bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitigating the Opioid Epidemic: The Role of Cannabinoids in Chronic Pain Management—A Systematic Review and Meta-Analysis of Clinical Evidence and Mechanisms
Authors: Borges Julian Yin Vieira 
Published: August 2024

AbstractBackground and ObjectivesAs the medical community seeks alternative pain management strategies, cannabinoids have emerged as a potential option. This review discusses the role of cannabinoids in chronic pain management and their potential as an alternative treatment in pain medicine, focusing on efficacy, safety, and possible opioid reduction. The objectives are to evaluate the efficacy and safety of cannabinoids in chronic pain management, explore their potential to reduce opioid use, and identify the mechanisms by which cannabinoids exert their analgesic effects. Additionally, the review seeks to highlight the clinical implications and limitations of using cannabinoids as an alternative to opioids.MethodsA comprehensive literature review and meta-analysis were conducted, focusing on studies from PubMed, MEDLINE, and Cochrane,focusing on various types of studies. Data were extracted and analyzed to assess the efficacy, safety, and potential opioid-sparing effects of cannabinoids. Mechanistic insights were also explored to understand how cannabinoids modulate pain.ResultsCannabinoids have shown efficacy in managing chronic pain, with evidence indicating their ability to reduce pain and improve quality of life. Studies suggest that cannabinoids can provide significant analgesic effects, although there is variability in efficacy across trials. Findings also show that Cannabinoids modulate pain through the endocannabinoid system, which plays a crucial role in pain perception and inflammation.LimitationsThe variability in efficacy across studies suggests a need for standardized formulations and dosing regimens. Long-term effects of cannabinoid use are not fully understood, necessitating further research. More high-quality trials are needed to confirm findings and address potential biases.ConclusionCannabinoids offer a promising alternative for chronic pain management, with the potential to mitigate the opioid epidemic. Integrating cannabinoids into clinical practice, guided by evidence-based protocols, can provide a safer and effective approach to chronic pain management.
Urinary Biomarkers for Lung Cancer Detection
Authors: Matov Alexandre 
Published: August 2024

ABSTRACTIntroductionThe current healthcare system relies largely on a passive approach toward disease detection, which typically involves patients presenting a “chief complaint” linked to a particular set of symptoms for diagnosis. Since all degenerative diseases occur slowly and initiate as changes in the regulation of individual cells within our organs and tissues, it is inevitable that with the current approach to medical care we are bound to discover some illnesses at a point in time when the damage is irreversible and meaningful treatments are no longer available.MethodsThere exist organ-specific sets (or panels) of nucleic acids, such as microRNAs (miRs), which regulate and help to ensure the proper function of each of our organs and tissues. Thus, dynamic readout of their relative abundance can serve as a means to facilitate real-time health monitoring. With the advent and mass utilization of next-generation sequencing (NGS), such a proactive approach is currently feasible. Because of the computational complexity of customized analyses of “big data”, dedicated efforts to extract reliable information from longitudinal datasets is key to successful early detection of disease.ResultsHere, we present our preliminary results for the analysis of healthy donor samples and drug-naïve lung cancer patients’ samples, for which we identify urinary biomarkers demonstrating that small RNAs can pass through the filtration by the kidneys.ConclusionsWe provide a proof-of-principle that it is possible to perform non-invasive health monitoring by sequencing of urinary small RNAs and that traces of neoplastic transformation originating in organs that are not adjacent to the urinary tract, like the lungs, can also be detected in urine.
Methamphetamine-Contaminated Residences in the United States: Assessment of the Environmental Health Significance of Third-Hand Exposure
Authors: Dennison James E. 
Published: August 2024

