bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial and Single Cell Mapping of Castleman Disease Reveals Key Stromal Cell Types and Cytokine Pathways
Authors: Smith David , Eichinger Anna , Rech Andrew , Wang Julia , Esteva Eduardo , Seyedian Arta , Yang Xiaoxu , Zhang Mei , Martinez Dan , Tan Kai , Luo Minjie , Park Christopher , Reizis Boris , Pillai Vinodh 
Published: September 2024

AbstractCastleman disease (CD) is inflammatory lymphoproliferative disorder of unclear etiology. To determine the cellular and molecular basis of CD, we analyzed the spatial proteome of 4,485,009 single cells, transcriptome of 50,117 single nuclei, immune repertoire of 8187 single nuclei, and pathogenic mutations in Unicentric CD, idiopathic Multicentric CD, HHV8-associated MCD, and reactive lymph nodes. CD was characterized by increased non-lymphoid and stromal cells that formed unique microenvironments where they interacted with lymphoid cells. Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle zone B cells was associated with B cell activation and differentiation. VEGF, IL-6, MAPK, and extracellular matrix pathways were elevated in stromal cells of CD. CXCL13+ FDCs, PDGFRA+ T-zone reticular cells (TRC), and ACTA2-positive perivascular reticular cells (PRC) were identified as the predominant source of increased VEGF expression and IL-6 signaling in CD. VEGF expression by FDCs was associated with peri-follicular neovascularization. FDC, TRC and PRC of CD activated JAK-STAT, TGFβ, and MAPK pathways via ligand-receptor interactions involving collagen, integrins, complement components, and VEGF receptors. T, B and plasma cells were polyclonal but showed class-switched and somatically hypermutated IgG1+ plasma cells consistent with stromal cell-driven germinal center activation. In conclusion, our findings show that stromal cell activation and associated B-cell activation and differentiation, neovascularization and stromal remodeling underlie CD and suggest new targets for treatment.Key pointsCastleman Disease is characterized by activation and proliferation of CXCL13+ FDCs, PDGFRA+ reticular cells, and ACTA2-positive PRCs.VEGF and IL-6 from lymph node stromal cells are associated with B-cell activation and differentiation, endothelial proliferation, and inflammation in CD
Andexanet alfa-associated heparin resistance in cardiac surgery: mechanism andin vitroperspectives
Authors: Chabata Charlene V. , Yu Haixiang , Ke Lei , Frederiksen James W. , Patel Prakash A. , Sullenger Bruce A. , Thalji Nabil K. 
Published: September 2024

AbstractBackgroundAndexanet alfa (andexanet) is the only FDA-approved antidote for direct factor Xa (FXa) inhibitors but has been reported to cause resistance to unfractionated heparin (UFH). This has delayed anticoagulation for procedures requiring cardiopulmonary bypass (CPB). The mechanism, andexanet and UFH dose dependence, and thrombotic risk of andexanet-associated heparin resistance are unknown.MethodsThe effect of andexanetin vitrowas determined using activated clotting times (ACT) and thromboelastography (TEG).Ex vivoCPB circuits were used to determine whether andexanet impaired anticoagulation for extracorporeal circulation. Kinetics of antithrombin (AT) inhibition of FXa and thrombin were measured in the presence of andexanet. Equilibrium modeling and thrombin generation assay (TGA) validation were used to predict the role of andexanet, AT, and UFH concentrations in andexanet-associated heparin resistance.ResultsAndexanet prevented UFH-mediated prolongation of ACT and TEG times. At lower concentrations of andexanet, heparin resistance could be overcome with suprapharmacologic doses of UFH, but not at higher andexanet concentrations. Andexanet rendered standard doses of UFH inadequate to prevent circuit thrombosis, and suprapharmacologic UFH doses were only partially able to overcome this. Scanning electron microscopy demonstrated coagulation activation in circuits. Andexanet prevented UFH enhancement of AT-mediated inhibition of FXa and thrombin. Equilibrium modeling and TGA validation demonstrated that andexanet creates a triphasic equilibrium with UFH and AT: initial UFH unresponsiveness, normal UFH responsiveness when andexanet is depleted, and finally AT depletion. Sufficient CPB heparinization can only occur at low therapeutic andexanet doses and normal AT levels. Higher andexanet doses or AT deficiency may require both AT supplementation and very high UFH doses.ConclusionsAndexanet causes heparin resistance due to redistribution of UFH-bound AT. If andexanet cannot be avoided prior to heparinization and direct thrombin inhibitors are undesirable, ourin vitrostudy suggests excess UFH should be considered as a potential strategy prior to AT supplementation.HighlightsAndexanet alfa causes heparin resistance not by depleting antithrombin, but rather by sequestering heparin-bound antithrombin such that it cannot act as an anticoagulant.Heparin responsiveness in the presence of Andexanet alfa is triphasic such that the effect of a dose of heparin can now be predicted in vitro based on the relative concentrations of andexanet, heparin, and antithrombin.The in vitro insights provided by this work provide a rational starting point for further clinical elucidation of the problem and management of andexanet-associated heparin resistance
Omission-responsive neurons encode negative prediction error and probability in the auditory cortex
Authors: Yaron Amit , Shiramatsu-Isoguchi Tomoyo , Kern Felix B. , Ohki Kenichi , Takahashi Hirokazu , Chao Zenas C. 
Published: September 2024

