Deville rebooted - practical N2O5 synthesis.

Dinitrogen pentoxide (N2O5), the anhydride of nitric acid, was synthesised by Henri Étienne Sainte-Claire Deville in Paris in 1849 using silver nitrate and chlorine gas. Herein, we revisit, optimise, and modify Deville's method using photocatalysis to enable a safe, clean, practical, and reproducible alternative for N2O5 synthesis in quantitative yields. Moreover, it is predicted that the modifications can accommodate an industrial scale-up, but the silver chloride generated must be recycled.

The potential role of chronic pain and the polytrauma clinical triad in predicting prodromal PD: A cross-sectional study of U.S. Veterans.

Introduction: The research criteria for prodromal Parkinson disease (pPD) depends on prospectively validated clinical inputs with large effect sizes and/or high prevalence. Neither traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), nor chronic pain are currently included in the calculator, despite recent evidence of association with pPD. These conditions are widely prevalent, co-occurring, and already known to confer risk of REM behavior disorder (RBD) and PD. Few studies have examined PD risk in the context of TBI and PTSD; none have examined chronic pain. This study aimed to measure the risk of pPD caused by TBI, PTSD, and chronic pain. Methods: 216 US Veterans were enrolled who had self-reported recurrent or persistent pain for at least three months. Of these, 44 met criteria for PTSD, 39 for TBI, and 41 for all three conditions. Several pain, sleep, affective, and trauma questionnaires were administered. Participants' history of RBD was determined via self-report, with a subset undergoing confirmatory video polysomnography. Results: A greater proportion of Veterans with chronic pain met criteria for RBD (36 % vs. 10 %) and pPD (18.0 % vs. 8.3 %) compared to controls. Proportions were increased in RBD (70 %) and pPD (27 %) when chronic pain co-occurred with TBI and PTSD. Partial effects were seen with just TBI or PTSD alone. When analyzed as continuous variables, polytrauma symptom severity correlated with pPD probability (r = 0.28, P = 0.03). Conclusion: These data demonstrate the potential utility of chronic pain, TBI, and PTSD in the prediction of pPD, and the importance of trauma-related factors in the pathogenesis of PD.

De novo motor learning creates structure in neural activity that shapes adaptation.

Animals can quickly adapt learned movements to external perturbations, and their existing motor repertoire likely influences their ease of adaptation. Long-term learning causes lasting changes in neural connectivity, which shapes the activity patterns that can be produced during adaptation. Here, we examined how a neural population's existing activity patterns, acquired through de novo learning, affect subsequent adaptation by modeling motor cortical neural population dynamics with recurrent neural networks. We trained networks on different motor repertoires comprising varying numbers of movements, which they acquired following various learning experiences. Networks with multiple movements had more constrained and robust dynamics, which were associated with more defined neural 'structure'-organization in the available population activity patterns. This structure facilitated adaptation, but only when the changes imposed by the perturbation were congruent with the organization of the inputs and the structure in neural activity acquired during de novo learning. These results highlight trade-offs in skill acquisition and demonstrate how different learning experiences can shape the geometrical properties of neural population activity and subsequent adaptation.

Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy.

