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Purpose: This research aims to empirically investigate the impacts of product and international diversification strategies on firm-level inventory performance. Design/methodology/approach: This study empirically examines the associations between product and international diversification strategies and inventory performance based on a sample of 64,124 observations across 7,367 US publicly traded firms between 1989 and 2019 from the COMPUSTAT Segment, Fundamental Annual and Fundamental Quarterly data files. We employ both linear and nonlinear regression models to perform our empirical analysis. Findings: This research provides strong evidence that there exists a U-shaped relationship between unrelated product diversification and inventory level and a partially inverted U-shaped relationship between international diversification and inventory level. We also find a positive impact of related product diversification on inventory level, but there is no significant curvilinear relationship between related product diversification and inventory level. Practical implications: Our research findings offer important insights into top management's strategic planning for diversification strategies and operations manager's inventory control policies to achieve the strategic fit between corporate diversification and inventory management. Originality/value: Product and international diversification strategies not only play an essential role in the firm's competitive advantage, but also have a significant influence on operations manager's inventory decision. This research is among the first to systematically investigate how top management's related product, unrelated product and international diversification strategies may have complex nonlinear impacts on inventory performance. [ABSTRACT FROM AUTHOR]

Background: Accurate triage is required for efficient allocation of resources and to decrease patients' length of stay. Triage decisions are often subjective and vary by provider, leading to patients being over-triaged or under-triaged. This study developed machine learning models that incorporated natural language processing (NLP) to predict patient disposition. The models were assessed by comparing their performance with the judgements of emergency physicians (EPs). Method: This retrospective study obtained data from patients visiting EDs between January 2018 and December 2019. Internal validation data came from China Medical University Hospital (CMUH), while external validation data were obtained from Asia University Hospital (AUH). Nontrauma patients aged ≥ 20 years were included. The models were trained using structured data and unstructured data (free-text notes) processed by NLP. The primary outcome was death in the ED or admission to the intensive care unit, and the secondary outcome was either admission to a general ward or transferal to another hospital. Six machine learning models (CatBoost, Light Gradient Boosting Machine, Logistic Regression, Random Forest, Extremely Randomized Trees, and Gradient Boosting) and one Logistic Regression derived from triage level were developed and evaluated using EPs' predictions as reference. Result: A total of 17,2101 and 41,883 patients were enrolled from CMUH and AUH, respectively. EPs achieved F1 core of 0.361 and 0.498 for the primary and secondary outcomes, respectively. All machine learning models achieved higher F1 scores compared to EPs and Logistic Regression derived from triage level. Random Forest was selected for further evaluation and fine-tuning, because of its robust calibration and predictive performance. In internal validation, it achieved Brier scores of 0.072 and 0.089 for the primary and secondary outcomes, respectively, and 0.076 and 0.095 in external validation. Further analysis revealed that incorporating unstructured data significantly enhanced the model's performance. Threshold adjustments were applied to improve clinical applicability, aiming to balance the trade-off between sensitivity and positive predictive value. Conclusion: This study developed and validated machine learning models that integrate structured and unstructured triage data to predict patient dispositions, distinguishing between general ward and critical conditions like ICU admissions and ED deaths. Integrating both structured and unstructured data significantly improved model performance. [ABSTRACT FROM AUTHOR]

Background: Tidal peritoneal dialysis (TPD) provides better fluid flow mechanics and is more comfortable for the patient, owing to fewer alarms and less pain during inflow and outflow. The long‐term characteristics of patients with TPD were not evident. In this randomized controlled follow‐up study, we aimed to explore the characteristics of patients with TPD, compared to IPD. Methods: A total of 85 patients were randomized to either IPD or 70% TPD between January 2019 and December 2020, and all patients were followed up on December 2021. The characteristics of patients between the two groups were analyzed using a t‐test or chi‐square as appropriate. The overall survival and technical survival were analyzed using Kaplan–Meier analysis. Results: Forty‐two patients were assigned to IPD, and 43 patients were assigned to TPD. The basal characteristics of patients were not different between the two groups. In an average of 16 months of follow‐up, 19 patients died, and 25 patients dropped out of peritoneal dialysis. The two groups had no difference in overall survival and technical survival. TPD was associated with high urine volume (p = 0.001), lower blood urea nitrogen (p = 0.002), lower phosphorus (p = 0.004), and fewer cycler alarms (p < 0.001). The chance of patients reporting abdominal fullness was higher in patients with TPD (p = 0.001). Conclusion: In the randomized, controlled, follow‐up study, TPD may preserve residual renal function and is associated with lower urea nitrogen and phosphorus in chronic peritoneal dialysis patients. TPD is associated with fewer cycler alarms but may increase the chance of patients reporting abdominal distension. [ABSTRACT FROM AUTHOR]