AbstractPredictive coding posits the brain predicts incoming sensory information and signals prediction errors when actual input differs from expectations. Positive prediction errors occur when input exceeds predictions, while negative prediction errors arise when input falls short. Specific neurons are theorized to encode negative prediction errors, linked to responses to omitted expected inputs. However, the information encoded in omission responses remains unclear. We recorded single-unit activity in rat auditory cortex during an omission paradigm with varying tone probabilities. We identified neurons selectively responding to omissions, with responses increasing with evidence accumulation and correlating with tone predictability—key characteristics of negative prediction-error neurons. Interestingly, these neurons showed selective omission responses but broad tone responses, revealing an asymmetry in error signaling. We propose a circuit model with laterally interconnected prediction-error neurons reproducing this asymmetry. Our model demonstrates that lateral connections enhance precision and efficiency of prediction encoding, supported by the free energy principle.
The Human T-cell Leukemia Virus capsid protein is a potential drug target
Authors: Yu Ruijie , Phalora Prabhjeet , Li Nan , Böcking Till , Jacques David Anthony 
Published: September 2024

AbstractHuman T-cell Leukemia Virus type 1 (HTLV-1) is an untreatable retrovirus that causes lethal malignancies and degenerative inflammatory conditions. Effective treatments have been delayed by substantial gaps in our knowledge of the fundamental virology, especially when compared to the closely related virus, HIV. A recently developed and highly effective anti-HIV strategy is to target the virus with drugs that interfere with capsid integrity and interactions with the host. Importantly, the first in class anti-capsid drug approved, lenacapavir, can provide long-acting pre-exposure prophylaxis. Such a property would provide a means to prevent the transmission of HTLV-1, but its capsid has not previously been considered as a drug target. Here we describe the first high-resolution crystal structures of the HTLV-1 capsid protein, define essential lattice interfaces, and identify a previously unknown ligand-binding pocket. We show that this pocket is essential for virus infectivity, providing a potential target for future anti-capsid drug development.
Ketamine treatment effects on DNA methylation and Epigenetic Biomarkers of aging
Authors: Dawson Kristin , Carangan Athena May Jean M. , Klunder Jessica , Carreras-Gallo Natalia , Sehgal Raghav , Megilligan Samantha , Askins Benjamin C. , Perkins Nicole , Mendez Tavis L. , Smith Ryan , Dawson Matthew , Mallin Michael , Higgins-Chen Albert T. , Dwaraka Varun B. 
Published: September 2024

