bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD1 is transcriptionally regulated by LEF1 in mature T cells
Authors: Zhao Pin , Sun Lanming , Zhao Cong , Malik Samiullah 
Published: March 2023

AbstractProgrammed cell death 1 (PD1) plays a vital role in cancer immune evasion. So monoclonal antibodies targeting PD-1 to boost the immune system are being developed for the treatment of cancer. But the effect of PD1/PD-L1 blocking antibody only works in a subset of patients or some tumors. It is well established that PD-1 can affect the positive selection of T cells. Mice lacking PD1 or PD-L1 had more DP T cells in the thymus. However, how it affects the T-cell repertoire is not very clear. For T cell development and maturation, TCF1 and its homolog LEF1, act as indispensable factors and TCF1 has been most studied. In our work, we found that LEF1, not TCF1, positively regulated the transcription of PD1 by generating two mice models, including ERT2-CRE-LEF1flox/floxmice and concanavalin A (ConA)-mediated T activation mice model. We investigated LEF1 and PD1 expression in mature T cells, including CD4+ T cells, CD8+ T cells, and Treg cells in these two mice models. And we also evaluated the expression of PD1 in tumor-infiltrating lymphocytes in the tumor-implantation experiments. Furthermore, the regulation of PD1 by LEF1 was verified in LEF1 knockdown cells. Our conclusions provided a novel insight into PD1 regulation in immune responses and explored potential strategies for clinical anti-PD1 treatment.
OprF impactsPseudomonas aeruginosabiofilm matrix eDNA levels in a nutrient-dependent manner
Authors: Cassin Erin K. , Araujo-Hernandez Sophia A. , Baughn Dena S. , Londono Melissa C. , Rodriguez Daniela Q. , Tseng Boo Shan 
Published: March 2023

ABSTRACTThe biofilm matrix is composed of exopolysaccharides, eDNA, membrane vesicles, and proteins. While proteomic analyses have identified numerous matrix proteins, their functions in the biofilm remain understudied compared to the other biofilm components. In thePseudomonas aeruginosabiofilm, several studies have identified OprF as an abundant matrix protein and, more specifically, as a component of biofilm membrane vesicles. OprF is a major outer membrane porin ofP. aeruginosacells. However, current data describing the effects of OprF in theP. aeruginosabiofilm is limited. Here we identify a nutrient-dependent effect of OprF in static biofilms, whereby ΔoprFcells form significantly less biofilm than wild type when grown in media containing glucose or low sodium chloride concentrations. Interestingly, this biofilm defect occurs during late static biofilm formation and is not dependent on the production of PQS, which is responsible for outer membrane vesicle production. Furthermore, while biofilms lacking OprF contain approximately 60% less total biomass than those of wild type, the number of cells in these two biofilms is equivalent. We demonstrate thatP. aeruginosaΔoprFbiofilms with reduced biofilm biomass contain less eDNA than wild-type biofilms. These results suggest that the nutrient-dependent effect of OprF is involved in the maintenance of matureP. aeruginosabiofilms by retaining eDNA in the matrix.IMPORTANCEMany pathogens form biofilms, which are bacterial communities encased in an extracellular matrix that protects them against antibacterial treatments. The roles of several matrix components of the opportunistic pathogenPseudomonas aeruginosahave been characterized. However, the effects ofP. aeruginosamatrix proteins remain understudied and are untapped potential targets for antibiofilm treatments. Here we describe a conditional effect of the abundant matrix protein OprF on late-stageP. aeruginosabiofilms. A ΔoprFstrain formed significantly less biofilm in low sodium chloride or with glucose. Interestingly, the defective ΔoprFbiofilms did not exhibit fewer resident cells but contained significantly less extracellular DNA (eDNA) than wild type. These results suggest that OprF is involved in matrix eDNA retention in mature biofilms.
Analysis of SARS-CoV-2 mutations associated with resistance to therapeutic monoclonal antibodies that emerge after treatment
Authors: Focosi Daniele , McConnell Scott , Sullivan David J. , Casadevall Arturo 
Published: March 2023