AbstractObjectivesMethamphetamine (meth) use in the United States has been a significant problem for many years. Beyond impacts to the users, two additional consequences of the meth problem are on-going exposure to non-users in contaminated homes and the significant cost of remediation. This study reports the first U.S. national and state-level estimates of the number of contaminated properties, the number of exposed non-users, and the costs associated with remediation.MethodsThe ability to estimate these endpoints relies on having random surveys of the frequency or incidence of residential contamination, but such surveys are difficult to perform and therefore scarce. The results of the only identified random survey were used in this study and appropriate geographical and temporal adjustments were made. The overall rate of contamination of Housing Units (HUs) was determined from estimates of the rates of HU contamination by meth smoking, rates of contamination from meth manufacturing, and rates of HU decontamination. Rates equations were integrated to estimate the number of contaminated HUs, the number of people living in contaminated HUs, and potential remediation costs.ResultsThe random survey found 3.5% of HUs to be contaminated in 2018. Currently, over 5,000,000 (4%) of U.S. HUs are estimated to be contaminated above average health standards. Based on this, the current estimated cost for remediation of all contaminated HUs would be $15 billion per year and $250 billion for the backlog of all currently contaminated HUs. The estimated number of persons currently exposed to meth above average health standards is 13,000,000 people.ConclusionsWhile the accuracy of these estimates is limited, they indicate that meth-contaminated housing is a significant environmental health and economic issue in the U.S. that has been previously under-recognized. Additional studies of health effects, fate and transport mechanisms, and remediation methods are needed.
Integrating genomic variants and developmental milestones to predict cognitive and adaptive outcomes in autistic children
Authors: Bourque Vincent-Raphaël , Schmilovich Zoe , Huguet Guillaume , England Jade , Okewole Adeniran , Poulain Cécile , Renne Thomas , Jean-Louis Martineau , Saci Zohra , Zhang Xinhe , Rolland Thomas , Labbé Aurélie , Vorstman Jacob , Rouleau Guy A. , Baron-Cohen Simon , Mottron Laurent , Bethlehem Richard A. I. , Warrier Varun , Jacquemont Sébastien 
Published: August 2024

ABSTRACTAlthough the first signs of autism are often observed as early as 18-36 months of age, there is a broad uncertainty regarding future development, and clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). Here, we developed predictive models of ID in autistic children (n=5,633 from three cohorts), integrating different classes of genetic variants alongside developmental milestones. The integrated model yielded an AUC ROC=0.65, with this predictive performance cross-validated and generalised across cohorts. Positive predictive values reached up to 55%, accurately identifying 10% of ID cases. The ability to stratify the probabilities of ID using genetic variants was up to twofold greater in individuals with delayed milestones compared to those with typical development. These findings underscore the potential of models in neurodevelopmental medicine that integrate genomics and clinical observations to predict outcomes and target interventions.
Identifying interactions between TDP-43’s N-terminal and RNA binding domains
Authors: Scott David D. , Jena Lipsa , Perez-Miller Samantha , Kumirov Vlad , Khanna Rajesh , Khanna May 
Published: August 2024

AbstractTAR DNA-binding Protein 43 (TDP-43) plays a crucial role in the pathophysiology and progression of Amyotrophic Lateral Sclerosis (ALS), affecting both familial and sporadic cases. TDP-43 is an intrinsically disordered multidomain protein that consists of an N-terminal domain (NTD1-102), two tandem RNA recognition motifs (RRM1102-177and RRM2191-260), and an intrinsically disordered glycine-rich C-terminal261-414domain. We previously identified a chemical probe which led to allosteric alterations between the RRM and NTD of TDP-43. We attributed these changes to potential interdomain interactions between the NTD and RRM segments. In this work, we compared the 2D [1H,15N] HSQC-NMR resonances of two constructs, TDP-43102-260(RRM domain alone) against TDP-431-260(NTD linked to RRM) and observed clustered shifts in the RNA binding sites of both RRM domains. To investigate why these shifts appeared in the RRM domains, in the absence of RNA, we hypothesized that the NTD domain could be stacking on the RRM domains. Thus, we modeled NTD-RRM interactions using protein-protein docking along withde novosequence-to-structure predictions of TDP-431-260that propose NTD stacking onto the RRM domains. Using Carr-Purcell-Meiboom-Gill (CPMG)-relaxation dispersion NMR spectroscopy, we demonstrated evidence of an interaction between NTD1-102and RRMs102-260. Finally, we investigated the impact of NTD on RNA binding using 2D15N-HSQC-NMR and microscale thermophoresis (MST) by titration of a short UG-rich RNA sequence and observed significant changes in RNA binding between TDP-43102-260and TDP-431-260, further suggesting the NTD plays a role in TDP-43 RNA interactions.
Dynorphin modulates motivation through a pallido-amygdala cholinergic circuit
Authors: Sun Qingtao , Liu Mingzhe , Guan Wuqiang , Xiao Xiong , Dong Chunyang , Bruchas Michael R. , Zweifel Larry S. , Li Yulong , Tian Lin , Li Bo 
Published: August 2024