Current genome-wide association studies (GWAS) for kidney function lack ancestral diversity, limiting the applicability to broader populations. The East-Asian population is especially under-represented, despite having the highest global burden of end-stage kidney disease. We conducted a meta-analysis of multiple GWASs (n = 244,952) on estimated glomerular filtration rate and a replication dataset (n = 27,058) from Taiwan and Japan. This study identified 111 lead SNPs in 97 genomic risk loci. Functional enrichment analyses revealed that variants associated with F12 gene and a missense mutation in ABCG2 may contribute to chronic kidney disease (CKD) through influencing inflammation, coagulation, and urate metabolism pathways. In independent cohorts from Taiwan (n = 25,345) and the United Kingdom (n = 260,245), polygenic risk scores (PRSs) for CKD significantly stratified the risk of CKD (p < 0.0001). Further research is required to evaluate the clinical effectiveness of PRSCKD in the early prevention of kidney disease. Here the authors present a large genetic study in East Asians that identifies 97 genetic regions linked to kidney function. These findings aim at better understanding chronic kidney disease in diverse populations. [ABSTRACT FROM AUTHOR]

Maternal use of e-cigarette (e-cig) aerosols poses significant risks to fetal brain development, potentially increasing susceptibility to neurodevelopmental disorders in later life. However, the underlying mechanisms remain incompletely understood. This study aimed to understand the effects of fetal e-cig exposure on DNA methylome and transcriptomic changes in the neonatal brain. Pregnant rats were exposed to e-cig aerosols, and neonatal brains (5 males and 5 females/group) from both control and e-cig-exposed groups were used for experimental analysis. Results indicated that prenatal e-cig exposure altered site-specific DNA methylation patterns at both CpG and CH (non-CpG) sites, predominantly in intergenic and intronic regions, with sex dimorphism in methylation and gene expression changes. Gene ontology analysis revealed that e-cig exposure not only affected neuron projection development and axonogenesis but also altered pathways related to neurodegeneration and long-term depression. These findings provide novel insights into the dynamic changes of CpG and CH methylation induced by e-cig exposure, underscoring the susceptibility of the developing brain to maternal e-cig exposure and its potential implications for developmental disorders and neurodegenerative diseases later in life. [ABSTRACT FROM AUTHOR]

