bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prehospital synergy: Tranexamic acid and blood transfusion in patients at risk for hemorrhage
Authors: Deeb Andrew-Paul , Hoteit Lara , Li Shimena , Guyette Francis X. , Eastridge Brian J. , Nirula Raminder , Vercruysse Gary A. , O’Keeffe Terence , Joseph Bellal , Neal Matthew D. , Sperry Jason L. , Brown Joshua B. 
Published: April 2022

BACKGROUND
Growing evidence supports improved survival with prehospital blood products. Recent trials show a benefit of prehospital tranexamic acid (TXA) administration in select subgroups. Our objective was to determine if receiving prehospital packed red blood cells (pRBC) in addition to TXA improved survival in injured patients at risk of hemorrhage.

METHODS
We performed a secondary analysis of all scene patients from the Study of Tranexamic Acid during Air and ground Medical Prehospital transport trial. Patients were randomized to prehospital TXA or placebo. Some participating EMS services utilized pRBC. Four resuscitation groups resulted: TXA, pRBC, pRBC+TXA, and neither. Our primary outcome was 30-day mortality and secondary outcome was 24-hour mortality. Cox regression tested the association between resuscitation group and mortality while adjusting for confounders.

RESULTS
A total of 763 patients were included. Patients receiving prehospital blood had higher Injury Severity Scores in the pRBC (22 [10, 34]) and pRBC+TXA (22 [17, 36]) groups than the TXA (12 [5, 21]) and neither (10 [4, 20]) groups (p < 0.01). Mortality at 30 days was greatest in the pRBC+TXA and pRBC groups at 18.2% and 28.6% compared with the TXA only and neither groups at 6.6% and 7.4%, respectively. Resuscitation with pRBC+TXA was associated with a 35% reduction in relative hazards of 30-day mortality compared with neither (hazard ratio, 0.65; 95% confidence interval, 0.45–0.94; p = 0.02). No survival benefit was observed in 24-hour mortality for pRBC+TXA, but pRBC alone was associated with a 61% reduction in relative hazards of 24-hour mortality compared with neither (hazard ratio, 0.39; 95% confidence interval, 0.17–0.88; p = 0.02).

CONCLUSION
For injured patients at risk of hemorrhage, prehospital pRBC+TXA is associated with reduced 30-day mortality. Use of pRBC transfusion alone was associated with a reduction in early mortality. Potential synergy appeared only in longer-term mortality and further work to investigate mechanisms of this therapeutic benefit is needed to optimize the prehospital resuscitation of trauma patients.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level III.
Developing a National Trauma Research Action Plan: Results from the geriatric research gap Delphi survey
Authors: Joseph Bellal , Saljuqi Abdul Tawab , Phuong Jimmy , Shipper Edward , Braverman Maxwell A. , Bixby Pamela J. , Price Michelle A. , Barraco Robert D. , Cooper Zara , Jarman Molly , Lack William , Lueckel Stephanie , Pivalizza Evan , Bulger Eileen ,   the Geriatric Trauma Panel
Published: April 2022

BACKGROUND
Treating older trauma patients requires a focus on the confluence of age-related physiological changes and the impact of the injury itself. Therefore, the primary way to improve the care of geriatric trauma patients is through the development of universal, systematic multidisciplinary research. To achieve this, the Coalition for National Trauma Research has developed the National Trauma Research Action Plan that has generated a comprehensive research agenda spanning the continuum of geriatric trauma care from prehospital to rehabilitation.

METHODS
Experts in geriatric trauma care and research were recruited to identify current gaps in clinical geriatric research, generate research questions, and establish the priority of these questions using a consensus-driven Delphi survey approach. Participants were identified using established Delphi recruitment guidelines ensuring heterogeneity and generalizability. On subsequent surveys, participants were asked to rank the priority of each research question on a nine-point Likert scale, categorized to represent low-, medium-, and high-priority items. The consensus was defined as more than 60% of panelists agreeing on the priority category.

RESULTS
A total of 24 subject matter experts generated questions in 109 key topic areas. After editing for duplication, 514 questions were included in the priority ranking. By round 3, 362 questions (70%) reached 60% consensus. Of these, 161 (44%) were high, 198 (55%) medium, and 3 (1%) low priority.

