bluuebunny/crossref_metadata_2025_split huggingface dataset:
SFSWAP is a negative regulator of OGT intron detention and global pre-mRNA splicing
Authors: Govindan Ashwin , Conrad Nicholas K. 
Published: October 2024

AbstractO-GlcNAcylation is the reversible post-translational addition of β-N-acetylglucosamine to serine and threonine residues of nuclear and cytoplasmic proteins. It plays an important role in several cellular processes through the modification of thousands of protein substrates. O-GlcNAcylation in humans is mediated by a single essential enzyme, O-GlcNAc transferase (OGT). OGT, together with the sole O-GlcNAcase OGA, form an intricate feedback loop to maintain O-GlcNAc homeostasis in response to changes in cellular O-GlcNAc using a dynamic mechanism involving nuclear retention of its fourth intron. However, the molecular mechanism of this dynamic regulation remains unclear. Using an O-GlcNAc responsive GFP reporter cell line, we identify SFSWAP, a poorly characterized splicing factor, as a trans-acting factor regulating OGT intron detention. We show that SFSWAP is a global regulator of retained intron splicing and exon skipping that primarily acts as a negative regulator of splicing. In contrast, knockdown of SFSWAP leads to reduced inclusion of a ‘decoy exon’ present in the OGT retained intron which may mediate its role in OGT intron detention. Global analysis of decoy exon inclusion in SFSWAP and UPF1 double knockdown cells indicate altered patterns of decoy exon usage. Together, these data indicate a role for SFSWAP as a global negative regulator of pre-mRNA splicing and positive regulator of intron retention.
Spillover rate is not a predictor of host jump risk
Authors: Simony Brandon J. , Kennedy David A. 
Published: October 2024

1AbstractSpillover of infectious diseases is a significant issue for human, animal, and plant health, in part due to their potential to host jump. Current approaches to predict and prevent host jumps are structured around discovering new viruses, drawing associations between pathogen characteristics and host jump risk, and managing spillover, but prediction and prevention are still elusive. Spillover is a critical step in the process of completing a host jump, so it is often assumed that a pathogen’s spillover rate is predictive of host jump risk. However, this may not necessarily be the case. While a pathogen that spills over into a novel host frequently will indeed have many opportunities to establish itself, the lack of success establishing itself in previous spillovers demonstrates a poor ability to do so. In comparison, a pathogen that rarely spills over will have few opportunities to establish itself, but may be well suited to do so, and could, in theory, be more likely to host jump despite these limited opportunities. Here we address the question of which of these poses the greater risk. Using a Bayesian framework, we create a model to quantify the probability that a host jump occurs in some future time interval. This model only depends on the number of spillover events in the past and future, and our uncertainty regarding the probability that a single spillover will result in a host jump. We derive an analytical solution to this model, which shows that when past and future spillover rates are linearly correlated, a pathogen’s inherent rate of spillover is a poor predictor of host jump risk owing to two complementary factors. First, the pathogens that pose the greatest host jump risk may be either those that spillover extremely rarely or extremely commonly, with the result depending on our prior uncertainly in the probability that a spillover will result in a host jump. Second, as spillover rate becomes large, the increase in the number of opportunities for a host jump to occur conferred by the increase in the number of spillover events is exactly balanced by a decrease in the probability of success for each individual spillover event. Therefore, we show that spillover rate is not a useful metric for evaluating host jump risk.
An 8-Week Oral Therapy with Ashwagandha (Withania Somnifera) Root Extract (600 mg/day) Improves Frailty and Quality of Life in Elderly: A Prospective, Randomized, Placebo-Controlled, Efficacy and Safety Study
Authors: Naik K. Sunil , Muralidhar Gudla , Rao Bade Srinivas , Wankhade Kalpana 
Published: October 2024