AbstractMajor depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are debilitating psychiatric conditions associated with poor health outcomes similarly observed in non-pathological aging. Ketamine is a dissociative anesthetic and NMDA receptor antagonist with demonstrated rapid reduction in symptoms associated with Treatment Resistant Depression (TRD) and PTSD. Ketamine’s effects on biological aging have not been extensively studied among patients with moderate to severe symptoms of depression and/or trauma. To address this gap, this study looked at the changes in non-epigenetic measures, DNA methylation levels, immune cell composition, and biological age based on various epigenetic biomarkers of aging, of 20 participants at baseline and after completion of a 2-3 week treatment course of 0.5 mg/kg ketamine infusions in individuals with MDD or PTSD. As expected, depression and PTSD scores decreased in participants following ketamine infusion treatments as measured by the PHQ-9 and PCL-5. We observed a reduction in epigenetic age in the OMICmAge, GrimAge V2, and PhenoAge biomarkers. In order to better understand the changes in epigenetic age, we also looked at the underlying levels of various Epigenetic Biomarker Proxies (EBPs) and surrogate protein markers and found significant changes following ketamine treatment. The results are consistent with existing literature on ketamine’s effects on different biomarkers. These results underline the ability of GrimAge V2, PhenoAge, and OMICmAge in particular, to capture signals associated with key clinical biomarkers, and add to the growing body of literature on ketamine’s epigenetic mechanisms and their effect on biological aging.
Antibiotic prescribing patterns by age and sex in England: why we need to take this variation into account to evaluate antibiotic stewardship and AMR selection
Authors: Waterlow Naomi R , Ashfield Tom , Knight Gwenan M 
Published: September 2024

Structured AbstractObjectivesThe drivers of antimicrobial resistance (AMR) likely vary substantially by diKerent demographics. However, few complete open national detailed data exist on how antibiotic use (ABU) varies by both age and sex.MethodsHere, prescriptions of antibiotics from General Practices in England for 2015-2023 disaggregated by 5-year age bands and sex were analysed at the national and Integrated Care Board (ICB) level. From a total of 249,578,795 prescriptions (across 9 years), 63% were given to women and the most prescribed were amoxicillin, nitrofurantoin and flucloxacillin sodium. Prescriptions per 100K population varied substantially across sex, age, geographical region, season, year, COVID-19 pandemic period and drug.ResultsMost antibiotics were prescribed more to women across most age bands (84% of antibiotics had more prescriptions to females across 50% of age bands). We show how this variation requires a more nuanced approach to comparing ABU across geographies and highlight that AWaRe targets are not met uniformly (young men have a higher proportion of “Watch” antibiotic prescriptions). We also show the impact on ABU of time-sensitive interruptions, including diKerential age-targeted influenza vaccination, COVID-19 restrictions and a shortage of amoxicillin combined with a Streptococcus A outbreak. Comparing to open access AMR data (MRSA in bloodstream infections) highlights the complexity of the link between ABU and AMR.ConclusionsThese detailed diKerences in ABU across England suggest that there should be large variation in AMR burden by age and sex, which now need to be quantified with detailed open access AMR data for a better intervention design.
Non-pharmaceutical interventions to reduce influenza transmission in households: a systematic review and meta-analysis
Authors: Wong Jessica Y. , Lim Wey Wen , Cheung Justin K. , Murphy Caitriona , Shiu Eunice Y. C. , Xiao Jingyi , Chen Dongxuan , Xie Yanmin , Li Mingwei , Xin Hualei , Szeto Michelle , Choi Sammi , Cowling Benjamin J. 
Published: September 2024

ABSTRACTBackgroundInfluenza pandemic plans often recommend non-pharmaceutical interventions (NPIs) in household settings, including hand hygiene and face masks. We reviewed the evidence supporting the recommendations of these measures to prevent the spread of influenza in households.MethodsWe performed systematic reviews between 26 May and 30 August 2022 in Medline, PubMed, EMBASE, and CENTRAL to identify evidence for the effectiveness of selected measures recommended by representative national influenza pandemic plans. We prioritized evidence from randomized controlled trials. Fixed-effects models were used to estimate the overall effects. Systematic reviews were registered in the OSF registry (https://osf.io/8kyth).ResultsWe selected 9 NPIs for evidence review. We identified 9 randomized-controlled trials related to hand hygiene and face masks in household settings. 2 studies reported that measures could delay the introduction of influenza virus infections into households. However, we did not identify evidence from randomized controlled trials that indicated a substantial effect of hand hygiene and face masks in preventing the spread of pandemic influenza within households.ConclusionLimited evidence indicated that within-household measures may likely be effective only when implemented before or as soon as possible after symptom onset in an infected case. Improving the evidence base for NPIs in households and elsewhere is a continuing priority.FundingWorld Health Organization and the Strategic Topic Grants Scheme
Performance of the Verily Study Watch for Measuring Sleep Compared to Polysomnography
Authors: Saeb Sohrab , Nelson Benjamin W. , Barman Poulami , Verma Nishant , Allen Hannah , de Zambotti Massimiliano , Baker Fiona C. , Arra Nicole , Sridhar Niranjan , Sullivan Shannon S. , Plowman Scooter , Rainaldi Erin , Kapur Ritu , Shin Sooyoon 
Published: September 2024