AbstractThe mutation rate of the Omicron sublineage has led to baseline resistance against all previously authorized anti-Spike monoclonal antibodies (mAbs). Nevertheless, in case more antiviral mAbs will be authorized in the future, it is relevant to understand how frequently treatment-emergent resistance has emerged so far, under different combinations and in different patient subgroups. We report the results of a systematic review of the medical literature for case reports and case series for treatment-emergent immune escape, which is defined as emergence of a resistance-driving mutation in at least 20% of sequences in a given host at a given timepoint. We identified 31 publications detailing 201 cases that included different variants of concern (VOC) and found that the incidence of treatment emergent-resistance ranged from 10% to 50%. Most of the treatment-emergent resistance events occurred in immunocompromised patients. Interestingly, resistance also emerged against cocktails of two mAbs, albeit at lower frequencies. The heterogenous therapeutic management of those cases doesn’t allow inferences about the clinical outcome in patients with treatment-emergent resistance. Furthermore, we noted a temporal correlation between the introduction of mAb therapies and a subsequent increase in SARS-CoV-2 sequences across the globe carrying mutations conferring resistance to that mAb, raising concern as to whether these had originated in mAb-treated individuals. Our findings confirm that treatment-emergent immune escape to anti-Spike mAbs represents a frequent and concerning phenomenon and suggests that these are associated with mAb use in immunosuppressed hosts.
Hearing loss after exposure to vincristine and platinum-based chemotherapy among childhood cancer survivors
Authors: Strebel Sven , Mader Luzius , Jörger Philippa , Waespe Nicolas , Uhlmann Seraina , von der Weid Nicolas , Ansari Marc , Kuehni Claudia E. 
Published: March 2023

ABSTRACTBackgroundVincristine poses a suspected additional risk factor for hearing loss among childhood cancer survivors (CCS) treated with platinum-based chemotherapy, yet evidence is scarce since no study reports vincristine doses. We examined the association of vincristine with hearing loss in a national cohort of CCS.MethodsWe included CCS registered in the Swiss Childhood Cancer Registry treated at age ≤ 18 years with platinum-based chemotherapy between 1990–2014. All participants in our retrospective cohort study had audiogram and treatment data from medical records. We identified CCS exposed to vincristine and calculated the total cumulative dose. We defined clinically relevant hearing loss as grade ≥ 2 using the International Society of Pediatric Oncology Boston Ototoxicity Scale at latest follow-up.ResultsOur study population included 270 CCS (43% female; median age at cancer diagnosis 6.8 years; interquartile range [IQR]: 2.1–11.7 years) with median age at audiogram 13.5 years (IQR: 9.3–17.0 years). Vincristine exposure was associated with an increased risk of hearing loss in the multivariable logistic regression analysis (odds ratio [OR] 4.8; 95% confidence interval [CI]: 1.8–12.9). We found no evidence of dose-response relationship (OR 1.0; 95% CI: 0.97–1.04) or effect modification from vincristine from other ototoxic treatments, such as type of platinum agent, cranial radiotherapy, and hematopoietic stem cell transplantation.ConclusionVincristine is associated with a higher risk of hearing loss in CCS treated with platinum-based chemotherapy. We suggest future studies investigate the underlying mechanism and causality among CCS without exposure to other ototoxic cancer treatments.
Precision MRI phenotyping of muscle volume and quality at a population scale
Authors: Thanaj Marjola , Basty Nicolas , Whitcher Brandon , Sorokin Elena P. , Liu Yi , Srinivasan Ramprakash , Cule Madeleine , Thomas E. Louise , Bell Jimmy D. 
Published: March 2023