ABSTRACTFrailty is a state of increased vulnerability resulting from aging due to cumulative decline in physiological system over a lifespan. Few pharmacological agents have been investigated for the treatment of frailty. In Ayurveda, Ashwagandha (Withania Somnifera) is a popular botanical medicine used for improvement in physical strength and mental stress and has a potential for treatment of frailty. This placebo-controlled study assessed the efficacy and safety of a capsule containing 300mg of Ashwagandha Root Extract (ARE) administered twice daily orally for 8 weeks. Fifty elderly subjects with a frailty score ≥7 based on Frailty Assessment and Screening Tool (FAST) were randomized in a 1:1 ratio to receive either Ashwagandha (ARE, n=25) or placebo (PL, n=25). Improvement in frailty after 8 weeks was assessed by FAST, 6-minute Walk Test (6MWT), Pittsburgh Sleep Quality Index (PSQI), Mini-Mental State Examination (MMSE) and Short Form Survey (SF-12) scores. Blood samples were collected at baseline and week 8 for estimation of C-Reactive Protein (CRP), cortisol and Creatinine Kinase (CK). Significant improvement (p<0.01) in scores for FAST, 6MWTs, PSQI, MMSE, and SF-12 were seen with ARE after 8 weeks. Also, significant improvements (p<0.05) were observed in CK and in CRP with ARE. These improvements were greater (p<0.05) with ARE as compared to placebo. ARE was well tolerated with no adverse effects, and no changes in hepatic and renal parameters. Thus, Ashwagandha root extract can be a valuable therapeutic option for improvement of health condition in frailty.
Circulating Adenoid Cystic Carcinoma associated MYB transcripts enable rapid and sensitive detection of metastatic disease in blood liquid biopsies
Authors: Moeyersoms Acadia H.M. , Knechtel Kendall W. , Rong Andrew J. , Gallo Ryan A. , Zhang Michelle , Marsh Harper M. , Sargi Zoukaa B. , Leibowitz Jason M. , Civantos Francisco J. , Weed Donald T. , Dubovy Sander R. , Tse David T. , Pelaez Daniel 
Published: October 2024

AbstractAdenoid cystic carcinoma (ACC) is a rare and lethal malignancy that originates in secretory glands of the head and neck. A prominent molecular feature of ACC is the overexpression of the proto-oncogene MYB. ACC has a poor long-term survival due to its high propensity for recurrence and protracted metastasis. Currently, clinical technologies lack the efficiency to distinguish patient prognosis prior to its redevelopment. We hypothesize that metastatic ACC can be detected by monitoring tumor-specific MYB expression in patients’ blood. We developed a quantitative polymerase chain reaction (qPCR) assay for MYB transcripts and screened blood samples from four patient cohorts: no history or evidence of ACC (n=23), past history of ACC and no evidence of disease (NED) for greater than three years (n=15), local ACC (n=6), and metastatic ACC (n=5). Our assay detected significantly elevated levels of MYB transcripts in the metastatic ACC cohort (p < 0.01). Receiver operating characteristic (ROC) curves comparing metastatic to NED and metastatic to local disease were significant, with p values < 0.0001 and 0.0008, respectively. Single-cell RNA sequencing (scRNA-seq) of blood from metastatic ACC identified a cluster of circulating tumor cells (CTCs) expressing MYB. Here, we report a sensitive, cost-effective, and minimally invasive diagnostic test that leverages tumor-specific signatures to screen for metastatic ACC disease, potentially enhancing detection earlier than the current clinical standard.
The Role of Predictive Processing and Perceptual Load in Selective Visual Attention: An Examination with Semantically Salient and Less Salient Distractors
Authors: Ozsu Ataol Burak , Urgen Burcu A. 
Published: October 2024

AbstractOur attentional resources are allocated to the various aspects of the environment based on the context, and predictive coding has been used as a model to explain the interaction between sensory-based information and top-down expectations in visual attention (Spratling, 2008; Rauss et al., 2011). On the other hand, the saliency of the environmental stimuli is also hypothesized to be capturing the attentional resources of the individuals involuntarily, and thus, it is thought to be playing a crucial role in attentional resource allocation. The current study investigates the role of predictive processing of task difficulty in selective visual attention in the presence of various distractors. Utilizing a letter search task, we provided brief cues about the upcoming task’s difficulty, and participants were asked to detect the target letters. We investigated whether predictive processing about task demands may cause a difference in behavioral measures in the presence of semantically less salient distractors in Experiment 1 (Gabor patches) and semantically more salient distractors in Experiment 2 (faces). Results showed that unmet expectations about the task demands caused longer reaction times in both studies. We observed that all independent variables, which are task difficulty, cue congruency, and distractor presence, affected reaction times in both experiments, but cue congruency interacted with distractor presence only in Experiment 2. Here, we argue that though predictive processing plays a role in attentional resource allocation and, distractors’ characteristics are also crucial as the saliency level interacts with the cue congruency.
Targeted, high-resolution sensing of volatile organic compounds by covalent nanopore detection
Authors: McGivern Lauren E , Lim Zhong Hui , Yuan Yizhi , Bo Zonghua , Bayley Hagan , Qing Yujia 
Published: October 2024