Maternal use of e-cigarette (e-cig) aerosols poses significant risks to fetal brain development, potentially increasing susceptibility to neurodevelopmental disorders in later life. However, the underlying mechanisms remain incompletely understood. This study aimed to understand the effects of fetal e-cig exposure on DNA methylome and transcriptomic changes in the neonatal brain. Pregnant rats were exposed to e-cig aerosols, and neonatal brains (5 males and 5 females/group) from both control and e-cig-exposed groups were used for experimental analysis. Results indicated that prenatal e-cig exposure altered site-specific DNA methylation patterns at both CpG and CH (non-CpG) sites, predominantly in intergenic and intronic regions, with sex dimorphism in methylation and gene expression changes. Gene ontology analysis revealed that e-cig exposure not only affected neuron projection development and axonogenesis but also altered pathways related to neurodegeneration and long-term depression. These findings provide novel insights into the dynamic changes of CpG and CH methylation induced by e-cig exposure, underscoring the susceptibility of the developing brain to maternal e-cig exposure and its potential implications for developmental disorders and neurodegenerative diseases later in life. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancer disparities in outcomes for Black Americans have been well recognized. However, the specific drivers of the inferior outcomes remain poorly understood. We investigated the biologic features of patient oral cancers and performed a follow-up study of the patient post-surgery recurrences and metastases aiming to explore potential mechanisms that might underpin the poorer outcomes among Black American patients. It was found that high levels of tumor stemness and tumor-promoting stromal characteristics were linked to patient recurrence and metastasis. There were more cases of Black American than White American exhibiting high stemness traits and strong tumor-promoting stromal features associated with tumor recurrences and metastases, although the investigated cases displayed comparable clinical diagnoses. Our findings revealed that the differences in tumor stemness and stromal property among cancers with similar diagnoses contribute to patient outcome disparities. Black Americans (BAs) with head and neck cancer (HNC) have worse survival outcomes compared to the White patients. While HNC disparities in patient outcomes for BAs have been well recognized, the specific drivers of the inferior outcomes remain poorly understood. Here, we investigated the biologic features of patient tumor specimens obtained during the surgical treatment of oral cancers and performed a follow-up study of the patients' post-surgery recurrences and metastases with the aim to explore whether tumor biologic features could be associated with the poorer outcomes among BA patients compared with White American (WA) patients. We examined the tumor stemness traits and stromal properties as well as the post-surgery recurrence and metastasis of oral cancers among BA and WA patients. It was found that high levels of tumor self-renewal, invasion, tumorigenesis, metastasis, and tumor-promoting stromal characteristics were linked to post-surgery recurrence and metastasis. There were more BA than WA patients demonstrating high stemness traits and strong tumor-promoting stromal features in association with post-surgery tumor recurrences and metastases, although the investigated cases displayed clinically comparable TNM stages and histological grades. These findings demonstrated that the differences in tumor stemness and stromal property among cancers with comparable clinical diagnoses contribute to the outcome disparity in HNCs. More research is needed to understand the genetic and molecular basis of the biologic characteristics underlying the inferior outcomes among BA patients, so that targeting strategies can be developed to reduce HNC disparity. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose transporter-2 inhibitors (SGLT-2i) are recommended for use in patients with type 2 diabetes comorbid atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease. Limited reports are currently available for their use in dialysis patients. In an observational, retrospective follow-up study, we reported the clinical characteristics of chronic peritoneal dialysis (PD) patients on SGLT-2i. Methods: We enrolled 50 diabetic chronic PD patients, and 11 continued SGLT-2i after PD treatment. We reported the patients' ultrafiltration, HbA1c, urinary tract infection episodes, and venous CO2 during follow-up and compared the differences in these factors between patients with and without SGLT-2i. Results: The mean age of the patients was 65 ± 15 years, and 16 (32%) patients were female. The age, gender, heart failure, and primary kidney disease were not different between patients with and without SGLT-2i at enrollment. In an average of 31 months follow-up, patients with SGLT-2i had higher ultrafiltration (1322 ± 200 ml/day vs. 985 ± 415 ml/day, p = 0.013), hemoglobin (11.2 ± 1.7 vs. 10.2 ± 1.7 g/dl), white blood cell count (9.2 ± 3.7 vs. 7.4 ± 2.1 109/L), and a lower venous CO2 (p = 0.036). The urine amount, the overall survival, the technical survival, and the chance of UTI were not different between patients with and without SGLT2i. Conclusion: SGLT-2i may increase ultrafiltration volume and hemoglobin levels in chronic PD patients. SGLT-2i did not increase urinary tract infection but was linked to subclinical metabolic acidosis. What was known: The effect of SGLT-2i in chronic PD patients is not clear? This study adds: SGLT-2i is associated with increased ultrafiltration, hemoglobin, white blood cell counts, and a decreased CO2 in PD patient. Potential impact: SGLT-2i may increase ultrafiltration in PD patients. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) necessitates a thorough understanding of intricate cellular interactions within the tumor microenvironment (TME). Mesenchymal stromal cells (MSCs) play a pivotal role in cancer generation, progression, and immunosuppressive tumor microenvironment. Within the TME, MSCs encompass both resident and circulating counterparts that dynamically communicate and actively participate in TME immunosurveillance and response to ICB. This review aims to reevaluate various facets of MSCs, including their potential self-transformation to function as cancer-initiating cells and contributions to the creation of a conducive environment for tumor proliferation and metastasis. Additionally, we explore the immune regulatory functions of tumor-associated MSCs (TA-MSCs) and MSC-derived extracellular vesicles (MSC-EVs) with analysis of potential connections between circulating and tissue-resident MSCs. A comprehensive understanding of the dynamics of MSC-immune cell communication and the heterogeneous cargo of tumor-educated versus naïve MSCs may unveil a new MSC-mediated immunosuppressive pathway that can be targeted to enhance cancer control by ICB. [ABSTRACT FROM AUTHOR]