SUMMARYThe endogenous opioid peptide dynorphin and its receptor κ-opioid receptor (KOR) have been implicated in divergent behaviors, but the underlying mechanisms remain elusive. Here we show that dynorphin released from nucleus accumbens dynorphinergic neurons exerts powerful modulation over a ventral pallidum (VP) disinhibitory circuit, thereby controlling cholinergic transmission to the amygdala and motivational drive in mice. On one hand, dynorphin acts postsynaptically via KORs on local GABAergic neurons in the VP to promote disinhibition of cholinergic neurons, which release acetylcholine into the amygdala to invigorate reward-seeking behaviors. On the other hand, dynorphin also acts presynaptically via KORs on dynorphinergic terminals to limit its own release. Such autoinhibition keeps cholinergic neurons from prolonged activation and release of acetylcholine, and prevents perseverant reward seeking. Our study reveals how dynorphin exquisitely modulate motivation through cholinergic system, and provides an explanation for why these neuromodulators are involved in motivational disorders, including depression and addiction.
Depletion of endomembrane reservoirs drives phagocytic appetite exhaustion in macrophages
Authors: Fountain Aaron , Mansat Mélanie , Soffiaturo Sierra , Gimenez Maria C. , Moussaoui Serene , Ezzo Maya , Verdawala Munira B. , Fung Karen , Lancaster Charlene , Somerville Elliott , Hinz Boris , Terebiznik Mauricio R. , Botelho Roberto J. 
Published: August 2024

AbstractDuring phagocytosis, F-actin and local membrane secretion grows a phagocytic cup around a bound particle ultimately entrapping the particle within a phagosome. The phagosome then fuses with endosomes and lysosomes to digest the particle. After particle degradation, phagosomes fragment to reform lysosomes and maintain phagocyte degradative capacity. As finite systems, phagocytes have a maximal phagocytic capacity, which should blunt further phagocytosis. However, the processes responsible for appetite exhaustion are not known. We found that macrophages at capacity retained Fcγ receptors levels and did not shrink in size. Instead, surface membrane in-folding, membrane tension, and cortical F-actin were reduced in exhausted macrophages. Moreover, exhausted macrophages were depleted for both endosomes and lysosomes, and consequently, focal endosome exocytosis in remaining externally bound particles was blunted. In comparison, if phagosome resolution was permitted macrophages regained the phagocytic appetite. Altogether, we propose that depletion of the endomembrane pools is a major determinant of phagocytic fatigue as macrophages reach their phagocytic capacity, though other processes are also at play.
Cascaded Antithetic Integral Feedback for Enhanced Stability and Performance
Authors: Zand Armin M. , Gupta Ankit , Khammash Mustafa 
Published: August 2024

AbstractPrecise intracellular regulation and robust perfect adaptation can be achieved using biomolecular integral controllers and it holds enormous potential for synthetic biology applications. In this letter, we consider the cascaded implementation of a class of such integrator motifs. Our cascaded integrators underpin proportional-integral-derivative (PID) control structures, which we leverage to suggest ways to improve dynamic performance. Moreover, we demonstrate how our cascaded strategy can be harnessed to enhance robust stability in a class of uncertain reaction networks. We also discuss the genetic implementation of our controllers and the natural occurrence of their cascaded sequestration pairs in bacterial pathogens.
Recurrent breakpoints in theBRD4locus reduce toxicity associated with gene amplification
Authors: Wala Jeremiah , Dalin Simona , Webster Sophie , Shapira Ofer , Busanovich John , Beroukhim Rameen , Bandopadhayay Pratiti , Rendo Veronica 
Published: August 2024

