bluuebunny/crossref_metadata_2025_split huggingface dataset:
A regimen compression strategy for commercial vaccines leveraging an injectable hydrogel depot technology for sustained vaccine exposure
Authors: Yan Jerry , Ou Ben S. , Saouaf Olivia M. , Meany Emily L. , Eckman Noah , Appel Eric A. 
Published: March 2023

AbstractEquitable global access to vaccines requires we overcome challenges associated with complex immunization schedules and their associated economic burdens that hinder delivery in under resourced environments. The rabies vaccine, for example, requires multiple immunizations for effective protection and each dose is cost prohibitive, and therefore inaccessibility disproportionately impacts low- and middle-income countries. In this work we developed an injectable hydrogel depot technology for sustained delivery of commercial inactivated rabies virus vaccines. In a mouse model, we showed that a single immunization of a hydrogel-based rabies vaccine elicited comparable antibody titers to a standard prime-boost bolus regimen of a commercial rabies vaccine, despite these hydrogel vaccines comprising only half of the total dose delivered in the bolus control. Moreover, these hydrogel-based vaccines elicited similar antigen-specific T-cell responses and neutralizing antibody responses compared to the bolus vaccine. Notably, we demonstrated that while addition of a potent clinical TLR4 agonist adjuvant to the gels slightly improved binding antibody responses, inclusion of this adjuvant to the inactivated virion vaccine was detrimental to neutralizing responses. Taken together, these results suggest that these hydrogels can enable an effective regimen compression and dosesparing strategy for improving global access to vaccines.
Endothelial Cell SMAD6 Balances ACVRL1/Alk1 Function to Regulate Adherens Junctions and Hepatic Vascular Development
Authors: Kulikauskas Molly R , Oatley Morgan , Yu Tianji , Liu Ziqing , Matsumura Lauren , Kidder Elise , Ruter Dana , Bautch Victoria L 
Published: March 2023

ABSTRACTBMP signaling is critical to blood vessel formation and function, but how pathway components regulate vascular development is not well-understood. Here we find that inhibitory SMAD6 functions in endothelial cells to negatively regulate ALK1/ACVRL1-mediated responses, and it is required to prevent vessel dysmorphogenesis and hemorrhage in the embryonic liver vasculature. ReducedAlk1gene dosage rescued embryonic hepatic hemorrhage and microvascular capillarization induced bySmad6deletion in endothelial cellsin vivo. At the cellular level, co-depletion of Smad6 and Alk1 rescued the destabilized junctions and impaired barrier function of endothelial cells depleted for SMAD6 alone. At the mechanistic level, blockade of actomyosin contractility or increased PI3K signaling rescued endothelial junction defects induced by SMAD6 loss. Thus, SMAD6 normally modulates ALK1 function in endothelial cells to regulate PI3K signaling and contractility, and SMAD6 loss increases signaling through ALK1 that disrupts endothelial junctions. ALK1 loss-of-function also disrupts vascular development and function, indicating that balanced ALK1 signaling is crucial for proper vascular development and identifying ALK1 as a “Goldilocks” pathway in vascular biology regulated by SMAD6.
Somatic small-variant calling methods in Illumina DRAGEN™ Secondary Analysis
Authors: Scheffler Konrad , Catreux Severine , O’Connell Taylor , Jo Heejoon , Jain Varun , Heyns Theo , Yuan Jeffrey , Murray Lisa , Han James , Mehio Rami 
Published: March 2023

AbstractWe present the DRAGEN™ somatic pipeline for calling small somatic variants from tumor samples, with or without paired normal samples. The DRAGEN somatic variant caller offers 1) a flexible architecture that can be used on a wide array of somatic use cases; 2) built-in noise models enabling robustness against various sources of noise artifacts (mapping, genome context, or sample specific); 3) performance of joint analysis of tumor and normal samples in the case of a tumor-normal workflow yielding improved accuracy; 4) benefits from FPGA acceleration for efficient run time. We demonstrate the speed and accuracy of the DRAGEN tumor-normal pipeline across a range of whole genome sequencing (WGS) datasets and compare against third party tools such as Mutect2/GATK4 [1] and Strelka2 [2]. DRAGEN secondary analysis outperforms all other tools with its ability to complete a 110x/40x T/N whole-genome analysis in less than two hours. It offers exceptional accuracy, with higher sensitivity and precision than third party tools. We also show that the DRAGEN T/N workflow supports analysis of liquid and late-stage solid tumors by tolerating tumor-in-normal (TiN) contamination.
FRS2-independent GRB2 interaction with FGFR2 is not required for embryonic development
Authors: Clark James F , Soriano Philippe 
Published: March 2023