BACKGROUND: Solute carrier (SLC) transporters, a diverse family of membrane proteins, are instrumental in orchestrating the intake and efflux of nutrients including amino acids, vitamins, ions, nutrients, etc, across cell membranes. This dynamic process is critical for sustaining the metabolic demands of cancer cells, promoting their survival, proliferation, and adaptation to the tumor microenvironment (TME). Amino acids are fundamental building blocks of cells and play essential roles in protein synthesis, nutrient sensing, and oncogenic signaling pathways. As key transporters of amino acids, SLCs have emerged as crucial players in maintaining cellular amino acid homeostasis, and their dysregulation is implicated in various cancer types. Thus, understanding the intricate connections between amino acids, SLCs, and cancer is pivotal for unraveling novel therapeutic targets and strategies. SCOPE OF REVIEW: In this review, we delve into the significant impact of amino acid carriers of the SLCs family on the growth and progression of cancer and explore the current state of knowledge in this field, shedding light on the molecular mechanisms that underlie these relationships and highlighting potential avenues for future research and clinical interventions. MAJOR CONCLUSIONS: Amino acids transportation by SLCs plays a critical role in tumor progression. However, some studies revealed the tumor suppressor function of SLCs. Although several studies evaluated the function of SLC7A11 and SLC1A5, the role of some SLC proteins in cancer is not studied well. To exert their functions, SLCs mediate metabolic rewiring, regulate the maintenance of redox balance, affect main oncogenic pathways, regulate amino acids bioavailability within the TME, and alter the sensitivity of cancer cells to therapeutics. However, different therapeutic methods that prevent the function of SLCs were able to inhibit tumor progression. This comprehensive review provides insights into a rapidly evolving area of cancer biology by focusing on amino acids and their transporters within the SLC superfamily.

A qualitative study of military service members undergoing medical separation.

OBJECTIVE: Little research explores military perspectives on medical disability-related transition. A qualitative study sought to understand transition experiences of United States military Service members found unfit for duty following medical and physical evaluation boards (MEBs and PEBs). METHODS: Confidential telephone interviews were conducted with 25 current and prior Service members. Participants were asked to share their experiences before, during, and after the MEB and PEB processes. Interview questions explored (1) health conditions that prompted the medical disability evaluation, (2) reactions to being recommended for separation, (3) transition-related stress and challenges, and (4) coping strategies. Salient themes were identified across chronological narratives. RESULTS: Participants expressed that debilitating physical (e.g., injury) and/or mental (e.g., post-traumatic stress disorder) illnesses prompted their medical evaluation. In response to the unfit for duty notice, some participants reported emotional distress (e.g., anxiety, anger) connected to uncertainty about the future. Other participants reported relief connected to a sense of progression toward their medical disability claim status. Transition stress included the length of the MEB/PEB process, impact of the COVID-19 pandemic on the process, financial stress, impact on family life, and compounded effect of these stressors on emotional distress, including depression and suicidal thoughts. Participants reported using adaptive (e.g., psychotherapy) and maladaptive (e.g., excessive drinking) strategies to cope with stress. CONCLUSION: Preliminary reports of emotional distress and transition stress following unfit for duty notices highlight the need for increased support and interventions to facilitate adaptive coping strategies during this vulnerable period.

Human cytomegalovirus infection coopts chromatin organization to diminish TEAD1 transcription factor activity.

Human cytomegalovirus (HCMV) infects up to 80% of the worlds population. Here, we show that HCMV infection leads to widespread changes in human chromatin accessibility and chromatin looping, with hundreds of thousands of genomic regions affected 48 hours after infection. Integrative analyses reveal HCMV-induced perturbation of Hippo signaling through drastic reduction of TEAD1 transcription factor activity. We confirm extensive concordant loss of TEAD1 binding, active H3K27ac histone marks, and chromatin looping interactions upon infection. Our data position TEAD1 at the top of a hierarchy involving multiple altered important developmental pathways. HCMV infection reduces TEAD1 activity through four distinct mechanisms: closing of TEAD1-bound chromatin, reduction of YAP1 and phosphorylated YAP1 levels, reduction of TEAD1 transcript and protein levels, and alteration of TEAD1 exon-6 usage. Altered TEAD1-based mechanisms are highly enriched at genetic risk loci associated with eye and ear development, providing mechanistic insight into HCMVs established roles in these processes.

Risk of Adverse Events Following Total Knee Arthroplasty in Asthma Patients.