CONCLUSION
Among the questions prioritized as high priority, questions related to three types of injuries (i.e., rib fracture, traumatic brain injury, and lower extremity injury) occurred with the greatest frequency. Among the 25 highest priority questions, the key topics with the highest frequency were pain management, frailty, and anticoagulation-related interventions. The most common types of research proposed were interventional clinical trials and comparative effectiveness studies, outcome research, and health care systems research.
The potyviral protein 6K2 from Turnip mosaic virus increases plant resilience to drought
Authors: Prakash Ved , Nihranz Chad T. , Casteel Clare L. 
Published: April 2022

AbstractDrought is a major cause of yield loss for crops worldwide. Climate change is predicted to increase global crop losses due to drought through rising temperature and decreased water availability. Virus infection can increase drought tolerance of infected plants compared to non-infected plants; however, the mechanisms mediating virus-induced drought tolerance remain unclear. In this study, we demonstrate Turnip mosaic virus (TuMV) infection increases Arabidopsis thaliana survival under drought compared to uninfected plants. To determine if specific TuMV proteins mediate drought tolerance, we cloned the coding sequence for each of the major viral proteins and generated transgenic A. thaliana that constitutively express each protein. Three TuMV proteins, 6K1, 6K2, and NIa-Pro, enhanced drought tolerance of A. thaliana when expressed constitutively in plants compared to controls. Expression of 6K2 also increased plant biomass relative to controls, but had no impact on root biomass, trichome numbers, or on the number of stomata. While drought induced transcripts related to abscisic acid (ABA) biosynthesis and ABA levels in control plants, compared to under well-watered conditions, there were no changes in ABA or related transcripts in plants expressing 6K2 under drought conditions compared to well-watered. 6K2 expression also conveyed drought tolerance in another host plant, Nicotiana benthamiana, when expressed using a virus over expression construct derived from Foxtail mosaic virus (FoMV). Although the exact mechanisms are still unknown, these results suggest 6K2-induced drought tolerance is ABA-independent and that plant viruses may represent novel sources of drought tolerance for crop plants.
Transmission of human influenza A virus in pigs selects for adaptive mutations on the HA gene
Authors: Mo Jong-suk , Abente Eugenio J. , Sutton Troy C. , Ferreri Lucas M. , Geiger Ginger , Gauger Phillip C. , Perez Daniel R. , Vincent Baker Amy L. , Rajao Daniela S. 
Published: April 2022

AbstractInfluenza A viruses (IAV) cause respiratory diseases in many host species, including humans and pigs. The spillover of IAV between swine and humans has been a concern for both public health and the swine industry. With the emergence of the triple reassortant internal gene (TRIG) constellation, establishment of human-origin IAVs in pigs has become more common, leading to increased viral diversity. However, little is known about the adaptation processes that are needed for a human-origin IAV to transmit and become established in pigs. We generated a reassortant IAV containing surface gene segments from a human IAV strain and internal gene segments from the 2009 pandemic and TRIG IAV lineages and demonstrated that it can replicate and transmit in pigs. Sequencing and variant calling analysis identified a mutant that emerged during replication in pigs, which was mapped to a region near the receptor binding site of the hemagglutinin (HA). The variant was present in all contact pigs and replicated more efficiently in differentiated swine tracheal cells compared to the virus containing the wildtype human-origin HA. These results show that variants are selected quickly after replication of human-origin HA in pigs, leading to improved fitness in the swine host, likely contributing to transmission.ImportanceInfluenza A viruses (IAV) cause respiratory disease in several species, including humans and pigs. The bidirectional transmission of IAV between humans and pigs plays a significant role in the generation of novel viral strains, greatly impacting viral epidemiology. However, little is known about the evolutionary processes that allow human IAV to become established in pigs. In this study, we generated reassortant viruses containing human seasonal HA and NA on different constellations of internal genes and tested their ability to replicate and transmit in pigs. We demonstrated that a virus containing a common internal gene constellation currently found in U.S. swine was able to transmit efficiently via the respiratory route. We identified a specific amino acid mutation that was fixed in the respiratory contact pigs that was associated with improved replication in primary swine tracheal epithelial cells, suggesting it was crucial for the transmissibility of the human virus in pigs.
Unsuppressed HIV infection impairs T cell responses to SARS-CoV-2 infection and abrogates T cell cross-recognition
Authors: Nkosi Thandeka , Chasara Caroline , Mbatha Anele , Nsimbi Mza , Papadopoulos Andrea O , Nguni Tiza L , Karim Farina , Moosa Mohomed Yunus S , Gazy Inbal , Jambo Kondwani ,   COMMIT-KZN, Hanekom Willem , Sigal Alex , Ndhlovu Zaza M 
Published: April 2022

