , Soria-Bustos Jorge , Yañez-Santos Jorge Antonio , Cedillo María L. , Girón Jorge A. , Martínez-Laguna Ygnacio , Leng Fenfei , Ibarra J. Antonio , De la Cruz Miguel A. 
Published: April 2024

ABSTRACT

Enterobacter cloacae
is an emerging pathogen isolated in healthcare-associated infections. A major virulence factor of this bacterium is the type VI secretion system (T6SS). The genome of
E. cloacae
harbors two T6SS gene clusters (T6SS-1 and T6SS-2), and the functional characterization of both systems showed that these two T6SSs are not expressed under the same conditions. Here, we report that the major histone-like protein HU positively regulates the expression of both T6SSs and, therefore, the function that each T6SS exerts in
E. cloacae
. Single deletions of the genes encoding the HU subunits (
hupA
and
hupB
) decreased mRNA levels of both T6SS. In contrast, the
hupA hupB
double mutant dramatically affected the T6SS expression, diminishing its transcription. The direct binding of HU to the promoter regions of T6SS-1 and T6SS-2 was confirmed by electrophoretic mobility shift assay. In addition, single and double mutations in the
hup
genes affected the ability of inter-bacterial killing, biofilm formation, adherence to epithelial cells, and intestinal colonization, but these phenotypes were restored when such mutants were
trans
-complemented. Our data broaden our understanding of the regulation of HU-mediated T6SS in these pathogenic bacteria.

IMPORTANCE

T6SS is a nanomachine that functions as a weapon of bacterial destruction crucial for successful colonization in a specific niche.
Enterobacter cloacae
expresses two T6SSs required for bacterial competition, adherence, biofilm formation, and intestinal colonization. Expression of T6SS genes in pathogenic bacteria is controlled by multiple regulatory systems, including two-component systems, global regulators, and nucleoid proteins. Here, we reported that the HU nucleoid protein directly activates both T6SSs in
E. cloacae
, affecting the T6SS-related phenotypes. Our data describe HU as a new regulator involved in the transcriptional regulation of T6SS and its impact on
E. cloacae
pathogenesis.
Neoarchean and Paleoproterozoic magmatism in the Longjiang area, NE China: Implications for the recycling history of supracrustal components in the eastern Central Asian Orogenic Belt
Authors: Sun Chenyang , Xu Wenliang , Zhao Guochun , Zhang Xiaoming , Li Yu , Tang Jie 
Published: April 2024

Abstract
Substantial Phanerozoic crustal growth and reworking in the eastern Central Asian Orogenic Belt has partly obscured the Precambrian geological record. Accurate identification of such Precambrian magmatism and its petrogenesis is paramount to unveiling the early crustal evolution of the eastern Central Asian Orogenic Belt. Two outcrops of Neoarchean and Paleoproterozoic magmatism in the Longjiang area of NE China, eastern Central Asian Orogenic Belt, were recently discovered. The Kaoquantun outcrop consists of monzogranites that yield a zircon 207Pb/206Pb age of 2568 ± 8 Ma and are similar to peraluminous A1-type granites. They were derived from the partial melting of a hybrid crustal source comprising newly accreted Mesoarchean crust and abundant supracrustal metapelites in a post-collisional extensional setting. Such metapelites were initially part of the upper crust but were buried in the middle–lower crust due to crustal thickening prior to ca. 2.6 Ga. In the Zhanbeitun outcrop, basaltic andesites overlie monzogranites, and both have been intruded by syenogranites. The monzogranites and syenogranites yield zircon 207Pb/206Pb ages of 1881 ± 10 Ma and 1843 ± 3 Ma, respectively, whereas the basaltic andesites are inferred to have formed at 1.88–1.84 Ga. The 1.88 Ga monzogranites have relatively enriched zircon Hf-O isotopic compositions and were derived from a hybrid melt of mafic rocks in the lower crust and ancient metabasalts that had undergone low-temperature alteration at supracrustal depths. The 1.88–1.84 Ga basaltic andesites are Nb-rich and were generated by the partial melting of a mantle wedge that was metasomatized by subduction-derived fluids, recycled sediments, and slab-derived melts. The 1.84 Ga syenogranites are peraluminous and K-rich, and record a profound mixing and assimilation process involving melts derived from supracrustal sediments and the lower crust. Three stages of Paleoproterozoic magmatism emerged from subduction-related crustal thickening, slab breakoff, and collision, respectively. The zircon Hf isotopic data further indicate that the eastern Central Asian Orogenic Belt underwent at least one stage of proto-crustal growth at ca. 3.0 Ga, followed by multiple phases of crustal reworking during the Neoarchean and Paleoproterozoic, with dominant involvement of supracrustal components.
Gastrointestinal effects of caffeine in preterm infants: a systematic review and Bayesian meta-analysis
Authors: Gama Beatriz , von Hafe Madalena , Vieira Rafael , Soares Henrique , Azevedo Inês , Rocha Gustavo 
Published: April 2024