INTRODUCTION: Total knee arthroplasty (TKA) is a common procedure for which patient factors are known to affect perioperative outcomes. Asthma has not been specifically considered in this regard, although it is the most common inflammatory airway disease and predisposes to osteoarthritis. METHODS: Adult patients undergoing TKA were identified from 2015 to 2021-Q3 M157 PearlDiver data sets. Asthma patients were matched to those without 1:1 based on age, sex, and Elixhauser Comorbidity Index (ECI). The incidence of 90-day adverse events and 5-year revisions were compared using multivariable logistic regression (P < 0.0023). The matched asthma group was then stratified based on disease severity for analysis of 90-day aggregated (any, severe, and minor) adverse events. RESULTS: Among 721,686 TKA patients, asthma was noted for 76,125 (10.5%). Multivariable analysis revealed that patients with asthma were at increased odds of multiple 90-day pulmonary, non-pulmonary, and aggregated adverse events, as well as emergency department visits. Furthermore, patients with asthma had 1.17 times greater odds of 5-year revisions (P < 0.0001). Upon secondary analysis stratifying asthma by severity, patients with all severity levels of asthma showed elevated odds of adverse events after TKA. These associations increased in odds with increasing severity of asthma. DISCUSSION: Over one-tenth of patients undergoing TKA were identified as having asthma, and these patients were at greater odds of numerous pulmonary and non-pulmonary adverse events (a trend that increased with asthma severity), as well as 5-year revisions. Clearly, patients with asthma need specific risk mitigation strategies when considering TKA. LEVEL OF EVIDENCE: III.

Diagnostic values of SurePath liquid-based cytology versus conventional smear in thyroid aspiration samples: A 13-year experience at a single institution.

BACKGROUND: Fine needle aspiration cytology (FNAC) is the most useful tool in the diagnosis of thyroid nodules. Liquid-based cytology (LBC) is replacing the conventional smear (CS) for evaluation of thyroid FNAC. In our institution, thyroid FNAC preparation was changed from CS to LBC SurePath in July 2016. This study aimed to compare the diagnostic value of SurePath with that of CS in thyroid lesions. METHODS: A total of 35,406 samples of thyroid FNAC (11,438 CS and 23,968 SurePath), collected from January 2010 to December 2022, were included in this study. We also examined the malignant rate using the surgical pathology diagnosis as the gold standard. RESULTS: The distribution of TBSRTC cytological categories was equivalent between CS and SurePath. The rate of nondiagnostic/unsatisfactory category was higher in CS compared to SurePath (43.4% vs. 22.3%; p < .05). After routine use of SurePath, the surgical resection rate was reduced from 12.0% to 8.6% (p < .05) and the malignant rate increased from 32.2% to 41.5% (p < .05). The sensitivities of CS and SurePath were 71.0% and 82.0%, respectively, and the specificities were 99.0% and 97.3%, respectively, whereas the positive predictive values were 97.8% and 96.8%, respectively, and the negative predictive values were 85.0% and 84.6%, respectively. Diagnostic accuracy of CS and SurePath were 88.5% and 89.7% respectively. CONCLUSION: SurePath can increase the sample adequacy, increase the sensitivity and reduce the workload and avoid unnecessary surgeries with similar accuracy to CS.

Effects of poor maternal diet during gestation are detected in F2 offspring.