Introduction: Chemotherapy resistance remains a significant challenge in the treatment of pancreatic adenocarcinoma (PDAC), particularly in relation to gemcitabine (Gem), a commonly used chemotherapeutic agent. MicroRNAs (miRNAs) are known to influence cancer progression and chemoresistance. This study investigates the association between miRNA expression profiles and gemcitabine resistance in PDAC. Methods: The miRNA expression profiles of a gemcitabine-sensitive (GS) PDAC cell line, MIA PaCa-2, and its gemcitabine-resistant (GR) progeny, MIA PaCa-2 GR, were analyzed. miRNA sequencing (miRNA-seq) was employed to identify miRNAs expressed in these cell lines. Differential expression analysis was performed, and Ingenuity Pathway Analysis (IPA) was utilized to elucidate the biological functions of the differentially expressed miRNAs. Results: A total of 1867 miRNAs were detected across both cell lines. Among these, 97 (5.2%) miRNAs showed significant differential expression between the GR and GS cell lines, with 65 (3.5%) miRNAs upregulated and 32 (1.7%) miRNAs downregulated in the GR line. The most notably altered miRNAs were implicated in key biological processes such as cell proliferation, migration, invasion, chemosensitization, alternative splicing, apoptosis, and angiogenesis. A subset of these miRNAs was further analyzed in patient samples to identify potential markers for recurrent tumors. Discussion: The differential miRNA expression profiles identified in this study highlight the complex regulatory roles of miRNAs in gemcitabine resistance in PDAC. These findings suggest potential targets for improving prognosis and tailoring treatment strategies in PDAC patients, particularly those showing resistance to gemcitabine. Future research should focus on validating these miRNAs as biomarkers for resistance and exploring their therapeutic potential in overcoming chemoresistance. [ABSTRACT FROM AUTHOR]

Background: Arthroscopic treatment of femoroacetabular impingement (FAI) and symptomatic labral tears confers short- to midterm benefits, yet further long-term evidence is needed. Moreover, despite the physiological and biomechanical significance of the chondrolabral junction (CLJ), the clinical implications of damage to this transition zone remain understudied. Purpose: To (1) report minimum 8-year survivorship and patient-reported outcome measures after hip arthroscopy for FAI and (2) characterize associations between outcomes and patient characteristics (age, body mass index, sex), pathological parameters (Tönnis angle, alpha angle, type of FAI, CLJ breakdown), and procedures performed (labral management, FAI treatment, microfracture). Study Design: Cohort study; Level of evidence, 3. Methods: This retrospective cohort study included patients who underwent primary hip arthroscopy for symptomatic labral tears secondary to FAI by a single surgeon between 2002 and 2013. All patients were ≥18 years of age with minimum 8-year follow-up and available preoperative radiographs. The primary outcome was conversion to total hip arthroplasty (THA), and secondary outcomes included revision arthroscopy, patient-reported outcome measures, and patient satisfaction. CLJ breakdown was assessed using the Beck classification. Kaplan-Meier estimates and weighted Cox regression were used to estimate 10-year survivorship (no conversion to THA) and identify risk factors associated with THA conversion. Results: In this study of 174 hips (50.6% female; mean age, 37.8 ± 11.2 years) with mean follow-up of 11.1 ± 2.5 years, the 10-year survivorship rate was 81.6% (95% CI, 75.9%-87.7%). Conversion to THA occurred at a mean 4.7 ± 3.8 years postoperatively. Unadjusted analyses revealed several variables significantly associated with THA conversion, including older age; higher body mass index; higher Tönnis grade; labral debridement; and advanced breakdown of the CLJ, labrum, or articular cartilage. Survivorship at 10 years was inferior in patients exhibiting severe (43.6%; 95% CI, 31.9%-59.7%) versus mild (97.9%; 95% CI, 95.1%-100%) breakdown of the CLJ (P <.001). Multivariable analysis identified worsening CLJ breakdown (weighted hazard ratio per 1-unit increase, 6.41; 95% CI, 3.11-13.24), older age (1.09; 95% CI, 1.04-1.14), and higher Tönnis grade (4.59; 95% CI, 2.13-9.90) as independent negative prognosticators (P <.001 for all). Conclusion: Although most patients achieved favorable minimum 8-year outcomes, several pre- and intraoperative factors were associated with THA conversion; of these, worse CLJ breakdown, higher Tönnis grade, and older age were the strongest predictors. [ABSTRACT FROM AUTHOR]

To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its histopathological and BRCA2 mutation status, and exposed to cisplatin in vitro. In the cisplatin-resistant cells, transcriptomics were carried out, and cell morphology, protein expression, and functional status were characterized. Additionally, potential signaling pathways involved in cisplatin resistance were explored. Our findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin-resistant PDX4 compared to their sensitive counterparts. Surprisingly, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic–features indicative of an underlying complex mechanism for cell survival. Furthermore, DNA damage tolerance and cellular stress management pathways were enriched. This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapies tailored to combat resistance in stem-like ovarian cancer. [ABSTRACT FROM AUTHOR]

