bluuebunny/crossref_metadata_2025_split huggingface dataset:
The α4 nicotinic acetylcholine receptor is necessary for the initiation of organophosphate-induced neuronal hyperexcitability
Authors: Andrew Peter M. , Feng Wei , Calsbeek Jonas J. , Antrobus Shane P. , Cherednychenko Gennady A. , MacMahon JA Jeremy A. , Bernardino Pedro N. , Liu Xiuzhen , Harvey Danielle J. , Lein Pamela J. , Pessah Isaac N. 
Published: January 2024

AbstractAcute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threateningstatus epilepticus. Significant research effort has been invested investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less effort focused on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination ofin vitroandin vivomodels. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and acute treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.
SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis
Authors: Coelho Ricardo , Seashore-Ludlow Brinton , Schütz Sarah , Christopher Lombardo Flavio , Moussaud-Lamodière Elisabeth , Casanova Ruben , Ficek-Pascual Joanna , Brunhilde Labrosse Kathrin , Hensler Michal , Lopez-Nunez Monica , Rimmer Natalie , Fedier Andre , Lima Renata , Montavon Sartorius Céline , Kurzeder Christian , Singer Franziska , Bertolini Anne ,   Tumor Profiler Consortium, Fucikova Jitka , Rätsch Gunnar , Bodenmiller Bernd , Kallioniemi Olli , Östling Päivi , David Leonor , Heinzelmann-Schwarz Viola , Jacob Francis 
Published: January 2024

AbstractResistance to chemotherapy and PARPi inhibitors remains a critical challenge in the treatment of epithelial ovarian cancer, mainly due to disabled apoptotic responses in tumor cells. Given mesothelin’s pivotal role in ovarian cancer and its restricted expression in healthy tissues, we conducted a drug-screening discovery analysis across a range of genetically modified cancer cells to unveil mesothelin’s therapeutic impact. We observed enhanced cell death in cancer cells with low mesothelin expression when exposed to a second mitochondria-derived activator of caspases (SMAC) mimetics, and demonstrated a compelling synergy when combined with chemotherapy inex vivopatient-derived cultures and zebrafish tumor xenografts. Mechanistically, the addition of the SMAC mimetics drug birinapant to either carboplatin or paclitaxel triggered the activation of the Caspase 8-dependent apoptotic program facilitated by TNFLJ signaling. Multimodal analysis of neoadjuvant-treated patient samples further revealed an association between tumor-associated macrophages and the activation of TNFLJ-related pathways. Our proposed bimodal treatment shows promise in enhancing the clinical management of patients by harnessing the potential of SMAC mimetics alongside conventional chemotherapy.
Dynamic Profiling and Prediction of Antibody Response to Booster Inactivated Vaccines by Microsample-driven Biosensor and Machine Learning
Authors: Bian Sumin , Shang Min , Tao Ying , Wang Pengbo , Xu Yankun , Wang Yao , Shen Zhida , Sawan Mahamad 
Published: January 2024

AbstractKnowledge on the antibody response to inactivated vaccines in third dose is crucial because it is one of the primary global vaccination programs. This study integrated microsampling with optical biosensors to profile neutralizing antibodies (NAbs) in fifteen vaccinated healthy donors, followed by application of machine learning to predict antibody response at given timepoints. Over a nine-month duration, microsampling and venipuncture were conducted at seven individual timepoints. A refined iteration of fiber optic-biolayer interferometry (FO-BLI) biosensor was designed, enabling rapid multiplexed biosensing of NAbs towards both wild-type and Omicron variants in minutes. Findings revealed a strong correlation (Pearson r of 0.919, specificity of 100%) between wild-type NAbs levels in microsamples and sera. Following the third dose, Sera NAbs levels for wide-type increased by 2.9-fold after seven days and 3.3-fold within a month, subsequently waning and becoming undetectable in three months. Considerable but incomplete escape of the latest omicron subvariants from booster vaccine elicited NAbs was confirmed, although a higher number of binding antibodies (BAbs) was identified by another rapid FO-BLI biosensor in minutes. Significantly, FO-BLI highly correlated with a pseudovirus neutralization assay in identifying neutralizing capacities (Pearson r of 0.983). Additionally, machine learning demonstrated exceptional accuracy in predicting antibody levels with an error of <5% for both NAbs and BAbs across multiple timepoints. Microsample-driven biosensing enables individuals to access their results within hours after self-collection, while precise models could guide personalized vaccination strategies. The technology’s innate adaptability positions its potential for effective translation in diseases prevention and vaccines development.
Quantitative MRI biomarker for classification of clinically significant prostate cancer: calibration for reproducibility across echo times
Authors: Kallis Karoline , Conlin Christopher C. , Ollison Courtney , Hahn Michael E. , Rakow-Penner Rebecca , Dale Anders M. , Seibert Tyler M. 
Published: January 2024