AbstractFGF activation is known to engage canonical signals, including ERK/MAPK and PI3K/AKT, through various effectors including FRS2 and GRB2.Fgfr2FCPG/FCPGmutants that abrogate canonical intracellular signaling exhibit a range of mild phenotypes but are viable in contrast to embryonic lethalFgfr2-/-mutants. GRB2 has been reported to interact with FGFR2 through a non-traditional mechanism, by binding to the C-terminus of FGFR2 independently of FRS2 recruitment. To investigate if this interaction provides functionality beyond canonical signaling, we generated mutant mice harboring a C-terminal truncation (T). We found thatFgfr2T/Tmice are viable and have no distinguishable phenotype, indicating that GRB2 binding to the C-terminal end of FGFR2 is not required for development or adult homeostasis. We further introduced theTmutation on the sensitizedFCPGbackground but found thatFgfr2FCPGT/FCPGTmutants did not exhibit significantly more severe phenotypes. We therefore conclude that, while GRB2 can bind to FGFR2 independently of FRS2, this binding does not have a critical role in development or homeostasis.
Deficits in mitochondrial function and glucose metabolism seen in sporadic and familial Alzheimer’s disease derived Astrocytes are ameliorated by increasing hexokinase 1 expression
Authors: Bell Simon M , Wareing Hollie , Hamshaw Alexander , De Suman , New Elizabeth , Shaw Pamela J , De Marco Matteo , Venneri Annalena , Blackburn Daniel J , Ferraiuolo Laura , Mortiboys Heather 
Published: March 2023

AbstractBackgroundAstrocytes have multiple roles including providing neurons with metabolic substrates and maintaining neurotransmitter synaptic homeostasis. Astrocyte glucose metabolism plays a key role in learning and memory with astrocytic glycogen a key substrate supporting memory encoding. The neuronal support provided by astrocytes has a high metabolic demand. Deficits in astrocytic mitochondrial metabolic functioning and glycolysis could impair neuronal function. Changes to cellular metabolism are seen early in Alzheimer’s disease (AD). Understanding cellular metabolism changes in AD astrocytes could be exploited as a new biomarker or synergistic therapeutic agent when combined with anti-amyloid treatments in AD.MethodsIn this project, we characterised mitochondrial and glycolytic function in astrocytes derived from patients with sporadic (n=6) and familial (PSEN1, n=3) forms of AD. Astrocytes were derived using direct reprogramming methods. Astrocyte metabolic outputs: ATP, and extracellular lactate levels were measured using luminescent and fluorescent protocols. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. Hexokinase deficits identified where corrected by transfecting astrocytes with an adenovirus viral vector containing the hexokinase 1 gene.ResultsThere was a reduction of total cellular ATP of 20% (p=0.05 in sAD astrocytes) and of 48% (p<0.01) in fAD. A 44% reduction (p<0.05), and 80% reduction in mitochondrial spare capacity was seen in sAD and fAD astrocytes respectively. Reactive oxygen species (ROS) were increased in both AD astrocyte types (p=0.05). Mitochondrial complex I and II was significantly increased in sAD (p<0.05) but not in fAD. Astrocyte glycolytic reserve and extracellular lactate was significantly reduced when compared to controls in both sAD and fAD (p<0.05). We identified a deficit in the glycolytic pathway enzyme hexokinase, and correcting this deficit restored most of the metabolic phenotype in sAD but not fAD astrocytes.ConclusionAD astrocytes have abnormalities in functional capacity of mitochondria and the process of glycolysis. These functional deficits can be improved by correcting hexokinase expression deficits with adenoviral vectors. This suggests that hexokinase 1 deficiency could potentially be exploited as a new therapeutic target for AD.
Karyopherin mimicry explains how the HIV capsid penetrates nuclear pores
Authors: Dickson C.F. , Hertel S. , Ruan J. , Ariotti N. , Tuckwell A. , Li N. , Al-Izzi S.C. , Sierecki E. , Gambin Y. , Morris R.G. , Towers G.J. , Böcking T. , Jacques D.A. 
Published: March 2023