AbstractIntroductionMagnetic resonance imaging (MRI) enables direct measurements of muscle volume and quality, allowing for an in-depth understanding of their associations with anthropometric traits, and health conditions. However, it is unclear which muscle volume measurements: total muscle volume, regional measurements, measurements of muscle quality: intermuscular adipose tissue (IMAT) or proton density fat fraction (PDFF), are most informative and associate with relevant health conditions such as dynapenia and frailty.MethodsWe developed a pipeline to automatically segment and extract image-derived phenotypes (IDPs) including total and regional muscle volumes and measures of muscle quality, and applied it to the neck-to-knee Dixon images in 44,520 UK Biobank participants. We further segmented paraspinal muscle from 2D quantitative MRI to quantify muscle PDFF and iron concentration. We defined dynapenia based on grip strength below sex-specific cut-off points and frailty based on five criteria. We used logistic regression to investigate the association between muscle volume and quality measurements and dynapenia and frailty.ResultsMuscle volumes were significantly higher in male compared with female participants, even after correcting for height while, IMAT, (corrected for muscle volume) and paraspinal muscle PDFF were significantly higher in female compared with male participants. From the overall cohort, 7.6% (N = 3,261) were identified with dynapenia, and 1.1% (N = 455) with frailty. Dynapenia and frailty were positively associated with age and negatively associated with physical activity levels. In dynapenia, muscle volume IDPs were most informative, particularly total muscle exhibiting odds ratios (OR) of 0.392 and 95% confidence intervals (CI) = 0.361 - 0.426, while for frailty, muscle quality was found to be most informative, in particular thigh IMAT volume indexed to height squared (OR = 1.396, 95% CI = 1.374 - 1.418), both with p-values below the Bonferroni-corrected threshold (p<8.6×10−5).ConclusionsOur fully automated method enables the quantification of muscle volumes and quality suitable for large population-based studies. For dynapenia, muscle volumes particularly those including greater body coverage such as total muscle are the most informative, whilst, for frailty, markers of muscle quality were the most informative IDPs. These results suggest that different measurements may have varying diagnostic values for different health conditions.
Colorectal Cancer Risk and Ancestry in Colombian admixed Populations
Authors: Criollo-Rayo Angel , Bohórquez Mabel Elena , Lott Paul , Carracedo Angel , Tomlinson Ian , Castro Jorge Mario , Mateus Gilbert , Molina Daniel , Vargas Catalina Rubio , Puentes Carlos ,   CHIBCHA Consortium, Echeverry Magdalena , Carvajal Luis 
Published: March 2023

ABSTRACTSeveral colorectal cancer susceptibility disease loci have been discovered through Genome-wide association studies. However most of the variants were originally identified in Caucasian populations. Demographic history and admixture background may impact the association of known CRC variants due to the differences in linkage disequilibrium across different populations. We performed a genomic study in a sample of 955 cases and 968 controls from admixed populations in Colombia by genotyping ∼1 million SNPs aimed to detect the impact of genetic structure in the association of 20 known SNPs risk for colorectal cancer. The replication was reached for eleven out of 20 nominally associated SNPs; with allelic odds ratios (OR) between 1.14 and 1.41, indicating a minimal individual risk increment; on the other hand, the overall OR for co-inherited SNPs was 5.4 (95% CI: 3.052-9.731,P=1.16E-08). Most of the variants followed a recessive model with significant homozygous ORs distributed between 1.3 and 1.65. The major associated markers were: rs4939827 (18q21.1,P=7.35E-6), rs10411210 (19q13.11,P=0.001) rs10795668 (10p14,P=0.0024), rs4444235 (14q.2.2,P=0.005), rs961253 (20p12.3,P=0.006), rs16892766 (8q23.3,P=0.011) and rs1050547 (8q24.21,P=0.017). Additionally, European ancestral component was associated with colorectal cancer risk (p=6.48E-04, OR = 4.244 95% IC: 1.701-10.68). Our findings in Colombia indicates a significant contribution of the known CRC risk SNPs to the disease in the Colombian population, which in turns can be explained by the genetic European component influx during the admixture process. The unassociated SNPs indicates frequency and genetic structure differences between European and Colombian populations or due to the sample process.
Multi-Site Analysis of Biosynthetic Gene Clusters (BGCs) from the Periodontitis Oral Microbiome
Authors: Koohi-Moghadam Mohamad , Watt Rory M. , Leung W. Keung 
Published: March 2023