BackgroundRestriction Spectrum Imaging restriction score (RSIrs) is a quantitative biomarker for detecting clinically significant prostate cancer (csPCa). However, the quantitative value of the RSIrs is affected by imaging parameters such as echo time (TE).PurposeThe purpose of the present study is to develop a calibration method to account for differences in echo times and facilitate use of RSIrs as a quantitative biomarker for the detection of csPCa.MethodsThis study included 197 consecutive patients who underwent MRI and biopsy examination; 97 were diagnosed with csPCa (grade group ≥ 2). RSI data were acquired three times during the same session: twice at minimum TE∼75ms and once at TE=90ms (TEmin1, TEmin2, and TE90, respectively). A proposed calibration method, trained on patients without csPCa, estimated a linear scaling factor (f) for each of the four diffusion compartments (C) of the RSI signal model. A linear regression model was determined to match C-maps of TE90 to the reference C-maps of TEmin1within the interval ranging from 95thto 99thpercentile of signal intensity within the prostate. RSIrs comparisons were made at 98thpercentile within each patient’s prostate.We compared RSIrs from calibrated TE90 (RSIrsTE90corr) and uncorrected TE90 (RSIrsTE90) to RSIrs from reference TEmin1(RSIrsTEmin1) and repeated TEmin2(RSIrsTEmin2). Calibration performance was evaluated with sensitivity, specificity, area under the ROC curve, positive predicted value, negative predicted value, and F1-score.ResultsScaling factors for C1, C2, C3, and C4were estimated as 1.70, 1.38, 1.03, and 1.19, respectively. In non-csPCa cases, the 98thpercentile of RSIrsTEmin2and RSIrsTEmin1differed by 0.27±0.86SI (mean±standard deviation), whereas RSIrsTE90differed from RSIrsTEmin1by 1.81±1.20SI. After calibration, this bias was reduced to -0.41±1.20SI, representing a 78% reduction in absolute error. For patients with csPCa, the difference was 0.54±1.98SI between RSIrsTEmin2and RSIrsTEmin1and 2.28±2.06SI between RSIrsTE90and RSIrsTEmin1. After calibration, the mean difference decreased to -0.86SI, a 38% reduction in absolute error. At the Youden index for patient-level classification of csPCa (8.94SI), RSIrsTEmin1has a sensitivity of 66% and a specificity of 72%. Prior to calibration, RSIrsTE90at the same threshold tended to over-diagnose benign cases (sensitivity 44%, specificity 88%). Post-calibration, RSIrsTE90corrperforms more similarly to the reference (sensitivity 71%, specificity 62%).ConclusionThe proposed linear calibration method produces similar quantitative biomarker values for acquisitions with different TE, reducing TE-induced error by 78% and 38% for non-csPCa and csPCa, respectively.
Mutation of the peptide-regulated transcription factor ComR for amidated peptide specificity and heterologous function inLactiplantibacillus plantarumWCFS1
Authors: Brasino Michael , Wagnell Eli , Ozdemir Sila , Ranganathan Srivathsan , Merritt Justin 
Published: January 2024