A dysbiotic microbial community whose members have specific/synergistic functions that are modulated by environmental conditions, can disturb homeostasis in the subgingival space leading to destructive inflammation, plays a role in the progression of periodontitis. Filifactor alocis, a gram‐positive, anaerobic bacterium, is a newly recognized microbe that shows a strong correlation with periodontal disease. Our previous observations suggested F. alocis to be more resistant to oxidative stress compared to Porphyromonas gingivalis. The objective of this study is to further determine if F. alocis, because of its increased resistance to oxidative stress, can affect the survival of other 'established' periodontal pathogens under environmental stress conditions typical of the periodontal pocket. Here, we have shown that via their interaction, F. alocis protects P. gingivalis W83 under H2O2‐induced oxidative stress conditions. Transcriptional profiling of the interaction of F. alocis and P. gingivalis in the presence of H2O2‐induced stress revealed the modulation of several genes, including those with ABC transporter and other cellular functions. The ABC transporter operon (PG0682–PG0685) of P. gingivalis was not significant to its enhanced survival when cocultured with F. alocis under H2O2‐induced oxidative stress. In F. alocis, one of the most highly up‐regulated operons (FA0894–FA0897) is predicted to encode a putative manganese ABC transporter, which in other bacteria can play an essential role in oxidative stress protection. Collectively, the results may indicate that F. alocis could likely stabilize the microbial community in the inflammatory microenvironment of the periodontal pocket by reducing the oxidative environment. This strategy could be vital to the survival of other pathogens, such as P. gingivalis, and its ability to adapt and persist in the periodontal pocket. [ABSTRACT FROM AUTHOR]

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Patients suffering from debilitating neurodegenerative diseases often lose the ability to communicate, detrimentally affecting their quality of life. One solution to restore communication is to decode signals directly from the brain to enable neural speech prostheses. However, decoding has been limited by coarse neural recordings which inadequately capture the rich spatio-temporal structure of human brain signals. To resolve this limitation, we performed high-resolution, micro-electrocorticographic (µECoG) neural recordings during intra-operative speech production. We obtained neural signals with 57× higher spatial resolution and 48% higher signal-to-noise ratio compared to macro-ECoG and SEEG. This increased signal quality improved decoding by 35% compared to standard intracranial signals. Accurate decoding was dependent on the high-spatial resolution of the neural interface. Non-linear decoding models designed to utilize enhanced spatio-temporal neural information produced better results than linear techniques. We show that high-density µECoG can enable high-quality speech decoding for future neural speech prostheses. Previous work has shown speech decoding in the human brain for the development of neural speech prostheses. Here the authors show that high density µECoG electrodes can record at micro-scale spatial resolution to improve neural speech decoding. [ABSTRACT FROM AUTHOR]

We introduce a parsimonious framework for choosing among alternative expected-return proxies (ERPs) when estimating treatment effects. By comparing ERPs' measurement error variances in the cross-section and in the time series, we provide new evidence on the relative performance of firm-level ERPs nominated by recent studies. Generally, "implied-costs-of-capital" metrics perform best in the time series, whereas "characteristic-based" proxies perform best in the cross-section. Factor-based ERPs, even the latest renditions, perform poorly. We revisit four prior studies that use ex ante ERPs and illustrate how this framework can potentially alter either the sign or the magnitude of prior inferences. [ABSTRACT FROM AUTHOR]

Integrated chemo- and mechanosensory pathways, along with activated calcium influxes, regulate nematocyst discharge from sea anemone tentacles. Discharge from vibration-sensitive Type A cnidocyte supporting cell complexes use calcium-conducting transient receptor potential V4-like channels. Because calcium influxes often couple with calcium-activated, large-conductance potassium (BK) channels, we hypothesized that BK channels function in nematocyst discharge. To verify this hypothesis, we first tested five selective BK channel blockers on nematocyst-mediated prey killing in Diadumene lineata (aka Haliplanella luciae). All tested BK channel blockers inhibited prey killing at concentrations comparable to their inhibition of vertebrate BK channels. In addition, the BK channel blocker paxilline selectively inhibited prey killing mediated by vibration-sensitive Type A cnidocyte supporting cell complexes. We queried a mammalian BK α amino acid sequence to the Exaiptasia diaphena database, from which we identified a putative anemone, pore-forming BK α subunit sequence. Using the E. diaphena BK α sequence as a template, we assembled a BK α transcript from our assembled D. lineata transcriptome. In addition, the hydra homolog of D. lineata BK α localizes to nematocytes on the hydra single-cell RNA sequencing map. Our findings suggest that D. lineata expresses BK channels that play a role in vibration-sensitive nematocyst discharge from Type A cnidocyte supporting cell complexes. We believe this is the first functional demonstration of BK channels in nonbilaterians. Because stimulated chemoreceptors frequency tune Type A cnidocyte supporting cell complexes to frequencies matching swimming movements of prey via a protein kinase A signaling pathway and protein kinase A generally activates BK channels, we suggest that D. lineata BK channels may participate in protein kinase A–mediated frequency tuning. [ABSTRACT FROM AUTHOR]