AbstractBacteria are key modulators of human health and disease. Biochemicals synthesized by bacterial biosynthetic gene clusters (BGCs) have been shown to play key roles in microbiome–host and microbe–microbe interactions. Whilst BGCs have been widely investigated in the human gut, very few studies have explored BGCs within oral niches. In this pilot study, we used shotgun metagenomic sequencing to profile the microbiota from three different oral sites: saliva, subgingival plaque, and supragingival plaque, within subjects with periodontitis (n = 23) versus controls (n = 16). Our aim was to identify BGCs associated with periodontitis, as well as BGCs that exhibited site (niche) selectivity. We identified 10,742 BGCs in the cohort, some of which were unique for a specific oral site. Aryl polyenes (APEs) and Bacteriocin were the most prevalent clusters, but we also found several ‘novel’ BGCs that were widely distributed across diverse bacterial phyla; other BGCs exhibited selectivity for periodontitis niches. Taken together, our findings significantly expand our metagenomic understanding of microbiota within healthy and diseased oral niches. By uncovering previously unexplored biosynthetic pathways, we provide a potential road-map for the future exploration of poorly understood host-microbe and microbe-microbe interactions in the oral cavity that may contribute to periodontitis.
Time perception reflects individual differences in motor and non-motor symptoms of Parkinson’s disease
Authors: DiMarco Emily , Sadibolova Renata , Jiang Angela , Liebenow Brittany , Jones Rachel E. , ul Haq Ihtsham , Siddiqui Mustafa S. , Terhune Devin B. , Kishida Kenneth T. 
Published: March 2023

AbstractDopaminergic signaling in the striatum has been shown to play a critical role in the perception of time. Decreasing striatal dopamine efficacy is at the core of Parkinson’s disease (PD) motor symptoms and changes in dopaminergic action have been associated with many comorbid non-motor symptoms in PD. We hypothesize that patients with PD perceive time differently and in accordance with their specific comorbid non-motor symptoms and clinical state. We recruited patients with PD and compared individual differences in patients’ clinical features with their ability to judge millisecond to second intervals of time (500ms-1100ms) while on or off their prescribed dopaminergic medications. We show that individual differences in comorbid non-motor symptoms, PD duration, and prescribed dopaminergic pharmacotherapeutics account for individual differences in time perception performance. We report that comorbid impulse control disorder is associated with temporal overestimation; depression is associated with decreased temporal accuracy; and PD disease duration and prescribed levodopa monotherapy are associated with reduced temporal precision and accuracy. Observed differences in time perception are consistent with hypothesized dopaminergic mechanisms thought to underlie the respective motor and non-motor symptoms in PD, but also raise questions about specific dopaminergic mechanisms. In future work, time perception tasks like the one used here, may provide translational or reverse translational utility in investigations aimed at disentangling neural and cognitive systems underlying PD symptom etiology.One Sentence SummaryQuantitative characterization of time perception behavior reflects individual differences in Parkinson’s disease motor and non-motor symptom clinical presentation that are consistent with hypothesized neural and cognitive mechanisms.
Density effects on a tropical copepodAcartiasp.: implications as live feed in aquaculture
Authors: Pham Hung Quoc , Van Bui Canh , Doan Nam Xuan , Dinh Khuong V. 
Published: March 2023

AbstractCalanoid copepodAcartiaspecies are major live feeds for the early stages of economically important marine fish in hatcheries in Southeast Asian countries. However, rearingAcartiacopepods at high densities to increase productivity remains a major challenge. To address the issue, we conducted two experiments on 1)Acartiasp. nauplii (1000, 3000, 6000, 9000, 12000, and 15000 individuals L-1) and 2) adults (1000, 1500, 2000, and 2500 individuals L-1). We assessed key parameters for biomass production: development, survival, and egg production. In general, increased density resulted in longer development time, and lowered survival and egg production, but did not affect the size of adult males and females. Despite survival to adulthood decreasing at higher stocking nauplii densities, the number of surviving adults was highest at a stocking density of 12000 ind L-1. Egg production was very low which may be the result of high egg predation. The total eggs harvested were highest at the lowest adult density. These results are essential for the biomass production ofAcartiasp. in central Vietnam.
Microfluidics on Stretchable Strings
Authors: DeCorwin-Martin Philippe , Ng Andy , Juncker David 
Published: March 2023

AbstractThis paper introduces string microfluidics (SM), which consists of stretchable strings trapping discrete microdroplets within a porous matrix, and the realization of elementary microfluidic operations such as droplet formation, transport, splitting, merging, and mixing by moving and stretching the strings. While performing these operations, SM was shown to be compatible with colorimetric biological assays. SM represents a new form of microfluidics that integrates the concepts of thread microfluidics and digital microfluidics, along with mobile or reconfigurable microfluidics where liquid transport is realized by manipulating the substrate.
Predicting individual traits from models of brain dynamics accurately and reliably using the Fisher kernel
Authors: Ahrends C , Woolrich M , Vidaurr D 
Published: March 2023