AbstractHIV infection has been identified as one of the major risk factors for severe COVID-19 disease, but the mechanisms underpinning this susceptability are still unclear. Here, we assessed the impact of HIV infection on the quality and epitope specificity of SARS-CoV-2 T cell responses in the first wave and second wave of the COVID-19 epidemic in South Africa. Flow cytometry was used to measure T cell responses following PBMC stimulation with SARS-CoV-2 peptide pools. Culture expansion was used to determine T cell immunodominance hierarchies and to assess potential SARS-CoV-2 escape from T cell recognition. HIV-seronegative individuals had significantly greater CD4+and CD8+T cell responses against the Spike protein compared to the viremic PLWH. Absolute CD4 count correlated positively with SARS-CoV-2 specific CD4+and CD8+T cell responses (CD4 r= 0.5, p=0.03; CD8 r=0.5, p=0.001), whereas T cell activation was negatively correlated with CD4+T cell responses (CD4 r= −0.7, p=0.04). There was diminished T cell cross-recognition between the two waves, which was more pronounced in individuals with unsuppressed HIV infection. Importantly, we identify four mutations in the Beta variant that resulted in abrogation of T cell recognition. Together, we show that unsuppressed HIV infection markedly impairs T cell responses to SARS-Cov-2 infection and diminishes T cell cross-recognition. These findings may partly explain the increased susceptibility of PLWH to severe COVID-19 and also highlights their vulnerability to emerging SARS-CoV-2 variants of concern.One sentence summaryUnsuppressed HIV infection is associated with muted SARS-CoV-2 T cell responses and poorer recognition of the Beta variant.
Heat and humidity sensors that alert mosquitoes to nearby human hosts
Authors: Laursen Willem J. , Budelli Gonzalo , Chang Elaine C. , Gerber Rachel , Tang Ruocong , Greppi Chloe , Albuquerque Rebecca , Garrity Paul A. 
Published: April 2022

AbstractMosquito-borne diseases sicken >500,000,000 people annually, killing >500,0001. Mosquito host-seeking is guided by multiple host-associated cues, which combine to drive blood feeding in a manner that remains poorly understood2,3. While heat is a powerful mosquito attractant, recent studies indicate that disruption of heat seeking has little impact on host detection by the malaria vectorAnopheles gambiae4, suggesting other cues act alongside heat in the complex sensory environment of a human host. Here we show mosquitoes requireIr93a(an Ionotropic Receptor5) to maintain attraction to a human host and feed on warmed blood. UsingIr93a, we uncover the previously uncharacterized mosquito hygrosensory system, and showIr93ais required for humidity detection by humidity sensors (hygrosensors) as well as temperature detection by thermosensors, and for attraction to each stimulus. These findings indicate that hygrosensation and thermosensation function in parallel, driving host proximity detection in response to the overlapping heat and humidity gradients humans produce6,7. These host cue sensors appear to have arisen by co-opting existing sensors of physical cues rather thande novo, asIr93a-dependent thermo- and hygro-sensors support physiological homeostasis in non-blood-feeding insects8–11. WhileIr93ais conserved among arthropods, reliance on heat and humidity evolved independently in multiple blood-feeding lineages, suggesting multiple, vector-specific implementations of this common host-seeking strategy.
An overlapped natural antisense lncRNA FCER1A-AS controls anaphylactic reaction by promoting FcεRIα expression
Authors: Tang Ruo-yu , Yin Lan , Yao Liang , Chen Xiao-Ping 
Published: April 2022