AbstractVolatile organic compounds are choice analytes in a variety of contexts. For example, humans release over 4000 volatile organic compounds, many of which are diagnostic of life-threatening medical conditions. A combination of a large number of potential analytes requires the application of costly, cumbersome technology. Here, we show that covalent nanopore sensing can be used for the targeted detection of a reduced set of analytes in a mixture: in this case aldehydes, which constitute ∼5% of human volatiles. Further, nanopore engineering permits high-resolution detection, which allows closely related aldehydes including isomers to be distinguished. Differential sensing of other chemical classes, such as alcohols, is demonstrated by leveraging their enzymatic conversion to aldehydes. Our approach is compatible with the use of cheap, portable, user-friendly diagnostic devices applicable to a wide variety of objectives, including pollutant monitoring, food and beverage testing and the quality control of pharmaceuticals, as well as disease diagnostics.
A lineage-specific nascent RNA assay unveils principles of gene regulation in tissue biology
Authors: Chovatiya Gopal , Wang Alex B , Versluis Philip , Bai Chris K , Huang Sean Y , DeBerardine Michael , Ray Judhajeet , Ozer Abdullah , Lis John T , Tumbar Tudorita 
Published: October 2024

AbstractGene regulatory mechanisms that modulate RNA Polymerase II activity are difficult to access in mammalian tissues composed of multiple cell lineages. Here, we develop a nascent RNA assay (PReCIS-seq) that measures lineage-specific transcriptionally-engaged Pol II on genes and DNA enhancer elements in intact mouse tissue. By employing keratinocytes as a prototype lineage, we unearth Pol II promoter-recruitment versus pause-release mechanisms operating in adult skin homeostasis. Moreover, we relate active enhancer proximity and transcription factor binding motifs on promoters to Pol II activity and promoter-proximal pausing level. Finally, we find Pol II firing rapidly into elongation on lineage identity genes and highly paused on cellular safeguarding genes in a context-dependent manner. Our work provides a basic platform to investigate mechanistic principles of gene regulation in individual lineages of complex mammalian tissues.
Fast Single-Cell MALDI Imaging of Low-Mass Metabolites Reveals Cellular Activation Markers
Authors: Cairns James L. , Huber Johanna , Lewen Andrea , Jung Jessica , Maurer Stefan J. , Bausbacher Tobias , Schmidt Stefan , Levkin Pavel A. , Sevin Daniel , Göpfrich Kerstin , Koch Philipp , Kann Oliver , Hopf Carsten 
Published: October 2024

AbstractSingle-cell MALDI mass spectrometry imaging (MSI) of lipids and metabolites >200 Da has recently come to the forefront of biomedical research and chemical biology, but fast metabolome-preserving methods without paraformaldehyde fixation for analysis of low mass, hydrophilic metabolites (<200 Da) in large cell populations are lacking. Introducing giant unilamellar vesicles (GUVs) as MSI ground truth for cell-sized objects and Monte Carlo reference-based consensus clustering for data-dependent identification of cell subpopulations. The PRISM-MS (PRescanImaging forSmallMolecule -MassSpectrometry) dual-scan MSI workflow is presented, enabling space-efficient and therefore faster lipid analysis in single GUVs and cells. Beyond lipids, PRISM-MS enables MSI and on-cell MS2-based identification of low-mass metabolites like amino acids or Krebs cycle intermediates involved in stimulus-dependent cell activation. The utility of PRISM-MS is demonstrated through the characterization of complex metabolome changes in lipopolysaccharide (LPS)-stimulated microglial cells and human-induced pluripotent stem cell-derived microglia. Translation of single cell results to endogenous microglia in organotypic hippocampal slice cultures indicates that LPS-activation involves changes of the itaconate-to-taurine ratio and alterations in neuron-to-glia glutamine-glutamate shuttling. The data suggests that PRISM-MS could serve as a standard method in single cell metabolomics, given its capability to characterize larger cell populations and low-mass metabolites.
Replacing Normalizations with Interval Assumptions Improves the Rigor and Robustness of Differential Expression and Differential Abundance Analyses
Authors: McGovern Kyle C. , Silverman Justin D. 
Published: October 2024