AbstractThere is a growing interest in the use of probiotic bacteria as biosensors for the detection of disease. However, there is a lack of bacterial receptors developed for specific disease biomarkers. Here, we have investigated the use of the peptide-regulated transcription factor ComR from Streptococcus spp. for specific peptide biomarker detection. ComR exhibits a number of attractive features that are potentially exploitable to create an exquisitely sensitive biomolecular switch for engineered biosensor circuitry within the probiotic organismLactiplantibacillus plantarumWCFS1. By screening a library of ComR mutant protein variants, we identified mutations that increased the specificity of ComR toward an amidated version of its cognate extracellular signaling peptide, demonstrating the potential for ComR to detect this important class of biomarker.
Population estimates of the number of adults in the United Kingdom with a hearing loss updated using 2021 and 2022 census data
Authors: Akeroyd Michael A , Munro Kevin J 
Published: January 2024

ABSTRACTWe update an earlier publication (Akeroyd MA et al., Int J Audiol. 2014 53(1):60-1) to derive new estimates of the number of adults in the UK with a hearing loss, using population data from the 2021/2022 UK censuses and prevalence data from the UK National Study of Hearing (Akeroyd MA et al. Trends In Hearing 2019 Jan-Dec;23:2331216519887614). Setting a criterion of a four-frequency hearing level >= 35 dB in the better ear gives an estimate of 4.6 million adults aged 18–80, which is a 17% increase on the earlier value from the 2011 census. With a criterion of >= 20 dB hearing level, the estimate is 12.3 million in total, or 1 in 4 of the population aged 18-80. The revised numbers highlight just how common hearing problems are in the population.
An ecological study of COVID-19 outcomes among Florida counties
Authors: Ali Sobur , Azarian Taj 
Published: January 2024

AbstractBackgroundDuring the COVID-19 pandemic, Florida reported some of the highest number of cases and deaths in the US; however, county-level variation in COVID-19 outcomes has not been comprehensively investigated. The present ecological study aimed to assess corelates of COVID-19 outcomes among Florida counties that explain variation in case rates, mortality rates, and case fatality rates (CFR) across pandemic waves.MethodWe obtained county-level administrative data and COVID-19 case reports from public repositories. We tested spatial autocorrelation to assess geographic clustering in COVID-19 outcomes: case rate, mortality rate, and CFR. Stepwise linear regression was employed to test the association between case, death, and CFR and 18 demographic, socioeconomic, and health-related county-level predictors.ResultsWe found mortality rate and CFR were significantly higher in rural counties compared to urban counties, among which significant differences in vaccination coverage was also observed. Multivariate analysis found that the percentage of the population aged over 65 years, the percentage of the obese people, and the percentage of rural population were significant predictors of COVID-19 case rate. Median age, vaccination coverage, percentage of people who smoke, and percentage of the population with diabetes were significant influencing factors for CFR. Importantly, vaccination coverage was significantly associated with a reduction in case rate (R = - 0.26, p = 0.03) and mortality (R = -0.51, p < 0.001). Last, we found that spatial dependencies play a role in explaining variations in COVID-19 CFR among Florida counties.ConclusionOur findings emphasize the need for targeted, equitable public health strategies to reduce disparities and enhance population resilience during public health crises. We further inform future spatial-epidemiological analyses and present actionable data for policies related to preparedness and response to current and future epidemics in Florida and elsewhere.
Hyper Flexible Neural Networks Rapidly Switch between Logic Operations in a Compact Four Neuron Circuit
Authors: White Alexander James , Liu Belle , Hsieh Ming-Ju , Chang Meng-Fan , Wu Kuo-An , Lo Chung-Chuan 
Published: January 2024

AbstractBiological neural circuits at various levels exhibit rapid adaptability to diverse environmental stimuli. Such fast response times imply that adaptation cannot rely solely on synaptic plasticity, which operates on a much slower timescale. Instead, circuits must be inherently hyper-flexible and receptive to switches in functionalities without changes in network structure. This biological flexibility is a fruitful mechanism for constructing artificial reconfigurable circuits, whether they are spiking or non-spiking. In this study, we demonstrate that a 4-neuron circuit can rapidly and controllably switch between 24 unique logical functions while maintaining the same set of synaptic weights. Moreover, we show that this reconfigurability works for several different underlying neuronal architectures and strikingly can be applied to a network composed of any sigmoid-shaped activation function. We conclude with proof-of-concept applications showing that we can perform standard tasks such as a full-adder, as well as event-based conditional computing, such as detecting unexpected motion.
Increased interaction between connexin43 and microtubules is critical for glioblastoma stem-like cell maintenance and tumorigenicity
Authors: Smyth James W. , Guo Sujuan , O’Rourke Lorie , Deaver Stacie , Dahlka Jacob , Nurmemmedov Elmar , Sheng Zhi , Gourdie Robert G. , Lamouille Samy 
Published: January 2024