Summary ParagraphHIV can infect non-dividing cells because the viral capsid can overcome the selective barrier of the nuclear pore complex and deliver the genome directly into the nucleus. Remarkably, the intact HIV capsid is over one thousand times greater than the size-limit prescribed by the nuclear pore’s diffusion barrier. This barrier is a phase-separated condensate in the central channel of the nuclear pore and is comprised of intrinsically-disordered nucleoporin domains enriched in phenylalanine-glycine (FG) dipeptides. Through multivalent FG-interactions, cellular karyopherins and their bound cargoes solubilise in this phase to drive nucleocytoplasmic transport. By performing anin vitrodissection of the nuclear pore complex, we show that a pocket on the surface of the HIV capsid similarly interacts with FG-motifs from multiple nucleoporins and that this interaction licenses capsids to penetrate nucleoporin condensates. This karyopherin mimicry model resolves a key conceptual challenge for the role of the HIV capsid in nuclear entry, and explains how an exogenous entity much larger than any known cellular cargo can non-destructively breach the nuclear envelope.
Environmental modulators of algae-bacteria interactions at scale
Authors: Gopalakrishnappa Chandana , Li Zeqian , Kuehn Seppe 
Published: March 2023

AbstractPhotosynthetic microbes associated with non-photosynthetic, heterotrophic, bacteria play a key role in the global primary production. Understanding these phototroph-heterotroph associations is therefore important, but remains challenging because they reside in chemically complex aquatic and terrestrial environments. We do not understand how the myriad of environmental parameters from nutrient availability to pH impact interactions between phototrophs and their heterotrophic partners. Here, we leverage a massively parallel droplet microfluidic platform that enables us to interrogate algae-bacteria interactions in>100,000 communities across ∼525 environmental conditions with varying pH, carbon availability and phosphorous availability. By developing a statistical framework to dissect interactions in this complex dataset, we reveal that dependance of algae-bacteria interactions on nutrient availability is strongly modulated by pH and buffering capacity. Furthermore, we show that the chemical identity of the available organic carbon source controls how pH, buffering capacity, and nutrient availability modulate algae-bacteria interactions. By leveraging a high-throughput platform, our study reveals the previously underappreciated role of pH in modulating phototroph-heterotroph interactions.
Elevated ENO2 Disrupts VSMCs Homeostasis Facilitating the Development of Aortic Dissection
Authors: Cai Weixing , Zhang Li , Lin Jing-Jing , Zou Qiuying , Wang Chaoyun , Yang Xi , Wu Xiaohui , Ye Jianqiang , Zheng Hui , Zhang Lin , Zhong Lin , Li Xinyao , Chen Keyuan , Wu Jiangbin , Chen Liangwan , Li Yumei 
Published: March 2023

AbstractOBJECTIVEAortic dissection (AD) is a dangerous cardiovascular disease. However, its regulatory mechanism remains poorly understood. Autophagy is an important pathway for maintaining cellular homeostasis. Recent studies have shown that glycolysis and autophagy are essential for the development of AD. Elevated glycolysis can promote cells autophagy, but the relationship between the two is unclear. Enolase 2 (ENO2) is a glycolytic enzyme. Here, we investigated whether ENO2 can regulate autophagy in vascular smooth muscle cells (VSMCs) involved in the progression of AD.APPROACH AND RESULTSThe levels of ENO2 and autophagy-related proteins in aortic tissues from AD patients were identified by qRT-PCR, Western blot and IHC. We found that autophagosome clearance was impaired in aortic tissues and positively correlated with elevated ENO2 expression. Furthermore, aortic application of smooth muscle-specific adeno-associated virus (AAV) inhibiting ENO2 expression attenuated the development of AD in mice. in vitro experiments, downregulation of ENO2 partially restored PDGF-BB-induced impairment of autophagic flux, as evidenced by reduced expression of Beclin-1, SQSTM1, LC3BII/I and increased levels of LAMP2 in human aortic vascular smooth muscle cells (HAVSMCs). Similarly, increased levels of ENO2 exacerbated the autophagic dysfunction in HAVSMCs. Mechanistically, ENO2 may block autophagic flux through the ENO2-GAP43-ATF4 pathway and disrupt cellular homeostasis.CONCLUSIONSOur data reveal a perturbing role of ENO2 in the homeostasis of VSMCs, suggesting ENO2 as a potential target for intervention in AD.
“Comparison of antibiotic protein binding in human plasma vs. rabbit plasma”
Authors: Pesta Maximilian , Datler Philip , Scheriau Georg , Wohlrab Peter , Eberl Sabine , Lackner Edith , Franz Claudia , Jäger Walter , Maier-Salamon Alexandra , Zeitlinger Markus , Tschernko Edda 
Published: March 2023