Poor maternal nutrition of F0 ewes impairs F1 offspring growth, with minimal differences in glucose tolerance or select metabolic circulating factors, and independent of differences in residual feed intake (RFI). To determine if poor maternal nutrition in F0 ewes alters F2 offspring growth, circulating leptin, feed efficiency, or glucose tolerance, F0 ewes (n = 46) pregnant with twins were fed 100% (control), 60% (restricted), or 140% (over) of National Research Council requirements from days 30 ±â€…0.02 of gestation until parturition. At 16 to 19 mo of age, female F1 (n = 36) offspring were bred to generate F2 offspring [CON-F2 (n = 12 ewes; 6 rams), RES-F2 (n = 7 ewes; 13 rams), or OVER-F2 (n = 13 ewes; 9 rams) corresponding to diets of the granddam (F0)]. Lamb body weights (BW) and blood samples were collected weekly from days 0 to 28 and every 14 d until day 252 of age. Circulating leptin was measured in serum at days 0, 7, 14, 56, 210, and 252. An intravenous glucose tolerance test was performed at days 133 ±â€…0.28. At days 167 ±â€…0.33, individual daily intake was recorded over a 77-d feeding period to determine RFI. Rams were euthanized at days 285 ±â€…0.93, and body morphometrics, loin eye area (LEA), back fat thickness, and organ weights were collected and bone mineral density (BMD) and length were determined in the right hind leg. During gestation, OVER-F1 ewes tended to be 8.6% smaller than CON-F1 ewes (P ≤ 0.06). F2 offspring were of similar BW from birth to day 70 (P ≥ 0.20). However, from days 84 to 252, RES-F2 offspring tended to be 7.3% smaller than CON-F2 (P ≤ 0.10). Granddam diet did not influence F2 ram body morphometrics, organ or muscle weights, LEA, adipose deposition, or leg BMD (P ≥ 0.84). RES-F2 (-0.20) and CON-F2 (-0.45) rams tended to be more feed efficient than CON-F2 ewes (0.31; P ≤ 0.08). No effects of granddam diet were observed on glucose or insulin average or baseline concentrations, area under the curve, first-phase response, or ratio (P ≥ 0.52). However, CON-F2 rams (297 mg/dL ±â€…16.5) had a greater glucose peak compared with RES-F2 rams (239 mg/dL ±â€…11.2; P = 0.05). Peak insulin concentrations were not influenced by granddam diet (P = 0.75). At d 56, RES-F2 and OVER-F2 offspring had 53.5% and 61.8% less leptin compared with CON-F2 offspring, respectively (P ≤ 0.02). These data indicate that poor maternal nutrition impacts offspring growth into the second generation with minimal impacts on offspring RFI, glucose tolerance, and circulating leptin.

BRAND: a platform for closed-loop experiments with deep network models.

Objective.Artificial neural networks (ANNs) are state-of-the-art tools for modeling and decoding neural activity, but deploying them in closed-loop experiments with tight timing constraints is challenging due to their limited support in existing real-time frameworks. Researchers need a platform that fully supports high-level languages for running ANNs (e.g. Python and Julia) while maintaining support for languages that are critical for low-latency data acquisition and processing (e.g. C and C++).Approach.To address these needs, we introduce the Backend for Realtime Asynchronous Neural Decoding (BRAND). BRAND comprises Linux processes, termednodes, which communicate with each other in agraphvia streams of data. Its asynchronous design allows for acquisition, control, and analysis to be executed in parallel on streams of data that may operate at different timescales. BRAND uses Redis, an in-memory database, to send data between nodes, which enables fast inter-process communication and supports 54 different programming languages. Thus, developers can easily deploy existing ANN models in BRAND with minimal implementation changes.Main results.In our tests, BRAND achieved <600 microsecond latency between processes when sending large quantities of data (1024 channels of 30 kHz neural data in 1 ms chunks). BRAND runs a brain-computer interface with a recurrent neural network (RNN) decoder with less than 8 ms of latency from neural data input to decoder prediction. In a real-world demonstration of the system, participant T11 in the BrainGate2 clinical trial (ClinicalTrials.gov Identifier: NCT00912041) performed a standard cursor control task, in which 30 kHz signal processing, RNN decoding, task control, and graphics were all executed in BRAND. This system also supports real-time inference with complex latent variable models like Latent Factor Analysis via Dynamical Systems.Significance.By providing a framework that is fast, modular, and language-agnostic, BRAND lowers the barriers to integrating the latest tools in neuroscience and machine learning into closed-loop experiments.

Interoperability of phenome-wide multimorbidity patterns: a comparative study of two large-scale EHR systems.

Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administration raise questions about the consistency and reproducibility of EHR-based multimorbidity research. Methods: Utilizing phecodes to represent the disease phenome, we analyzed pairwise comorbidity strengths using a dual logistic regression approach and constructed multimorbidity as an undirected weighted graph. We assessed the consistency of the multimorbidity networks within and between two major EHR systems at local (nodes and edges), meso (neighboring patterns), and global (network statistics) scales. We present case studies to identify disease clusters and uncover clinically interpretable disease relationships. We provide an interactive web tool and a knowledge base combing data from multiple sources for online multimorbidity analysis. Findings: Analyzing data from 500,000 patients across Vanderbilt University Medical Center and Mass General Brigham health systems, we observed a strong correlation in disease frequencies ( Kendall's τ = 0.643) and comorbidity strengths (Pearson ρ = 0.79). Consistent network statistics across EHRs suggest a similar structure of multimorbidity networks at various scales. Comorbidity strengths and similarities of multimorbidity connection patterns align with the disease genetic correlations. Graph-theoretic analyses revealed a consistent core-periphery structure, implying efficient network clustering through threshold graph construction. Using hydronephrosis as a case study, we demonstrated the network's ability to uncover clinically relevant disease relationships and provide novel insights. Interpretation: Our findings demonstrate the robustness of large-scale EHR data for studying complex disease interactions. The alignment of multimorbidity patterns with genetic data suggests the potential utility for uncovering shared etiology of diseases. The consistent core-periphery network structure offers a strategic approach to analyze disease clusters. This work also sets the stage for advanced disease modeling, with implications for precision medicine. Funding: VUMC Biostatistics Development Award, UL1 TR002243, R21DK127075, R01HL140074, P50GM115305, R01CA227481.

Verified hypotheses on the "nurse" and "burial" effects on introduced Quercus rubra regeneration in a mesic Scots pine forest.

A previous study on the encroachment of North American northern red oak Quercus rubra L. into the mesic Scots pine forest (in central Poland) revealed high abundances of seedlings and saplings under shrubs, with lower abundances in open areas or clumps of bilberry Vaccinium myrtillus L. It was unclear whether the regeneration success of Q. rubra is enhanced by the presence of shrubs due to their "nurse effect", and how burying acorns of different sizes in soil or moss affects the survival of oak seeds and seedlings (a "burial effect"). Results of a previous observational study were verified in an experimental study: a pool of 900 large-, medium-, and small-sized acorns was sown under moss cover in open areas and within bilberry clumps and in soil under shrubs in 2018 and monitored for 3 years in natural conditions. The majority of sown acorns were lost, mainly due to acorn pilferage, lack of germination and the death of sprouting acorns. However, acorn and seedling survival depended significantly on acorn size and differed among the microsites studied. Viable seedlings were twice as likely to develop from large- and medium-sized as from small-sized acorns, and they grew mainly from acorns sown under moss cover, confirming a positive "burial effect." Seedling survival was three times higher in bilberry and open areas, than under shrubs; however, seedlings "nursed" by shrubs were less threatened by large ungulates. Only a small part of the pool of sown acorns contributes to the reproductive success of Q. rubra in the mesic Scots pine forest. Microsites characteristic to this type of forest are suitable for northern red oak regeneration; however, bilberry favors acorn survival and germination and early seedling growth, moss cover favors acorn survival and germination, while shrubs protect surviving seedlings from herbivory.