AbstractGlioblastoma (GBM) is the most common primary tumor of the central nervous system. One major challenge in GBM treatment is the resistance to chemotherapy and radiotherapy observed in subpopulations of cancer cells, including GBM stem-like cells (GSCs). These cells hold the ability to self-renew or differentiate following treatment, participating in tumor recurrence. The gap junction protein connexin43 (Cx43) has complex roles in oncogenesis and we have previously demonstrated an association between Cx43 and GBM chemotherapy resistance. Here, we report, for the first time, increased direct interaction between non-junctional Cx43 with microtubules in the cytoplasm of GSCs. We hypothesize that non-junctional Cx43/microtubule complexing is critical for GSC maintenance and survival and sought to specifically disrupt this interaction while maintaining other Cx43 functions, such as gap junction formation. Using a Cx43 mimetic peptide of the carboxyl terminal tubulin-binding domain of Cx43 (JM2), we successfully ablated Cx43 interaction with microtubules in GSCs. Importantly, administration of JM2 significantly decreased GSC survivalin vitro, and limited GSC-derived tumor growthin vivo. Together, these results identify JM2 as a novel peptide drug to ablate GSCs in GBM treatment.
The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir
Authors: Dinh Tung , Tber Zahira , Rey Juan S. , Mengshetti Seema , Annamalai Arun S. , Haney Reed , Briganti Lorenzo , Amblard Franck , Fuchs James R. , Cherepanov Peter , Kim Kyungjin , Schinazi Raymond F. , Perilla Juan R. , Kim Baek , Kvaratskhelia Mamuka 
Published: January 2024

ABSTRACTAllosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1(Y99H/A128T IN)variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. While both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCDY99H/A128T+ PIR complex. Consequently, full-length INY99H/A128Twas substantially less susceptible to the PIR induced hyper-multimerization than the WT protein, and HIV-1(Y99H/A128T IN)conferred >150- fold resistance to the inhibitor compared to the WT virus. By rationally modifying PIR we have developed its analog EKC110, which readily induced hyper-multimerization of INY99H/A128Tin vitroand was ∼14-fold more potent against HIV-1(Y99H/A128T IN)than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use.IMPORTANCEAntiretroviral therapies save the lives of millions of people living with HIV (PLWH). However, evolution of multi-drug-resistant viral phenotypes is a major clinical problem, and there are limited or no treatment options for heavily treatment-experienced PLWH. Allosteric HIV-1 integrase inhibitors (ALLINIs) are a novel class of antiretroviral compounds which work by a unique mechanism of binding to the non-catalytic site on the viral protein and inducing aberrant integrase multimerization. Accordingly, ALLINIs potently inhibit both wild type HIV-1 and all drug-resistant viral phenotypes that have so far emerged against currently used therapies. Pirmitegravir, a highly potent and safe investigational ALLINI, is currently advancing through clinical trials. Here we have elucidated structural and mechanistic bases behind the emergence of HIV-1 integrase mutations in infected cell that confer resistance to pirmitegravir. In turn, our findings allowed us to rationally develop an improved ALLINI with substantially enhanced potency against the pirmitegravir resistant virus.
Ketone body 3-hydroxybutyrate alleviates CCl4-induced liver fibrosis in mice through regulation of mitochondrial fission and reduction of oxidative stress
Authors: Zhang Yudian , Liu Xinyi , Wang Yifan , Liu Mengyuan , Guo Ziyi , Zhang Jinbo , Wu Fuqing , Chen Guo-Qiang 
Published: January 2024