ObjectiveCaffeine is widely used in preterm infants to prevent or treat apnoea of prematurity. Adverse gastrointestinal effects of caffeine have not been thoroughly researched in preterm infants. With this systematic review and meta-analysis, we aim to summarise the results of trials on the gastrointestinal effects of caffeine in preterm infants.DesignWe searched MEDLINE, Web of Science, Scopus and ClinicalTrials.gov up to 21 April 2023. We included randomised controlled trials assessing caffeine versus placebo in preterm neonates and reporting gastrointestinal side effects. Risk of bias was assessed using the Cochrane Risk of Bias tool. A Bayesian meta-analysis was performed to estimate the pooled OR of gastrointestinal side effects.ResultsNine trials involving 2746 preterm infants were analysed. Seven trials assessing necrotising enterocolitis and four trials assessing feeding intolerance in our meta-analysis found no differences between caffeine and placebo (OR=1.007 (95% credible interval 0.021, 5.462), I2=97.4%, and OR=1.266 (95% credible interval 0.064, 28.326), I2=84.8%, respectively). Four trials assessed the outcomes spontaneous intestinal perforation, constipation, gastrointestinal disorder (composite outcome: gastro-oesophageal regurgitation or dilated bowel loops), age at oral feeding and cholestasis syndrome and found no differences between groups. One trial assessed the outcomes gastro-oesophageal symptoms and duration of tube feeding and found that caffeine was associated with a reduced burden of gastro-oesophageal reflux symptoms at 2 weeks (p<0.05), but not at term.ConclusionsAccording to this systematic review and meta-analysis, the use of caffeine at usual doses in preterm infants does not seem to be associated with significant gastrointestinal adverse effects.
Towards comprehensive clinical trials for new tuberculosis drug regimens: policy recommendations from a stakeholder analysis
Authors: Villa Simone , de Colombani Pierpaolo , Dall’Olio Lucia , Gargioni Giuliano , Raviglione Mario 
Published: April 2024

BackgroundResearch and development (R&D) of new drugs and regimens against tuberculosis (TB) is evolving to meet new challenges and face limited investments in the sector. To effectively improve and fill existing gaps, researchers and trialists should engage a broad spectrum of stakeholders. With this study, we aim to map the interests in TB R&D raised by the main stakeholders in the TB field.MethodsWe conducted semistructured, short interviews to gather insight and viewpoints on innovation on TB drugs and regimens R&D of policy-makers, national TB programme officers, donors, funders, non-governmental organisations and research institutions.A composite measure of the relevance of topics that emerged was computed by implementing different models considering the importance for researchers and the urgency to implement those changes during the trial, the number of citations each topic received, and the maximum value of the influence of stakeholders who had raised the topic.Results50 stakeholders, out of 56 identified, were interviewed and almost half were policy-makers and governmental institutions. Several stakeholders highlighted the importance of disseminating information about clinical trials’ methodology and emerging preliminary results, followed by the need to pursue early discussion around access and pricing of safe and effective TB innovations, although different categories of stakeholders prioritised different topics. Using different methods for ranking topics, the results remained almost unchanged. Notably, post-trial operational research ranked higher in models with higher weight for the parameter considering the number of citations.ConclusionResearchers and research consortia embarking on phase 2 and 3 clinical trials should consider a broad set of elements when planning and designing trials’ protocols, all aiming at lowering the price and improving access to emerging TB innovations, besides meeting regulatory criteria. This can only be achieved by consulting and engaging relevant stakeholders in the discussion.
Can hospitalists improve COVID-19 vaccination rates?
Authors: Yu Nina , Punatar Nisha , Shaikh Ulfat , Agrawal Garima 
Published: April 2024

Three years after the start of the SARS-CoV-2 virus (COVID-19) pandemic, its effects continue to affect society and COVID-19 vaccination campaigns continue to be a topic of controversy and inconsistent practice. After experiencing spikes in COVID-19 cases, our University of California Davis Health Division of Hospital Medicine sought to understand the reasons underlying the low COVID-19 vaccination rates in our county and find approaches to improve the number of vaccinations among adults admitted to the inpatient setting. This quality improvement project aimed to increase COVID-19 primary and booster vaccine efforts through a multi-pronged approach of increased collaboration with specialised staff and optimisation of use of our electronic health record system.Our key interventions focused on developing a visual reminder of COVID-19 vaccine status using the functionality of our electronic medical record (EMR), standardising documentation of COVID-19 vaccine status and enhancing team-based vaccination discussions through team huddles and partnering with inpatient care coordinators. While our grassroots approach enhanced COVID-19 vaccination rates in the inpatient setting and had additional benefits such as increased collaboration among teams, system-level efforts often made a greater impact at our healthcare centre. For other institutions interested in increasing COVID-19 vaccination rates, our top three recommendations include integrating vaccination into pre-existing workflows, optimising EMR functionality and increasing vaccine accessibility in the inpatient setting.
Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials
Authors: Roller Andreas , Davydov Iakov I , Schwalie Petra C , Serrano-Serrano Martha L , Heller Astrid , Staedler Nicolas , Ferreira Cláudia S , Dietmann Gabriele , Klaman Irina , Valdeolivas Alberto , Korski Konstanty , Cannarile Michael A 
Published: April 2024