Dietary fasting and time-restricted eating in Huntington's disease: therapeutic potential and underlying mechanisms.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein, resulting from a CAG repeat expansion in the huntingtin gene HTT. HD is characterized by a variety of debilitating symptoms including involuntary movements, cognitive impairment, and psychiatric disturbances. Despite considerable efforts, effective disease-modifying treatments for HD remain elusive, necessitating exploration of novel therapeutic approaches, including lifestyle modifications that could delay symptom onset and disease progression. Recent studies suggest that time-restricted eating (TRE), a form of intermittent fasting involving daily caloric intake within a limited time window, may hold promise in the treatment of neurodegenerative diseases, including HD. TRE has been shown to improve mitochondrial function, upregulate autophagy, reduce oxidative stress, regulate the sleep-wake cycle, and enhance cognitive function. In this review, we explore the potential therapeutic role of TRE in HD, focusing on its underlying physiological mechanisms. We discuss how TRE might enhance the clearance of mHTT, recover striatal brain-derived neurotrophic factor levels, improve mitochondrial function and stress-response pathways, and synchronize circadian rhythm activity. Understanding these mechanisms is critical for the development of targeted lifestyle interventions to mitigate HD pathology and improve patient outcomes. While the potential benefits of TRE in HD animal models are encouraging, future comprehensive clinical trials will be necessary to evaluate its safety, feasibility, and efficacy in persons with HD.

Ameliorating effect of 2'-Fucosyllactose and 6'-Sialyllactose on lipopolysaccharide-induced intestinal inflammation.

Human milk oligosaccharides (HMO) affect gut microbiota during neonatal development, particularly with respect to the immune system. Bovine milk-based infant formulas have low oligosaccharide contents. Thus, efforts to fortify infant formulas with HMO are being undertaken. Two major HMO, 2'-fucosyllactose (2'-FL) and 6'-sialyllactose (6'-SL), exert anti-inflammatory effects; however, the associations between anti-inflammatory effects induced by 2'-FL and 6'-SL co-treatment and gut microbiota composition and metabolite modulation remain unclear. Therefore, in this study, we evaluated the effects of a mixture of these HMO. To determine the optimal HMO ratio for anti-inflammatory effects and elucidate its mode of action, LPS-induced inflammatory HT-29 epithelial cells and intestinal inflamed suckling mice were treated with various mixtures of 2'-FL and 6'-SL. 2'-FL:6'-SL ratio of 5:1 was identified as the most effective pre-treatment HMO mixture in vitro; thus, this ratio was selected and used for low, middle, and high-dose treatments for subsequent in vivo studies. In vivo, high-dose HMO treatment restored LPS-induced inflammation symptoms, such as body weight loss, colon length reduction, histological structural damage, and intestinal gene expression related to inflammatory responses. High-dose HMO was the only treatment that modulated the major phyla Bacteroidetes and Firmicutes and the genera Ihubacter, Mageeibacillus, and Saccharofermentans. These changes in microbial composition were correlated with intestinal inflammation-related gene expression and short-chain fatty acid production. To our knowledge, our study is the first to report the effects of Ihubacter, Mageeibacillus, and Saccharofermentans on short chain fatty acid levels, which can subsequently affect inflammatory cytokine and tight junction protein levels. Conclusively, the HMO mixture exerted anti-inflammatory effects through changes in microbiota and metabolite production. These findings suggested that supplementation of infant formula with HMO may benefit formula-fed infants by forming unique microbiota contributing to neonatal development.

Task-driven neural network models predict neural dynamics of proprioception.

Proprioception tells the brain the state of the body based on distributed sensory neurons. Yet, the principles that govern proprioceptive processing are poorly understood. Here, we employ a task-driven modeling approach to investigate the neural code of proprioceptive neurons in cuneate nucleus (CN) and somatosensory cortex area 2 (S1). We simulated muscle spindle signals through musculoskeletal modeling and generated a large-scale movement repertoire to train neural networks based on 16 hypotheses, each representing different computational goals. We found that the emerging, task-optimized internal representations generalize from synthetic data to predict neural dynamics in CN and S1 of primates. Computational tasks that aim to predict the limb position and velocity were the best at predicting the neural activity in both areas. Since task optimization develops representations that better predict neural activity during active than passive movements, we postulate that neural activity in the CN and S1 is top-down modulated during goal-directed movements.

Outcomes Following Total Hip Arthroplasty in Patients Who Have Von Willebrand Disease Depend on Postoperative Anticoagulation.