Techniques to study brain activities have evolved dramatically, yet tremendous challenges remain in acquiring high-throughput electrophysiological recordings minimally invasively. Here, we develop an integrated neuroelectronic array that is filamentary, high-density and flexible. Specifically, with a design of single-transistor multiplexing and current sensing, the total 256 neuroelectrodes achieve only a 2.3 × 0.3 mm2 area, unprecedentedly on a flexible substrate. A single-transistor multiplexing acquisition circuit further reduces noise from the electrodes, decreases the footprint of each pixel, and potentially increases the device's lifetime. The filamentary neuroelectronic array also integrates with a rollable contact pad design, allowing the device to be injected through a syringe, enabling potential minimally invasive array delivery. Successful acute auditory experiments in rats validate the ability of the array to record neural signals with high tone decoding accuracy. Together, these results establish soft, high-density neuroelectronic arrays as promising devices for neuroscience research and clinical applications. [ABSTRACT FROM AUTHOR]

Patients with advanced prostate cancer (PCa) invariably develop resistance to anti-androgen therapy and taxane-based chemotherapy. Glucocorticoid receptor (GR) has been implicated in PCa therapy resistance; however, the mechanisms underlying GR-mediated chemoresistance remain unclear. Lens epithelium-derived growth factor p75 (LEDGF/p75, also known as PSIP1 and DFS70) is a glucocorticoid-induced transcription co-activator implicated in cancer chemoresistance. We investigated the contribution of the GR–LEDGF/p75 axis to docetaxel (DTX)-resistance in PCa cells. GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression. ChIP-sequencing revealed GR binding sites in the LEDGF/p75 promoter. STRING protein–protein interaction analysis indicated that GR and LEDGF/p75 belong to the same transcriptional network, and immunochemical studies demonstrated their co-immunoprecipitation and co-localization in DTX-resistant cells. The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR–LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa. [ABSTRACT FROM AUTHOR]

Porphyromonas gingivalis, the causative agent of adult periodontitis, must gain resistance to frequent oxidative and nitric oxide (NO) stress attacks from immune cells in the periodontal pocket to survive. Previously, we found that, in the wild‐type and under NO stress, the expression of PG1237 (CdhR), the gene encoding for a putative LuxR transcriptional regulator previously called community development and hemin regulator (CdhR), was upregulated 7.7‐fold, and its adjacent gene PG1236 11.9‐fold. Isogenic mutants P. gingivalis FLL457 (ΔCdhR::ermF), FLL458 (ΔPG1236::ermF), and FLL459 (ΔPG1236‐CdhR::ermF) were made by allelic exchange mutagenesis to determine the involvement of these genes in P. gingivalis W83 NO stress resistance. The mutants were black pigmented and β hemolytic and their gingipain activities varied with strains. FLL457 and FLL459 mutants were more sensitive to NO compared to the wild type, and complementation restored NO sensitivity to that of the wild type. DNA microarray analysis of FLL457 showed that approximately 2% of the genes were upregulated and over 1% of the genes downregulated under NO stress conditions compared to the wild type. Transcriptome analysis of FLL458 and FLL459 under NO stress showed differences in their modulation patterns. Some similarities were also noticed between all mutants. The PG1236‐CdhR gene cluster revealed increased expression under NO stress and may be part of the same transcriptional unit. Recombinant CdhR showed binding activity to the predicted promoter regions of PG1459 and PG0495. Taken together, the data indicate that CdhR may play a role in NO stress resistance and be involved in a regulatory network in P. gingivalis. [ABSTRACT FROM AUTHOR]