BackgroundThe immune status of a patient’s tumor microenvironment (TME) may guide therapeutic interventions with cancer immunotherapy and help identify potential resistance mechanisms. Currently, patients’ immune status is mostly classified based on CD8+tumor-infiltrating lymphocytes. An unmet need exists for comparable and reliable precision immunophenotyping tools that would facilitate clinical treatment-relevant decision-making and the understanding of how to overcome resistance mechanisms.MethodsWe systematically analyzed the CD8 immunophenotype of 2023 patients from 14 phase I–III clinical trials using immunohistochemistry (IHC) and additionally profiled gene expression by RNA-sequencing (RNA-seq). CD8 immunophenotypes were classified by pathologists into CD8-desert, CD8-excluded or CD8-inflamed tumors using CD8 IHC staining in epithelial and stromal areas of the tumor. Using regularized logistic regression, we developed an RNA-seq-based classifier as a surrogate to the IHC-based spatial classification of CD8+tumor-infiltrating lymphocytes in the TME.ResultsThe CD8 immunophenotype and associated gene expression patterns varied across indications as well as across primary and metastatic lesions. Melanoma and kidney cancers were among the strongest inflamed indications, while CD8-desert phenotypes were most abundant in liver metastases across all tumor types. A good correspondence between the transcriptome and the IHC-based evaluation enabled us to develop a 92-gene classifier that accurately predicted the IHC-based CD8 immunophenotype in primary and metastatic samples (area under the curve inflamed=0.846; excluded=0.712; desert=0.855). The newly developed classifier was prognostic in The Cancer Genome Atlas (TCGA) data and predictive in lung cancer: patients with predicted CD8-inflamed tumors showed prolonged overall survival (OS) versus patients with CD8-desert tumors (HR 0.88; 95% CI 0.80 to 0.97) across TCGA, and longer OS on immune checkpoint inhibitor administration (phase III OAK study) in non-small-cell lung cancer (HR 0.75; 95% CI 0.58 to 0.97).ConclusionsWe provide a new precision immunophenotyping tool based on gene expression that reflects the spatial infiltration patterns of CD8+ lymphocytes in tumors. The classifier enables multiplex analyses and is easy to apply for retrospective, reverse translation approaches as well as for prospective patient enrichment to optimize the response to cancer immunotherapy.
Resistance training and cardiometabolic risk in women with metabolically healthy and unhealthy obesity
Authors: Tremblay Eve-Julie , Peyrel Paul , Karelis Antony D. , Rabasa-Lhoret Rémi , Tchernof André , Joanisse Denis R. , Mauriège Pascale 
Published: April 2024

Despite some reported benefits, there is a low quality of evidence for resistance training (RT) improving metabolic health of individuals with overweight or obesity. We evaluated the impact of RT on body composition, cardiorespiratory fitness (CRF) and physical performance, lipid–lipoprotein profile, inflammation, and glucose–insulin homeostasis in 51 postmenopausal women versus 29 controls matched for age, obesity, and physical activity. Exercised women were further subdivided for comparison of RT effects into those presenting metabolically healthy obesity (MHO) and those with metabolically unhealthy obesity (MUHO) classified according to Karelis and Rabasa-Lhoret or an approach based on adipose tissue secretory dysfunction using the plasma adiponectin(A)/leptin (L) ratio. Participants followed a 4-month weekly RT program targeting major muscle groups (3 × 10 repetitions at 80% one repetition maximum (1-RM)). Percent fat marginally decreased and lean body mass increased (0.01 < p < 0.05) while CRF and muscular strength improved in all women, after RT (effect size (ES): 0.11–1.21 (trivial to large effects), p ˂ 0.01). Fasting plasma triacylglycerol and high-density lipoprotein-cholesterol levels slightly increased and decreased, respectively, in participants with MHO using the A/L ratio approach (ES: −0.47 to 1.07 (small to large effects), p ˂ 0.05). Circulating interleukin-6 soluble receptor decreased in both groups and soluble tumor necrosis factor receptor-1/soluble tumor necrosis factor receptor-2 in women with MUHO only, irrespective of definition (ES: −0.42 to −0.84 (small to large effects), p ˂ 0.05). Glucose–insulin homeostasis was unchanged regardless of group or definition. RT improved physical performance and body composition but had a lesser impact on cardiometabolic risk in women with obesity, irrespective of their metabolic phenotype.
Photon scattering by an electric field in noncommutative spacetime
Authors: D’Ascanio Daniela , Pisani Pablo , Wainstein Haimovichi Ulises 
Published: April 2024