BACKGROUND: Von Willebrand disease (VWD) is the most common congenital bleeding disorder. This autosomal dominant condition arises from quantitative or qualitative defects of Von Willebrand factor. To our knowledge, this study leveraged a national database to characterize the largest VWD cohort of total hip arthroplasty (THA) patients to date, assessing 90-day postoperative adverse events and 5-year revision-free survival. METHODS: Adult patients who underwent primary THA for osteoarthritis were identified from January 2010 to October 2021 in a nationwide database. Patients who had and did not have VWD were matched (4:1) on age, sex, and Elixhauser Comorbidity Index and compared with multivariable logistic regression. Patients were then categorized based upon venous thromboembolism (VTE) chemoprophylaxis prescription patterns to compare bleeding and thrombotic adverse events. RESULTS: Of 544,851 THA patients, VWD was identified in 309 patients (0.06%). The matched cohorts contained 1,221 patients who did not have VWD and 306 patients who have VWD. On multivariable analysis, VWD patients had increased odds of 90-day VTE (odds ratio [OR] = 1.86) and hematoma (OR = 3.40) (P < .05 for all). No difference in 5-year revision-free survival was found. The VWD patients receiving aspirin or no prescriptions had greater odds of VTE (OR = 2.39, P = .048). Those on other chemoprophylaxis agents had greater odds of hematoma (OR = 4.84, P = .006). CONCLUSIONS: Patients with VWD undergoing THA had increased odds of 90-day VTE if using aspirin or no prescriptions, or hematoma if using other chemoprophylaxis. There is a delicate balancing act of clotting versus bleeding that must be considered in managing such patients, but it was reassuring that no difference in overall 5-year revision-free survival was found.

Ligand-gated ion channels as potential biomarkers for ADT-mediated cognitive decline in prostate cancer patients.

Men with prostate cancer are at increased risk of developing cognitive decline by the use of second-generation androgen signaling inhibitors. To date, reliable and sensitive biomarkers that could distinguish men at high risk of cognitive dysfunction under androgen deprivation therapy (ADT) have not been characterized. We used high-throughput transcriptional profiling utilizing human prostate cancer cell culture models mimicking ADT, biomarker selection using minimal common oncology data elements-cytoscape, and bioinformatic analyses employing Advaita® iPathwayGuide and DisGeNET for identification of disease-related gene associations. Validation analysis of genes was performed on brain neuronal and glial cells by quantitative real-time polymerase chain reaction assay. Our systematic analysis of androgen deprivation-associated genes involved multiple biological processes, including neuroactive ligand-receptor interaction, axon guidance, cytokine-cytokine receptor interaction, and metabolic and cancer signaling pathways. Genes associated with neuroreceptor ligand interaction, including gamma-aminobutyric acid (GABA) A and B receptors and nuclear core proteins, were identified as top upstream regulators. Functional enrichment and protein-protein interaction network analysis highlighted the role of ligand-gated ion channels (LGICs) and their receptors in cognitive dysfunction. Gene-disease association assigned forgetfulness, intellectual disability, visuospatial deficit, bipolar disorder, and other neurocognitive impairment with upregulation of type-1 angiotensin II receptor, brain-derived neurotrophic factor, GABA type B receptor subunit 2 (GABBR2), GABRA3, GABRA5, GABRB1, glycine receptor beta, glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 1, glutamate ionotropic receptor NMDA type subunit 2D, 5-hydroxytryptamine receptor 1D, interferon beta 1, and nuclear receptor subfamily 3 group C member 1 as top differentially expressed genes. Validation studies of brain glial cells, neurons, and patients on ADT demonstrated the association of these genes with cognitive decline. Our findings highlight LGICs as potential biomarkers for ADT-mediated cognitive decline. Further validation of these biomarkers may lead to future practical clinical use.