ABSTRACT3-Hydroxybutyrate (3HB) is an important metabolite and regulatory molecule produced in liver. Previous studies have shown that 3HB could be beneficial to many diseases, including brain diseases, diabetes, and most importantly, inflammation and liver related injury. Therefore, the effect of 3HB on liver fibrosis, one key step of liver diseases which proved to be reversible, is urgent to explore. In this study, the CCl4-induced mouse model of liver fibrosis has been successfully constructed and treated by 3HB. The results demonstrate that 3HB could alleviate CCl4-induced liver injury and inflammation in mice, decrease the accumulation of collagen, the expression of pro-fibrotic genes as well as inflammatory factors, and finally the degree of liver fibrosis. The transcriptome data recovers that the anti-fibrotic effect of 3HB might be exerted through several ways, such as regulating mitochondrial function, reducing oxidative stress and p53 signaling pathways, proposing a safe and relatively fast possibility for the treatment of liver fibrosis.
Frontal-Auditory Cortical Interactions and Sensory Prediction During Vocal Production in Marmoset Monkeys
Authors: Tsunada Joji , Eliades Steven J. 
Published: January 2024

ABSTRACTThe control of speech and vocal production involves the calculation of error between the intended vocal output and the resulting auditory feedback. Consistent with this model, recent evidence has demonstrated that the auditory cortex is suppressed immediately before and during vocal production, yet is still sensitive to differences between vocal output and altered auditory feedback. This suppression has been suggested to be the result of top-down signals containing information about the intended vocal output, potentially originating from motor or other frontal cortical areas. However, whether such frontal areas are the source of suppressive and predictive signaling to the auditory cortex during vocalization is unknown. Here, we simultaneously recorded neural activity from both the auditory and frontal cortices of marmoset monkeys while they produced self-initiated vocalizations. We found increases in neural activity in both brain areas preceding the onset of vocal production, notably changes in both multi-unit activity and local field potential theta-band power. Connectivity analysis using Granger causality demonstrated that frontal cortex sends directed signaling to the auditory cortex during this pre-vocal period. Importantly, this pre-vocal activity predicted both vocalization-induced suppression of the auditory cortex as well as the acoustics of subsequent vocalizations. These results suggest that frontal cortical areas communicate with the auditory cortex preceding vocal production, with frontal-auditory signals that may reflect the transmission of sensory prediction information. This interaction between frontal and auditory cortices may contribute to mechanisms that calculate errors between intended and actual vocal outputs during vocal communication.
Development of a spontaneous preterm birth predictive model using a panel of serum protein biomarkers for early pregnant women: A nested case–control study
Authors: Liang Shuang , Chen Yuling , Jia Tingting , Chang Ying , Li Wen , Piao Yongjun , Chen Xu 
Published: January 2024

AbstractObjectiveTo develop a model based on first trimester maternal serum LC-MS/MS to predict spontaneous preterm birth (sPTB) < 37weeks.MethodsA cohort of 2,053 women were enrolled in a tertiary maternity hospital in China from July 1, 2018 to January 31, 2019. In total, 110 singleton pregnancies (26 cases of sPTB and 84 controls) at 11–136/7gestational weeks were used for model development and internal validation. A total of 72 pregnancies (25 cases of sPTB and 47 controls) at 20-32 gestational weeks from an additional cohort of 2,167 women were used to evaluate the scalability of the prediction model. Maternal serum samples were collected at enrollment and analyzed by LC-MS/MS, and candidate proteins were used to develop an optimal predictive model by machine learning algorithms.ResultsA novel predictive panel with four proteins, including sFlt-1, MMP-8, ceruloplasmin, and SHBG, which was the most discriminative subset, was developed. The optimal model of logistic regression had an AUC of 0.934, with additional prediction of sPTB in second and third trimester (0.868 AUC). Importantly, higher-risk subjects defined by the prediction generally gave birth earlier than lower-risk subjects.ConclusionFirst trimester modeling based on maternal serum LC-MS/MS identifies pregnant women at risk of sPTB, which may provide utility in identifying women at risk at an early stage of pregnancy before clinical presentation to allow for earlier intervention.