AbstractStandard methods for differential expression and differential abundance analysis rely on normalization to address sample-to-sample variation in sequencing depth. However, normalizations imply strict, unrealistic assumptions about the unmeasured scale of biological systems (e.g., microbial load or total cellular transcription). This introduces bias that can lead to false positives and false negatives. To overcome these limitations, we suggest replacing normalizations with interval assumptions. This approach allows researchers to explicitly define plausible lower and upper bounds on the unmeasured biological system’s scale, making these assumptions more realistic, transparent, and flexible than those imposed by traditional normalizations. Compared to recent alternatives like scale models and sensitivity analyses, interval assumptions are easier to use, resulting in potentially reduced false positives and false negatives, and have stronger guarantees of Type-I error control. We make interval assumptions accessible by introducing a modified version of ALDEx2 as a publicly available software package. Through simulations and real data studies, we show these methods can reduce false positives and false negatives compared to normalization-based tools.
Subtractive proteomics unravel the potency of D-Alanine-D-Alanine Ligase as the drug target forBurkholderia pseudomallei
Authors: Rahman Shakilur , Bhattacharya Ayush , Jana Prerona , Ganguly Manisha , Das Amit Kumar , Hazra Ditipriya , Roychowdhury Amlan 
Published: October 2024

ABSTRACTMelioidosis, also known as Whitmore’s disease, is caused by the deadly pathogenBurkholderia pseudomalleiand remains a significant global health concern, particularly in South Asia. The disease is contracted through exposure to contaminated soil, water, air, and food. Infected individuals often present with abscesses in internal organs such as the lungs, spleen, and liver, and in soft tissues, with severe cases leading to septic shock and acute pneumonia. The rising incidence and mortality rates, coupled withB. pseudomallei’sability to form biofilms and develop resistance to antibiotics like cephalosporins, make treatment increasingly challenging. This highlights the urgent need for novel therapeutic approaches.D-Alanine-D-Alanine ligase (Ddl), a crucial enzyme involved in the final stage of bacterial cell wall synthesis, which protects the pathogen from the hostile cellular environment of the host. While many bacteria have two isoforms of this enzyme,B. pseudomalleipossesses only the DdlB isoform, presenting a significant vulnerability. Our study represents the first successful attempt to target DdlB through a combination of molecular docking and molecular dynamics simulations. These investigations provide strong evidence that Conivaptan acts as an effective inhibitor of DdlB, offering a novel therapeutic approach for combating melioidosis.
Micro-RNA 7975 directly regulates MDTH expression and mediates endothelial cell proliferation and migration in the development of early atherosclerosis
Authors: Wagner Nathan , Karere Genesio 
Published: October 2024

ABSTRACTCardiovascular disease (CVD) is commonly due to the development of atherosclerosis. Endothelial integrity is critical in the prevention of pathogenesis of atherosclerosis. The key to prevention of CVD is understanding the molecular mechanisms responsible for initiation of early atherosclerosis. MiRNAs are mediators of endothelial homeostasis, and their dysregulation could lead to early atherosclerotic disorder. We previously revealed the expression of miR-7975 in early atherosclerotic lesions. The aim of this study was to investigate the novel roles of miR-7975 on endothelial cell proliferation and migration, and in the regulation of metadherin (MTDH) expression. We performed proliferation and migration assays coupled with luciferase assay. We show that miR-7975 promotes proliferation and migration of endothelial cells and that miR-7976 directly regulates (MTDH), previously associated with cancer pathogenesis. In conclusion our results show miR-7975 could be a potential mediator of endothelial homeostasis and that MTDH is a novel target of miR-7975.
Co-delivery of Paclitaxel and Cannabidiol in Lipid Nanoparticles Enhances Cytotoxicity Against Melanoma Cells
Authors: de Carvalho Fabíola V. , Geronimo Gabriela , de Moura Ludmilla D. , Mendonça Talita C. , Breitkreitz Márcia Cristina , de Paula Eneida , da Silva Gustavo H. Rodrigues 
Published: October 2024