AbstractStructural variants (SVs) represent a mechanism by which cancer cells activate oncogenes or disrupt the function of genes with tumor suppressor roles. A recent study by the PCAWG Consortium investigated structural variants in 30 tumor types, identifying focal rearrangements in the oncogenic BRD4 gene in ovarian, endometrial and breast cancers. These rearrangements resulted in decreased BRD4 expression despite increased copy number, suggesting a novel mechanism to finetune gene over-expression. In this study, we show that focal deletions of BRD4 disrupt genomic regulatory regions and impact gene isoform expression in breast and ovarian tumors when compared to their expression across normal tissues. To determine the functional impact of these concomitant amplification and focal deletion events, we first leveraged open-reading-frame (ORF) screen data from 16 cancer cell lines, where we observed that overexpression of BRD4-long and BRD4-short isoforms is toxic for cancer cell growth. We confirmed these results in OVSAHO ovarian cancer cells, where overexpression of both isoforms significantly reduced tumor growth. Next, we mimicked the focal deletions occurring in BRD4 regulatory regions by CRISPR-Cas9 technology, and observed that their depletion functionally ablates tumor cell growth. We finally show that these focal deletions rescue ovarian carcinoma cells from the toxicity effects associated with gene overexpression, suggesting that global BRD4 gene expression levels must be fine tuned to ensure proper cancer cell proliferation. Our study provides experimental evidence for BRD4 deletions constituting the first example of a driver SV alteration reducing toxicity in cancer, therefore expanding the landscape of cancer progression mechanisms.
Preferential assimilation, metabolism, and transfer of organic nitrogen to host plants by Mucoromycotina ‘fine root endophytes’
Authors: Howard Nathan OA , Williams Alex , Durant Emily , Pressel Silvia , Daniell Tim J , Field Katie J 
Published: August 2024

SummaryMucoromycotina ‘fine root endophytes’ (MFRE) are an understudied group of plant fungal symbionts that usually co-occur with arbuscular mycorrhizal fungi. The functional significance of MFRE in plant nutrition remains under-explored, particularly their role in plant N assimilation from the variety of sources typically found in soils.Using four15N-labelled N sources to track N transfer between MFRE andPlantago lanceolata,applied singly and in tandem, we investigated N source discrimination, preference, and transfer to host plants by MFRE. We traced movement of14C from plants to MFRE to determine the impact of N source type on plant C allocation to MFRE.We found MFRE preferentially transferred N derived from glycine and ammonium to plant hosts over that derived from nitrate and urea, regardless of other N sources present. MFRE mycelium supplied with glycine and ammonium contained more plant-derived carbon than those supplied with other N sources.We show that MFRE directly assimilates and metabolises organic compounds, retaining C to meet its own metabolic requirements and transferring N to plant hosts. Our findings highlight diversity in function of endomycorrhizal associations with potentially profound implications for our understanding of the physiology and ecology of plant-fungal symbioses.
Sustained Strain Applied at High Rates Drives Dynamic Tensioning in Epithelial Cells
Authors: Safa Bahareh Tajvidi , Rosenbohm Jordan , Esfahani Amir Monemian , Minnick Grayson , Moghaddam Amir Ostadi , Lavrik Nickolay V. , Huang Changjin , Charras Guillaume , Kabla Alexandre , Yang Ruiguo 
Published: August 2024

ABSTRACTEpithelial cells experience long lasting loads of different magnitudes and rates. How they adapt to these loads strongly impacts tissue health. Yet, much remains unknown about the evolution of cellular stress in response to sustained strain. Here, by subjecting cell pairs to sustained strain, we report a bimodal stress response, where in addition to the typically observed stress relaxation, a subset of cells exhibits a dynamic tensioning process with significant elevation in stress within 100s, resembling active pulling-back in muscle fibers. Strikingly, the fraction of cells exhibiting tensioning increases with increasing strain rate. The tensioning response is accompanied by actin remodeling, and perturbation to actin abrogates it, supporting cell contractility’s role in the response. Collectively, our data show that epithelial cells adjust their tensional states over short timescales in a strain-rate dependent manner to adapt to sustained strains, demonstrating that the active pulling-back behavior could be a common protective mechanism against environmental stress.
Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates the expression of genes associated with anxiolytic-like behavior
Authors: Castro-Vildosola Jose , Bryan Chris-Ann , Tajamal Nasira , Jonnalagadda Sai Anusha , Kasturi Akhila , Tilly Jaqueline , Garcia Isabel , Kumar Renuka , Fried Nathan T. , Hala Tamara , Corbett Brian F. 
Published: August 2024