AbstractFunctioned as α-subunit of the high-affinity immunoglobulin E receptor (Fcε RIα), Fcε RIα plays a central role in the pathogenesis of Ig-E-mediated allergy and other IgE-related disorders. Fcε RIα is normally expressed only in limited spectrum of cells like basophils and mast cells, but the mechanism of controlling Fcε RIα expression in these cells is less well understood. In this study, we found fully overlapped natural antisense transcript (NATs) of Fcε RIα (FCER1A-AS) is co-expressed with cognate sense transcript (FCER1A-S) in IL-3 induced Fcε RIα-expressing cells or in high Fcε RIα-expressing cell line MC/9. When FCER1A-AS is selectively knocked down by CRISPR/RfxCas13d (CasRx) approach in MC/9, expression of mRNA and proteins of FCER1A-S is also markedly decreased. Furthermore, deficiency of FCER1A-AS along with lack of FCER1A-S expression is found in two different lines of gene-targeted mice in which FCER1A locus is disturbed at different sites. More importantly, the FCER1A-AS-deficient homozygous mice display similarly diminished anaphylactic reaction as FCER1A gene knockout mice. Thus, we uncovered in this investigation that the expression of FCER1A-S is positively regulated by co-expressed fully overlapped antisense transcript.
Unexpected contributions of striatal projection neurons coexpressing dopamine D1 and D2 receptors in balancing motor control
Authors: Bonnavion Patricia , Varin Christophe , Fakhfouri Ghazal , Olondo Pilar Martinez , De Groote Aurélie , Cornil Amandine , Lopez Ramiro Lorenzo , Fernandez Elisa Pozuelo , Isingrini Elsa , Rainer Quentin , Xu Kathleen , Tzavara Eleni , Vigneault Erika , Dumas Sylvie , de Kerchove d’Exaerde Alban , Giros Bruno 
Published: April 2022

AbstractThe central function of the striatum and its dopaminergic (DA) afferents in motor control and the integration of cognitive and emotional processes is commonly explained by the two striatal efferent pathways characterized by striatal projection neurons (SPNs) expressing DA D1 receptors and D2 receptors (D1-SPNs and D2-SPNs), without regard to SPNs coexpressing both receptors (D1/D2-SPNs). We developed an approach that enables the targeting of these hybrid SPNs and demonstrated that although these SPNs are less abundant, they play a major role in guiding the motor function of the other two main populations. D1/D2-SPNs project exclusively to the external globus pallidus (GPe) and have specific electrophysiological features with distinctive integration of DA signals. Optogenetic stimulation and loss-of-function experiments indicated that D1/D2-SPNs potentiate the prokinetic and antikinetic functions of D1-SPNs and D2-SPNs, respectively, and restrain the integrated motor response to psychostimulants. Overall, our findings demonstrate the essential role of this third unacknowledged population of D1/D2 coexpressing neurons, which orchestrates the fine-tuning of DA regulation in the thalamo-cortico-striatal loops.One-Sentence SummaryD1/D2 SPNs modulate the motor function of both D1- and D2-SPNs
Genotypic sex shapes maternal care in the African Pygmy mouse,Mus minutoides
Authors: Heitzmann Louise D. , Challe Marie , Perez Julie , Castell Laia , Galibert Evelyne , Martin Agnes , Valjent Emmanuel , Veyrunes Frederic 
Published: April 2022

AbstractSexually dimorphic behaviours, such as parental care, have long been thought to be driven mostly, if not exclusively, by gonadal hormones. In the past two decades, a few studies have challenged this view, highlighting the direct influence of the sex chromosome complement (XX vs XY or ZZ vs ZW). The African pygmy mouse,Mus minutoides, is a wild mouse species with naturally occurring XY sex reversal induced by a third, feminizing X* chromosome, leading to three female genotypes: XX, XX* and X*Y. Here, we show that sex reversal in X*Y females shapes a divergent maternal care strategy from both XX and XX* females, rather than altering care quality. In addition, we show that sex reversal may also impact the dopaminergic system in the anteroventral periventricular nucleus of the hypothalamus, consistent with one component of maternal care: pup retrieval. Combining behavioural ecology and neurobiology in a rodent subject to natural selection, we evaluate potential candidates for the neural basis of maternal behaviours and strengthen the underestimated role of the sex chromosomes in shaping sex differences in brain and behaviours. All things considered, we further highlight the emergence of a third sexual phenotype, challenging the binary view of phenotypic sexes.
The RNA content of extracellular vesicles fromPRPF31+/−hiPSC-RPE show potential as biomarkers of retinal degeneration
Authors: Getachew Heran , Mehrotra Sudeep , Kaur Tarandeep , Fernandez-Godino Rosario , Pierce Eric A. , Garita-Hernandez Marcela 
Published: April 2022