AbstractRabbits are frequently used for the examination of the pharmacokinetics and effectiveness of antibiotic substances. However, antibiotics vary substantially in protein binding affecting the concentration of the antimicrobially effective unbound drug. We hypothesized that the binding properties of vancomycin, meropenem and ceftriaxone might vary between human and rabbit plasma. In an in-vitro study we observed dose dependent variability in protein binding of antibiotics between species. Thus, in-vitro-pre-studies are required to guarantee for translational conditions.
Serine peptidases and increased amounts of soluble proteins contribute to heat priming of the plant pathogenic fungusBotrytis cinerea
Authors: Zhang Mingzhe , Trushina Naomi Kagan , Lang Tabea , Hahn Matthias , Chor Metsada Pasmanik , Sharon Amir 
Published: March 2023

AbstractBotrytis cinereacauses grey mold disease in leading crop plants. The disease develops only at cool temperatures, but the fungus remains viable in warm climates and can survive periods of extreme heat. We discovered a strong heat priming effect in which the exposure ofB. cinereato moderately high temperatures greatly improves its ability to cope with subsequent, potentially lethal temperature conditions. We showed that priming promotes protein solubility during heat stress and discovered a group of priming-induced serine-type peptidases. Several lines of evidence, including transcriptomics, proteomics, pharmacology, and mutagenesis data, link these peptidases to theB. cinereapriming response, highlighting their important roles in regulating priming-mediated heat adaptation. By imposing a series of sub-lethal temperature pulses that subverted the priming effect, we managed to eliminate the fungus and prevent disease development, demonstrating the potential for developing temperature-based plant protection methods by targeting the fungal heat priming response.ImportancePriming is a general and important stress adaptation mechanism. Our work highlights the importance of priming in fungal heat adaptation, reveals novel regulators and aspects of heat adaptation mechanisms, and demonstrates the potential of affecting microorganisms, including pathogens through manipulations of the heat adaptation response.
Low circulating adropin concentrations predict increased risk of cognitive decline in community-dwelling older adults
Authors: Aggarwal Geetika , Morley John E. , Vellas Bruno , Nguyen Andrew D. , Butler Andrew A. ,   the MAPT/DSA Group
Published: March 2023

ABSTRACTThe secreted peptide adropin is highly expressed in human brain tissues and correlates with RNA and proteomic risk indicators for dementia. Here we report that plasma adropin concentrations predict risk for cognitive decline in the Multidomain Alzheimer Preventive Trial (ClinicalTrials.govIdentifier,NCT00672685; mean age 75.8y, SD=4.5y, 60.2% female, n=452). Cognitive ability was evaluated using a composite cognitive score (CCS) that assessed four domains: memory, language, executive function, and orientation. Relationships between plasma adropin concentrations and changes in CCS (ΔCCS) were examined using Cox Proportional Hazards Regression, or by grouping into tertiles ranked low to high by adropin values and controlling for age, time between baseline and final visits, baseline CCS, and other risk factors (e.g., education, medication, APOE4 status). Risk of cognitive decline (defined as a ΔCCS of -0.3 or more) decreased with increasing plasma adropin concentrations (hazard ratio = 0.873, 95%CI 0.780-0.977, P=0.018). Between adropin tertiles, ΔCCS was significantly different (P=0.01; estimated marginal mean±SE for the 1st-to 3rd-tertile, -0.317±0.064; -0.275±0.063; -0.042±0.071; n=133,146, and 130, respectively; P<0.05 for 1stvs. 2ndand 3rdadropin tertiles). Normalized plasma Aβ42/40ratio and plasma neurofilament light chain, indicators of neurodegeneration, were significantly different between adropin tertile. These differences were consistent with reduced risk of cognitive decline with higher plasma adropin levels. Overall, these results suggest cognitive decline is reduced in community-dwelling older adults with higher circulating adropin levels. Further studies are needed to determine the underlying causes of the relationship and whether increasing adropin levels can delay cognitive decline.
Dementia Risk Analysis Using Temporal Event Modeling on a Large Real-World Dataset
Authors: Taylor Richard Andrew , Gilson Aidan , Chi Ling , Haimovich Adrian D. , Crawford Anna , Brandt Cynthia , Magidson Phillip , Lai James , Levin Scott , Mecca Adam P. , Hwang Ula 
Published: March 2023