AbstractWe previously demonstrated that sphingosine-1-phosphate receptor 3 (S1PR3) in the medial prefrontal cortex (mPFC) prevents stress-mediated reductions in sociability. S1PR3 is a ubiquitously expressed G-protein coupled receptor that regulates immune system function, although its regulation of other biological processes is not well understood. Pharmacological activators of S1PR3 might provide important insights for understanding the neural substrates underlying sociability and/or serve as novel, preclinical treatments for social anxiety. Here we show that in mice, systemic injections of an S1PR3-specific agonist, CYM5541, promotes sociability in males and females whereas an S1PR3-specific antagonist, CAY10444, increases amygdala activation and promotes social anxiety-like behavior in females. S1PR3 expression is increased in the mPFC and dentate gyrus of females compared to males. RNA sequencing in the mPFC reveals that S1PR3 activation alters the expression of transcripts related to immune function, neurotransmission, transmembrane ion transport, and intracellular signaling. This work provides evidence that S1PR3 agonists, which have classically been used as immune modulators, might also be used as novel anxiolytics. S1PR3 might be an important hub gene for anxiolytic effects as it reduces inflammatory processes caused by stress and increases transcripts linked to anxiolytic neurotransmission.HighlightsThe Sphingosine-1-phosphate receptor 3 (S1PR3) agonist CYM5541 promotes sociabilityThe S1PR3 antagonist CAY10444 reduces sociability and promotes anxiety-like behavior in femalesCAY10444 increases neuronal activity markers in the amygdalaPharmacological activation of S1PR3 regulates the expression of genes in the prefrontal cortex that control a wide range of biological processes, including increasing GABAergic neurotransmission and reducing inflammatory processes
T cells promote distinct transcriptional programs of cutaneous inflammatory disease in keratinocytes and dermal fibroblasts
Authors: DeBerg Hannah A. , Fahning Mitch L. , Varkhande Suraj R. , Schlenker James D. , Schmitt William P. , Gupta Aayush , Singh Archana , Gratz Iris K. , Carlin Jeffrey S. , Campbell Daniel J. , Morawski Peter A. 
Published: August 2024

ABSTRACTT cells and structural cells coordinate appropriate inflammatory responses and restoration of barrier integrity following insult. Dysfunctional T cells precipitate skin pathology occurring alongside altered structural cell frequencies and transcriptional states, but to what extent different T cells promote disease-associated changes remains unclear. We show that functionally diverse circulating and skin-resident CD4+CLA+T cell populations promote distinct transcriptional outcomes in human keratinocytes and fibroblasts associated with inflamed or healthy tissue. We identify Th17 cell-induced genes in keratinocytes that are enriched in psoriasis patient skin and normalized by anti-IL-17 therapy. We also describe a CD103+skin-resident T cell-induced transcriptional module enriched in healthy controls that is diminished during psoriasis and scleroderma and show that CD103+T cell frequencies are altered during disease. Interrogating clinical data using immune-dependent transcriptional signatures defines the T cell subsets and genes distinguishing inflamed from healthy skin and allows investigation of heterogeneous patient responses to biologic therapy.GRAPHICAL ABSTRACT
Natural Selection in a Synthetic Yeast Endosymbiont Promotes Stable Coexistence
Authors: Supekova Lubica , Zhou Han , Barcellos Izabella H. , Nguyen Catherine , Dik David A. , Schultz Peter G. 
Published: August 2024

ABSTRACTBacteria engulfment by a higher order host is believed to be the beginning of an evolutionary process that ultimately formed mitochondria. In an effort to experimentally elucidate the early effects of natural selection on bacteria resident in a eukaryotic host, a synthetic endosymbiont model system has been exploited. Here we describe a reproducible series of mutations that were observed afterEscherichia coliwas passaged withinSaccharomyces cerevisiaefor >8 passages which led to enhanced coexistence of bacteria within the yeast. These naturally selected mutations, formed by gene acquisition of trans-posable elements inrcsC, cpxA, andidnK, result in both functional and non-functional protein products with phenotypic effects on the bacteria that promote endosymbiont stability.