AbstractRetinitis pigmentosa (RP), is the most common inherited retinal degeneration (IRD), leading to vision loss via dysfunction and death of photoreceptor cells and retinal pigment epithelium (RPE). Mutations in the pre-mRNA processing factor 31 (PRPF31) gene are associated with autosomal dominant RP, impairing RPE function. While adeno-associated virus (AAV)-mediated gene therapy shows promise for treating IRDs, the slow progression of these diseases often makes timely measurement of clinical efficacy challenging. Extracellular vesicles (EVs) are lipid enclosed vesicles secreted by cells and their RNA contents are being explored as circulating biomarkers of cancer and other diseases. We hypothesize that EV RNAs could serve as biomarkers of the health status of the neural retina and RPE health. To test this, we usedPRPF31+/+andPRPF31+/−human-induced pluripotent stem cell (hiPSC)-derived RPE (hi-RPE) to investigate the RNAs contained in RPE-derived EVs, and how they change in disease. We also compared the RNA contents of RPE-EVs with the RNAs contained in the hi-RPE cells themselves. We found that EVs from mutantPRPF31+/−hi-RPE cells have distinct RNA profiles compared to those from control cells, suggesting EV RNA contents change during disease and could serve as biomarkers for retinal degeneration.
Niclosamide targets macrophages to rescue the disrupted peritoneal homeostasis in endometriosis
Authors: Zhao Liang , Shi Mingxin , Winuthayanon Sarayut , MacLean James A. , Hayashi Kanako 
Published: April 2022

AbstractDue to the vital roles of macrophages in the pathogenesis of endometriosis, targeting macrophages could be a new therapeutic direction. Here, we investigated the efficacy of niclosamide for the resolution of perturbed microenvironment caused by dysregulated macrophages in a mouse model of endometriosis. Single-cell transcriptomic analysis revealed the heterogeneity of macrophage subpopulations including three newly identified intermediate subtypes with sharing characteristics of traditional “small” or “large” peritoneal macrophages (SPMs and LPMs) in the peritoneal cavity. Endometriosis-like lesions (ELL) enhanced the differentiation of recruited macrophages, promoted the replenishment of resident LPMs, and increased ablation of embryo-derived LPMs, which were stepwise suppressed by niclosamide. In addition, niclosamide reversed intercellular communications between macrophages and B cells which were disrupted by ELL. Therefore, niclosamide rescued the perturbed microenvironment in endometriosis through its fine regulations on the dynamic progression of macrophages and could be a new promising therapy for endometriosis.SummaryNiclosamide tunes the dynamic progression of peritoneal macrophages and their intercellular communications with B cells to rescue the disrupted microenvironment in the peritoneal cavity in a mouse model of endometriosis.Graphic Abstract
Delineating antibody escape from Omicron sublineages
Authors: Gruell Henning , Vanshylla Kanika , Korenkov Michael , Tober-Lau Pinkus , Zehner Matthias , Münn Friederike , Janicki Hanna , Augustin Max , Schommers Philipp , Sander Leif Erik , Kurth Florian , Kreer Christoph , Klein Florian 
Published: April 2022

AbstractSARS-CoV-2 neutralizing antibodies play a critical role in prevention and treatment of COVID-19 but are challenged by viral evolution and antibody evasion, exemplified by the highly resistant Omicron BA.1 sublineage.1–12 Importantly, the recently identified Omicron sublineages BA.2.12.1 and BA.4/5 with differing spike mutations are rapidly emerging in various countries. By determining polyclonal serum activity of 50 convalescent or vaccinated individuals against BA.1, BA.1.1, BA.2, BA.2.12.1, and BA.4/5, we reveal a further reduction of BA.4/5 susceptibility to vaccinee sera. Most notably, delineation of the sensitivity to an extended panel of 163 antibodies demonstrates pronounced antigenic differences of individual sublineages with distinct escape patterns and increased antibody resistance of BA.4/5 compared to the most prevalent BA.2 sublineage. These results suggest that the antigenic distance from BA.1 and the increased resistance compared to BA.2 may favor immune escape-mediated expansion of BA.4/5 after the first Omicron wave. Finally, while most monoclonal antibodies in clinical stages are inactive against all Omicron sublineages, we identify promising novel antibodies with high pan-Omicron neutralizing potency. Our study provides a detailed understanding of the antibody escape from the most recently emerging Omicron sublineages that can inform on effective strategies to prevent and treat COVID-19.