Objective: Effective surgical treatment of drug‐resistant epilepsy depends on accurate localization of the epileptogenic zone (EZ). High‐frequency oscillations (HFOs) are potential biomarkers of the EZ. Previous research has shown that HFOs often occur within submillimeter areas of brain tissue and that the coarse spatial sampling of clinical intracranial electrode arrays may limit the accurate capture of HFO activity. In this study, we sought to characterize microscale HFO activity captured on thin, flexible microelectrocorticographic (μECoG) arrays, which provide high spatial resolution over large cortical surface areas. Methods: We used novel liquid crystal polymer thin‐film μECoG arrays (.76–1.72‐mm intercontact spacing) to capture HFOs in eight intraoperative recordings from seven patients with epilepsy. We identified ripple (80–250 Hz) and fast ripple (250–600 Hz) HFOs using a common energy thresholding detection algorithm along with two stages of artifact rejection. We visualized microscale subregions of HFO activity using spatial maps of HFO rate, signal‐to‐noise ratio, and mean peak frequency. We quantified the spatial extent of HFO events by measuring covariance between detected HFOs and surrounding activity. We also compared HFO detection rates on microcontacts to simulated macrocontacts by spatially averaging data. Results: We found visually delineable subregions of elevated HFO activity within each μECoG recording. Forty‐seven percent of HFOs occurred on single 200‐μm‐diameter recording contacts, with minimal high‐frequency activity on surrounding contacts. Other HFO events occurred across multiple contacts simultaneously, with covarying activity most often limited to a.95‐mm radius. Through spatial averaging, we estimated that macrocontacts with 2–3‐mm diameter would only capture 44% of the HFOs detected in our μECoG recordings. Significance: These results demonstrate that thin‐film microcontact surface arrays with both highresolution and large coverage accurately capture microscale HFO activity and may improve the utility of HFOs to localize the EZ for treatment of drug‐resistant epilepsy. [ABSTRACT FROM AUTHOR]

Human exposure to low-to-moderate dose ionizing radiation (LMD-IR) is increasing via environmental, medical, occupational sources. Acute exposure to LMD-IR can cause subclinical damage to cells, resulting in altered gene expression and cellular function within the human brain. It has been difficult to identify diagnostic and predictive biomarkers of exposure using traditional research models due to factors including lack of 3D structure in monolayer cell cultures, limited ability of animal models to accurately predict human responses, and technical limitations of studying functional human brain tissue. To address this gap, we generated brain/cerebral organoids from human induced pluripotent stem cells to study the radiosensitivity of human brain cells, including neurons, astrocytes, and oligodendrocytes. While organoids have become popular models for studying brain physiology and pathology, there is little evidence to confirm that exposing brain organoids to LMD-IR will recapitulate previous in vitro and in vivo observations. We hypothesized that exposing brain organoids to proton radiation would (1) cause a time- and dose-dependent increase in DNA damage, (2) induce cell type-specific differences in radiosensitivity, and (3) increase expression of oxidative stress and DNA damage response genes. Organoids were exposed to 0.5 or 2 Gy of 250 MeV protons and samples were collected at 30 minute, 24 hour, and 48 hour timepoints. Using immunofluorescence and RNA sequencing, we found time- and dose-dependent increases in DNA damage in irradiated organoids; no changes in cell populations for neurons, oligodendrocytes, and astrocytes by 24 hours; decreased expression of genes related to oligodendrocyte lineage, astrocyte lineage, mitochondrial function, and cell cycle progression by 48 hours; increased expression of genes related to neuron lineage, oxidative stress, and DNA damage checkpoint regulation by 48 hours. Our findings demonstrate the possibility of using organoids to characterize cell-specific radiosensitivity and early radiation-induced gene expression changes within the human brain, providing new avenues for further study of the mechanisms underlying acute neural cell responses to IR exposure at low-to-moderate doses. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) have great value in cell therapies. The MSC therapies have many challenges due to its inconsistent potency and limited quantity. Here, we report a strategy to generate induced MSCs (iMSCs) by directly reprogramming human peripheral blood mononuclear cells (PBMCs) with OCT4, SOX9, MYC, KLF4, and BCL-XL using a nonintegrating episomal vector system. While OCT4 was not required to reprogram PBMCs into iMSCs, omission of OCT4 significantly impaired iMSC functionality. The omission of OCT4 resulted in significantly downregulating MSC lineage specific and mesoderm-regulating genes, including SRPX, COL5A1, SOX4, SALL4, TWIST1. When reprogramming PBMCs in the absence of OCT4, 67 genes were significantly hypermethylated with reduced transcriptional expression. These data indicate that transient expression of OCT4 may serve as a universal reprogramming factor by increasing chromatin accessibility and promoting demethylation. Our findings represent an approach to produce functional MSCs, and aid in identifying putative function associated MSC markers. Induced MSCs (iMSCs) are generated by direct reprogramming of human PBMCs using 5 factor transfection, including OCT4, SOX9, MYC, KLF4, and BCL-XL. [ABSTRACT FROM AUTHOR]