ABSTRACTAlthough chemotherapy regimens are well-established in clinical practice, chemoresistance and adverse side effects pose significant obstacles in cancer treatment. Paclitaxel (PTX), a widely used chemotherapeutic agent, faces formulation challenges due to its poor solubility and permeability. Research suggests that the phytochemical Cannabidiol (CBD) holds potential not only in targeting cancer cells but also in alleviating pain and nausea, thereby improving the quality of life for cancer patients. However, CBD’s clinical application is also limited by its poor solubility, low bioavailability, and susceptibility to oxidation. Nanostructured lipid carriers (NLCs) represent a promising drug delivery system for hydrophobic compounds like PTX and CBD and allows their co-encapsulation. Nonetheless, achieving a stable formulation requires identifying suitable preparation methods and excipients. The aim of this study was to develop and optimize an NLC formulation for the co-encapsulation of PTX and CBD. Using factorial design, an optimized formulation was obtained with homogeneous particle sizes (200 nm), negative zeta potentials (−17 mV), particle concentration of 1013particles/mL, spherical morphology (TEM images), and a lipid core with low crystallinity (as confirmed by XRD). To evaluate the therapeutic potential of the drug combination, cell viability assays were conducted on murine melanoma cells (B16-F10) at different exposure times (24 and 48 hours). The NLC-CBD-PTX formulation significantly reduced cell viability in a time- and concentration-dependent manner, demonstrating at least 75% greater activity at 24 hours compared to each drug individually whether free (PTX, CBD) or encapsulated (NLC-PTX, NLC-CBD). This indicates a synergistic effect of the encapsulated drugs on cytotoxicity. In conclusion, an innovative pharmaceutical formulation co-encapsulating PTX and CBD was validated, showing potential to enhance antitumor efficacy, overcome chemoresistance, reduce side effects, and broaden therapeutic applications. The resulting NLCs exhibited favorable physicochemical properties, supporting their suitability for various routes of administration.
Regulator of G-Protein Signaling 2 Knockout in CD4+ T Cells Promotes Anti-Inflammatory T Cells, Enhancing Ovulation, and Oocyte Yield
Authors: Raff Marika , Benton Trinity , Brummond Daniel , Kovach Denali , Bunton Olivia , Janky Ella , Duran Eyup Hakan , Scroggins Douglas G. , Gray Gabrielle , Scroggins Sabrina Marie 
Published: October 2024

Structured AbstractObjectiveTo determine the downstream effects on ovarian function and immune cell differentiation in the ovary and uterus using a model in which RGS2 was knocked out specifically in CD4+ T cells.DesignLaboratory based experiments with female mice.AnimalsFemale congenic (fully backcrossed) and non-congenic (mixed strain) mice with CD4 T cell-specific RGS2 knockout.ExposureFour-week-old female CD4 RGS2 knockout (CD4 RGS2KO) mice and their littermate controls (CD4 RGS2CTL) were subjected to superovulation using pregnant mare serum gonadotropins.Main Outcome MeasuresOocyte numbers, lymphocyte populations in the ovary and uterus, and serum estradiol and progesterone concentrations.ResultIn non-congenic (mixed strain) mice, CD4 RGS2 knockout (KO) promoted higher oocyte ovulation and increased uterine total leukocyte numbers. Similarly, congenic (fully backcrossed strain) mice showed higher oocyte numbers and increased uterine total leukocytes in the CD4 RGS2KOmice compared to CD4 RGS2CTLmice. Pro-inflammatory CD4+ T helper (TH) 1 and TH17 cell frequencies in the ovary and uterus were unchanged, while Treg and TH2 cell frequencies were elevated, along with increased concentrations of estradiol and progesterone in the serum of CD4 RGS2KOmice.ConclusionOur study highlights the important role of RGS2 in CD4+ T cells within the context of reproduction. The dysregulation of immune responses due to RGS2 knockout in CD4+ T cells appears to enhance oocyte production. Further research is warranted to elucidate the precise mechanisms by which RGS2 influences reproductive outcomes, including its impact on fecundability, endometrial receptivity, and successful implantation.