Shared and distinct interactions of type 1 and type 2 Epstein-Barr Nuclear Antigen 2 with the human genome.

BACKGROUND: There are two major genetic types of Epstein-Barr Virus (EBV): type 1 (EBV-1) and type 2 (EBV-2). EBV functions by manipulating gene expression in host B cells, using virus-encoded gene regulatory proteins including Epstein-Barr Nuclear Antigen 2 (EBNA2). While type 1 EBNA2 is known to interact with human transcription factors (hTFs) such as RBPJ, EBF1, and SPI1 (PU.1), type 2 EBNA2 shares only ~ 50% amino acid identity with type 1 and thus may have distinct binding partners, human genome binding locations, and functions. RESULTS: In this study, we examined genome-wide EBNA2 binding in EBV-1 and EBV-2 transformed human B cells to identify shared and unique EBNA2 interactions with the human genome, revealing thousands of type-specific EBNA2 ChIP-seq peaks. Computational predictions based on hTF motifs and subsequent ChIP-seq experiments revealed that both type 1 and 2 EBNA2 co-occupy the genome with SPI1 and AP-1 (BATF and JUNB) hTFs. However, type 1 EBNA2 showed preferential co-occupancy with EBF1, and type 2 EBNA2 preferred RBPJ. These differences in hTF co-occupancy revealed possible mechanisms underlying type-specific gene expression of known EBNA2 human target genes: MYC (shared), CXCR7 (type 1 specific), and CD21 (type 2 specific). Both type 1 and 2 EBNA2 binding events were enriched at systemic lupus erythematosus (SLE) and multiple sclerosis (MS) risk loci, while primary biliary cholangitis (PBC) risk loci were specifically enriched for type 2 peaks. CONCLUSIONS: This study reveals extensive type-specific EBNA2 interactions with the human genome, possible differences in EBNA2 interaction partners, and a possible new role for type 2 EBNA2 in autoimmune disorders. Our results highlight the importance of considering EBV type in the control of human gene expression and disease-related investigations.

Computational modeling of dorsal root ganglion stimulation using an Injectrode.

Objective.Minimally invasive neuromodulation therapies like the Injectrode, which is composed of a tightly wound polymer-coated Platinum/Iridium microcoil, offer a low-risk approach for administering electrical stimulation to the dorsal root ganglion (DRG). This flexible electrode is aimed to conform to the DRG. The stimulation occurs through a transcutaneous electrical stimulation (TES) patch, which subsequently transmits the stimulation to the Injectrode via a subcutaneous metal collector. However, it is important to note that the effectiveness of stimulation through TES relies on the specific geometrical configurations of the Injectrode-collector-patch system. Hence, there is a need to investigate which design parameters influence the activation of targeted neural structures.Approach.We employed a hybrid computational modeling approach to analyze the impact of Injectrode system design parameters on charge delivery and neural response to stimulation. We constructed multiple finite element method models of DRG stimulation, followed by the implementation of multi-compartment models of DRG neurons. By calculating potential distribution during monopolar stimulation, we simulated neural responses using various parameters based on prior acute experiments. Additionally, we developed a canonical monopolar stimulation and full-scale model of bipolar bilateral L5 DRG stimulation, allowing us to investigate how design parameters like Injectrode size and orientation influenced neural activation thresholds.Main results.Our findings were in accordance with acute experimental measurements and indicate that the minimally invasive Injectrode system predominantly engages large-diameter afferents (Aß-fibers). These activation thresholds were contingent upon the surface area of the Injectrode. As the charge density decreased due to increasing surface area, there was a corresponding expansion in the stimulation amplitude range before triggering any pain-related mechanoreceptor (Aδ-fibers) activity.Significance.The Injectrode demonstrates potential as a viable technology for minimally invasive stimulation of the DRG. Our findings indicate that utilizing a larger surface area Injectrode enhances the therapeutic margin, effectively distinguishing the desired Aßactivation from the undesired Aδ-fiber activation.