AbstractPredicting an individual’s cognitive traits or clinical condition using brain signals is a central goal in modern neuroscience. This is commonly done using either structural aspects, such as structural connectivity or cortical thickness, or aggregated measures of brain activity that average over time. But these approaches are missing a central aspect of brain function: the unique ways in which an individual’s brain activity unfolds over time. One reason why these dynamic patterns are not usually considered is that they have to be described by complex, high-dimensional models; and it is unclear how best to use these models for prediction. We here propose an approach that describes dynamic functional connectivity and amplitude patterns using a Hidden Markov model (HMM) and combines it with the Fisher kernel, which can be used to predict individual traits. The Fisher kernel is constructed from the HMM in a mathematically principled manner, thereby preserving the structure of the underlying model. We show here, in fMRI data, that the HMM-Fisher kernel approach is accurate and reliable. We compare the Fisher kernel to other prediction methods, both time-varying and time-averaged functional connectivity-based models. Our approach leverages information about an individual’s time-varying amplitude and functional connectivity for prediction and has broad applications in cognitive neuroscience and personalised medicine.
Gene essentiality in cancer is better predicted by mRNA abundance than by gene regulatory network-inferred activity
Authors: Tudose Cosmin , Bond Jonathan , Ryan Colm J. 
Published: March 2023

AbstractGene regulatory networks (GRNs) are often deregulated in tumor cells, resulting in altered transcriptional programs that facilitate tumor growth. These altered networks may make tumor cells vulnerable to the inhibition of specific regulatory proteins. Consequently, the reconstruction of GRNs in tumors is often proposed as a means to identify therapeutic targets. While there are examples of individual targets identified using GRNs, the extent to which GRNs can be used to predict sensitivity to targeted intervention in general remains unknown. Here we use the results of genome-wide CRISPR screens to systematically assess the ability of GRNs to predict sensitivity to gene inhibition in cancer cell lines. Using GRNs derived from multiple sources, including GRNs reconstructed from tumor transcriptomes and from curated databases, we infer regulatory gene activity in cancer cell lines from ten cancer types. We then ask, in each cancer type, if the inferred regulatory activity of each gene is predictive of sensitivity to CRISPR perturbation of that gene. We observe slight variation in the correlation between gene regulatory activity and gene sensitivity depending on the source of the GRN and the activity estimation method used. However, we find that there is consistently a stronger relationship between mRNA abundance and gene sensitivity than there is between regulatory gene activity and gene sensitivity. This is true both when gene sensitivity is treated as a binary and a quantitative property. Overall, our results suggest that gene sensitivity is better predicted by measured expression than by GRN-inferred activity.
Not one size fits all: influence of EEG type when training a deep neural network for interictal epileptiform discharge detection
Authors: da Silva Lourenço Catarina , Tjepkema-Cloostermans Marleen C. , van Putten Michel J. A. M. 
Published: March 2023

AbstractObjectiveDeep learning methods have shown potential in automating interictal epileptiform discharge (IED) detection in electroencephalograms (EEGs). While it is known that these algorithms are dependent on the type of data used for training, this has not been explored in EEG analysis applications. We study the difference in performance of deep learning algorithms on routine and ambulatory EEG data.MethodsWe trained the same neural network on three datasets: 166 routine EEGs (VGGC–R), 75 ambulatory EEGs (VGGC–A) and a combination of the two data types (VGGC-C, 241 EEGs total). Networks were tested on 34 routine EEGs and 33 ambulatory recordings, where all 2 s non-overlapping epochs were labeled with a probability that expressed the likelihood of containing an epileptiform discharge. Performance was quantified as sensitivity, specificity and the rate of false detections (FPR).ResultsThe VGGC-R led to 84% sensitivity at 99% specificity on the routine EEGs, but its sensitivity was only 53% on ambulatory EEGs, with a FPR > 3 FP/min. The VGGC-C and VGGC-A yielded sensitivities of 79% and 60%, respectively, at 99% specificity on ambulatory data, but their sensitivity was less than 60% for routine EEGs.ConclusionWe show that performance of deep nets for IED detection depends critically on the type of recording. The VGGC-R should be used for routine recordings and the VGGC-C should be used for ambulatory recordings for IED detection.SignificanceThe type of data used to train algorithms should be optimized according to their application, as this has a significant impact on algorithm performance.