AbstractIntroductionThis study evaluated the performance of a wrist-worn wearable, Verily Study Watch (VSW), in detecting key sleep measures against polysomnography (PSG).MethodsWe collected data from 41 adults without obstructive sleep apnea or insomnia during a single overnight laboratory visit. We evaluated epoch-by-epoch performance for sleep versus wake classification, sleep stage classification and duration, total sleep time (TST), wake after sleep onset (WASO), sleep onset latency (SOL), sleep efficiency (SE), and number of awakenings (NAWK). Performance metrics included sensitivity, specificity, Cohen’s kappa, and Bland-Altman analyses.ResultsSensitivity and specificity (95% CIs) of sleep versus wake classification were 0.97 (0.96, 0.98) and 0.70 (0.66, 0.74), respectively. Cohen’s kappa (95% CI) for 4-class stage detection was 0.64 (0.18, 0.82). Most VSW sleep measures had proportional bias. The mean bias values (95% CI) were 14.0 minutes (5.55, 23.20) for TST, - 13.1 minutes (-21.33, -6.21) for WASO, 2.97% (1.25, 4.84) for SE, -1.34 minutes (-7.29, 4.81) for SOL, 1.91 minutes (-8.28, 11.98) forlight sleepduration, 5.24 minutes (-3.35, 14.13) fordeep sleepduration, and 6.39 minutes (-0.68, 13.18) forREM sleepduration. Mean and median NAWK count differences (95% CI) were 0.05 (-0.42, 0.53) and 0.0 (0.0, 0.0), respectively.DiscussionResults support applying the VSW to track overnight sleep measures in free-living settings. Registered atclinicaltrials.gov(NCT05276362).
Risk factors for typhoid fever: A desk review
Authors: Boakye Okyere Portia , Twumasi-Ankrah Sampson , Newton Sam , Darko Samuel Nkansah , Owusu Ansah Michael , Darko Eric , Agyapong Francis Opoku , Jin Jeon Hyon , Adu-Sarkodie Yaw , Marks Florian , Owusu-Dabo Ellis 
Published: September 2024

AbstractBackground and AimTyphoid fever, a significant global health problem, demonstrates a multifaceted transmission pattern. Knowledge of the factors driving the transmission of infection is critical for developing effective control strategies and resource allocation. This comprehensive desk review aimed at synthesizing evidence from 1928 to 2023 on risk factors associated with typhoid fever transmission.MethodWe conducted article searches in PubMed, Scopus, Google Scholar, and Semantic Scholar, using keywords related to risk, contributors, determinants, causes etc. associated with typhoid fever. We followed a registered protocol to support our search and triangulated the results.ResultsIn all, we retrieved 1614 articles, of which 216 were reviewed. Of these articles reviewed, 106 provided data on typhoid fever risk factors. Unsurprisingly, of the total articles reviewed on risk factors, about 72% (76/106) originated from the Asian (48.1%, 51/106) and African (23.6%, 25/106) continents. A higher proportion, 47.2% (50/106) of the articles indicated risk factors related to socio-economic and housing transmission. Additional risk factors included foodborne transmissions (45.3%, 48/106), WASH:Waterborne transmissions (42.5%, 45/106),Sanitation andHygiene practices (32.1%, 34/106), travel-related risk (16.0%, 17/106), antimicrobial agents (13.2%, 14/106), climate (13.2%, 14/106), environmental (8.5%, 9/106), typhoid carriers (10.4%, 11/106), and host risk (5.7%, 6/106) factors to disease transmission.ConclusionThese findings highlight the necessity for targeted and combined interventions including improved sanitation infrastructure, enhanced WASH practices and the use of vaccines in endemic areas. Implementing effective strategies informed by this review can aid clinicians, public health experts, and policymakers in efficiently mitigating the burden of typhoid fever.
Epistasis drives rapid divergence across multiple traits during the adaptive evolution of a carbapenemase
Authors: Dabos Laura , Nedjari Inssaf , Couce Alejandro 
Published: September 2024