AbstractAs is known, the existence of a small noncommutativity between coordinates would generate nonlocal self-interactions in the electromagnetic theory. To explore some consequences of this effect on the propagation of photons we consider Moyal space half-filled with a static and homogeneous electric field and analyze electromagnetic fluctuations on top of this step-like background. Both the localization of photons and the possibility of photon production by strong electric fields are addressed. Several aspects of the Klein paradox in this setup are discussed as well.
A Bispecific Antibody That Targets the Membrane-Proximal Region of Mesothelin and Retains High Anticancer Activity in the Presence of Shed Mesothelin
Authors: Chakraborty Anirban , Onda Masanori , O’Shea Tara , Wei Junxia , Liu Xiufen , Bera Tapan K. , Pastan Ira 
Published: April 2024

Abstract
Mesothelin (MSLN) is a cell-surface protein that is expressed in many cancers, which makes it a popular target for Ab-based cancer therapy. However, MSLN is shed from cancer cells at high levels via proteases that cleave at its membrane-proximal C-terminal region. Shed MSLN accumulates in patients’ fluids and tumors and can block Ab-based MSLN-targeting drugs from killing cancer cells. A previously established mAb, 15B6, binds MSLN at its protease-sensitive C-terminal region and does not bind shed MSLN. Moreover, 15B6 variable fragment (Fv)–derived chimeric antigen receptor T cells are not inhibited by shed MSLN and kill tumors in mice more effectively than mAb SS1 Fv-derived chimeric antigen receptor T cells, which bind an epitope retained in shed MSLN. In this study, we have established 15B6 Fv-derived MSLN × CD3 bispecific antibodies (BsAb) that target MSLN-expressing cancers. We identified our lead candidate BsAb 5 after screening multiple 15B6-derived BsAb formats in vitro for cytotoxic activity. BsAb 5 activates T cells to kill various cancer cell lines in a MSLN-specific manner. MSLN 296-591 His, a recombinant protein mimicking shed MSLN, does not inhibit 15B6-derived BsAb 5 but completely inhibits humanized SS1-derived BsAb 7. Furthermore, BsAb 5 inhibits and delays tumor growth and is not inhibited by MSLN 296-585 His in mice. Our findings indicate that by targeting the protease-sensitive region of MSLN, BsAb 5 has high MSLN-specific anticancer activity that is not inhibited by shed MSLN. BsAb 5 may be a promising immunotherapy candidate for MSLN-expressing cancers.
A Selective FGFR1/2 PROTAC Degrader with Antitumor Activity
Authors: Kong Ying , Zhao Xinyue , Wang Zhaofu , Yuan Siqi , Chen Sheng , Lou Shidi , Ma Shichao , Li Yunfeng , Wang Xinghao , Ge Yangfeng , Li Guobin , Yang Hongbing , Zhao Mengxi , Li Dandan , Zhang Hailong , Tan Wenfu , Wang Juan 
Published: April 2024

Abstract
The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.
Antitumor Activity of a Novel LAIR1 Antagonist in Combination with Anti-PD1 to Treat Collagen-Rich Solid Tumors
Authors: Rodriguez Bertha L. , Huang Jiawei , Gibson Laura , Fradette Jared J. , Chen Hung-I.H. , Koyano Kikuye , Cortez Czrina , Li Betty , Ho Carmence , Ashique Amir M. , Lin Vicky Y. , Crawley Suzanne , Roda Julie M. , Chen Peirong , Fan Bin , Kim Jeong , Sissons James , Sitrin Jonathan , Kaplan Daniel D. , Gibbons Don L. , Rivera Lee B. 
Published: April 2024

Abstract
We recently reported that resistance to PD-1 blockade in a refractory lung cancer–derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Thus, we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. In this study, we report that LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist mAb, elicits myeloid inflammation and allogeneic T-cell responses by binding to LAIR1 and blocking collagen engagement. Furthermore, a mouse-reactive NGM438 surrogate antibody sensitized refractory KP mouse lung tumors to anti-PD-1 therapy and resulted in increased intratumoral CD8+ T-cell content and inflammatory gene expression. These data place LAIR1 at the intersection of stroma and suppressive myeloid cells and support the notion that blockade of the LAIR1/collagen axis can potentially address resistance to checkpoint inhibitor therapy in the clinic.