AbstractThe objective of the study is to identify healthcare events leading to a diagnosis of dementia from a large real-world dataset. This study uses a data-driven approach to identify temporally ordered pairs and trajectories of healthcare codes in the electronic health record (EHR). This allows for discovery of novel temporal risk factors leading to an outcome of interest that may not otherwise be obvious. We identified several known (Down syndrome RR: 116.1, thiamine deficiency RR: 76.1, and Parkinson’s disease RR: 41.1) and unknown (Brief psychotic disorder RR: 68.6, Toxic effect of metals RR: 40.4, and Schizoaffective disorders RR: 40.0) factors for a specific dementia diagnosis. The associations with the greatest risk for any dementia diagnosis were found to be primarily related to mental health (Brief psychotic disorder RR: 266.5, Dissociative and conversion disorders RR: 169.8), or neurologic conditions or procedures (Dystonia RR: 121.9, Lumbar Puncture RR: 119.0). Trajectory and clustering analysis identified factors related to cerebrovascular disorders, as well as diagnoses which increase the risk of toxic imbalances. The results of this study have the ability to provide valuable insights into potential patient progression towards dementia and improve recognition of patients at risk for developing dementia.
Dietary and metabolic factors contributing to Barrett’s esophagus: a univariate and multivariate Mendelian randomization study
Authors: Li Zijie , Zhuang Weitao , Wu Junhan , Xu Haijie , Tang Yong , Qiao Guibin 
Published: March 2023

AbstractBackgroundDietary and metabolic factors have been associated with the risk of Barrett’s esophagus (BE) in observational epidemiological studies. However, the aforementioned associations may be influenced by confounding bias. The present study aimed to evaluate these causal relationships through univariate and multivariate Mendelian randomization (MR) analysis.MethodsGenetic instruments associated with dietary and metabolic factors were obtained in the large-scale genome-wide association studies (GWAS), respectively. Summary data for BE were available from a GWAS of 13,358 cases and 43,071 controls of European descent. Univariable MR analysis was initially performed to estimate the causal relationship between exposures and BE. The inverse-variance weighted (IVW) method was adopted as the primary MR analysis. Multivariate MR analysis was further conducted to evaluate the independent effects of exposures on BE.ResultsIn univariate MR analysis, BE was causally associated with higher body mass index (odds ratio (OR) = 2.575, 95% confidence interval (CI): 2.301-2.880, P = 7.369E-61), larger waist circumference (OR = 2.028, 95% CI: 1.648-2.496, P = 2.482E-11), and smoking per day (OR = 1.241, 95% CI: 1.085-1.419, P = 0.002). Dried fruit intake showed a protective effect on BE (OR = 0.228, 95% CI: 0.135-0.384, P = 2.783E-08), whereas alcohol drinking, coffee intake, tea intake, fresh fruit intake, and type 2 diabetes mellitus were not associated with BE (P = 0.351, P = 0.458, P = 0.125, P = 0.847, P = 0.413, respectively). No pleiotropy was found in the sensitivity analysis. The relationships of obesity, smoking, and dried fruit intake with BE risk remained strong after adjustment.ConclusionsOur study provided MR evidence supporting obesity and smoking were independent risk factors for BE. Conversely, dried fruit intake was a protective factor for BE.