ABSTRACTInteractions among beneficial mutations (i.e., epistasis) are often strong enough as to direct adaptation through alternative mutational paths. While alternative solutions should display similar fitness under the primary selective conditions, their properties across secondary environments may differ widely. The extent to which these cryptic differences are to be expected is largely unknown, despite their fundamental and practical importance, such as in the search for exploitable collateral sensitivities among antibiotic resistance mutations. Here we use directed evolution to characterize the diversity of mutational paths through which the prevalent carbapenemase KPC-2 can evolve high activity against the clinically-relevant antibiotic ceftazidime, an initially poor substrate. We identified 40 different substitutions, including many common clinical settings, spread along 18 different mutational trajectories. Initial mutations determined four major groups into which the trajectories can be classified, a signature of strong epistasis. Of note, despite minor variation in final ceftazidime resistance, groups diverged markedly across multiple phenotypic dimensions, from molecular traits such as stability and hydrolitic efficiency to macroscopic traits such as growth rate and activity against other β-lactam antibiotics. Our results indicate that cryptic yet consequential phenotypic differences can readily accumulate under strong selective pressures, bearing implications for efforts to prevent unwanted evolution in microbes.
Highly Iterated Palindrome 1 (HIP1) sequence improvesSynechococcussp. PCC 7002 transformation efficiencies in a homology- and methylation-dependent manner
Authors: Kamoku Cody , Nielsen David R. 
Published: September 2024

AbstractThe ability to precisely control cyanobacterial metabolism first requires the ability to efficiently deliver engineered DNA constructs. Here, we investigate how natural transformation efficiencies inSynechococcussp. PCC 7002 can be greatly improved by leveraging the native and abundant cyanobacterial Highly Iterated Palindrome 1 (HIP1) sequence. While including at least one homologous HIP1 site within the homology arms of an integrating plasmid increased integration efficiency by up to 7-fold, methylation of those sites by HIP1 methyltransferase (encoded byslr0214fromSynechococcussp. PCC 6803) boosted this to greater than a 100-fold improvement overall. Non-homologous HIP1 sites also improved transformation efficiencies of both integrating and replicating episomal plasmids (by up to 60- and 9-fold, respectively), but only when methylated. The collective data further reveal that HIP1 does not function as part of a native restriction enzyme system in PCC 7002, but rather may improve transformation efficiency via two complementary mechanisms: i) altering DNA binding/uptake/processing prior to homologous recombination, and ii) increasing the efficiency of homologous recombination in a manner reminiscent of a crossover hotspot instigator (Chi) site. Future studies are needed, however, to more clearly elucidate the specific role of HIP1 during natural transformation of cyanobacteria.
In vivoCRISPR screens identify GRA12 as a transcendent secreted virulence factor acrossToxoplasma gondiistrains and mouse subspecies
Authors: Torelli Francesca , Butterworth Simon , Lockyer Eloise , Song Ok-Ryul , Pearson-Farr Jennifer , Treeck Moritz 
Published: September 2024

SummaryToxoplasma gondiiparasites exhibit extraordinary host promiscuity owing to over 250 putative secreted proteins that disrupt host cell functions, enabling parasite persistence. However, most of the known effector proteins are specific toToxoplasmagenotypes or hosts. To identify virulence factors that function across different parasite isolates and mouse strains that differ in susceptibility to infection, we performed systematic pooledin vivoCRISPR-Cas9 screens targeting theToxoplasmasecretome. We identified several proteins required for infection across parasite strains and mouse species, of which the dense granule protein 12 (GRA12) emerged as the most important effector protein during acute infection. GRA12 deletion in IFNγ-activated macrophages results in collapsed parasitophorous vacuoles and increased host cell necrosis, which is partially rescued by inhibiting early parasite egress. GRA12 orthologues from related coccidian parasites, includingNeospora caninumandHammondia hammondi,complement TgΔGRA12in vitro, suggesting a common mechanism of protection from immune clearance by their hosts.