We establish the equivalence between two formulations of superstring perturbation theory, one based on integration over the supermoduli space of super Riemann surfaces (SRS), the other based on integration over the bosonic moduli space with insertions of picture changing operators (PCO) on the worldsheet and the vertical integration prescription, by showing how the latter arises from a specific construction of the supermoduli integration contour. [ABSTRACT FROM AUTHOR]

Background: Fetal hypoxia causes vital, systemic, developmental malformations in the fetus, particularly in the brain, and increases the risk of diseases in later life. We previously demonstrated that fetal hypoxia exposure increases the susceptibility of the neonatal brain to hypoxic-ischemic insult. Herein, we investigate the effect of fetal hypoxia on programming of cell-specific transcriptomes in the brain of neonatal rats. Results: We obtained RNA sequencing (RNA-seq) data from neurons, microglia, oligodendrocytes, A2B5+ oligodendrocyte precursor cells, and astrocytes from male and female neonatal rats subjected either to fetal hypoxia or control conditions. Substantial transcriptomic responses to fetal hypoxia occurred in neurons, microglia, oligodendrocytes, and A2B5+ cells. Not only were the transcriptomic responses unique to each cell type, but they also occurred with a great deal of sexual dimorphism. We validated differential expression of several genes related to inflammation and cell death by Real-time Quantitative Polymerase Chain Reaction (qRT-PCR). Pathway and transcription factor motif analyses suggested that the NF-kappa B (NFκB) signaling pathway was enriched in the neonatal male brain due to fetal hypoxia, and we verified this result by transcription factor assay of NFκB-p65 in whole brain. Conclusions: Our study reveals a significant impact of fetal hypoxia on the transcriptomes of neonatal brains in a cell-specific and sex-dependent manner, and provides mechanistic insights that may help explain the development of hypoxic-ischemic sensitive phenotypes in the neonatal brain. [ABSTRACT FROM AUTHOR]

We establish the equivalence between two formulations of superstring perturbation theory, one based on integration over the supermoduli space of super Riemann surfaces (SRS), the other based on integration over the bosonic moduli space with insertions of picture changing operators (PCO) on the worldsheet and the vertical integration prescription, by showing how the latter arises from a specific construction of the supermoduli integration contour. [ABSTRACT FROM AUTHOR]

Enterococcus faecalis virulence requires cell wall‐associated proteins, including the sortase‐assembled endocarditis and biofilm associated pilus (Ebp), important for biofilm formation in vitro and in vivo. The current paradigm for sortase‐assembled pilus biogenesis in Gram‐positive bacteria is that sortases attach substrates to lipid II peptidoglycan (PG) precursors, prior to their incorporation into the growing cell wall. Contrary to prevailing dogma, by following the distribution of Ebp and PG throughout the E. faecalis cell cycle, we found that cell surface Ebp do not co‐localize with newly synthesized PG. Instead, surface‐exposed Ebp are localized to the older cell hemisphere and excluded from sites of new PG synthesis at the septum. Moreover, Ebp deposition on the younger hemisphere of the E. faecalis diplococcus appear as foci adjacent to the nascent septum. We propose a new model whereby sortase substrate deposition can occur on older PG rather than at sites of new cell wall synthesis. Consistent with this model, we demonstrate that sequestering lipid II to block PG synthesis via ramoplanin, does not impact new Ebp deposition at the cell surface. These data support an alternative paradigm for sortase substrate deposition in E. faecalis, in which Ebp are anchored directly onto uncrosslinked cell wall, independent of new PG synthesis. [ABSTRACT FROM AUTHOR]

We illustrate the relation between supermoduli integration and picture changing operators (PCOs) particularly concerning the role of vertical integration, in the context of superstring vacuum amplitudes, by an explicit comparison of different parameterizations of the supermoduli space of genus two super Riemann surfaces. [ABSTRACT FROM AUTHOR]

The objective of the NASA Psyche mission gravity science investigation is to map the mass distribution within asteroid (16) Psyche to elucidate interior structure and to resolve the question of whether this metal-rich asteroid represents a remnant metal core or whether it is a primordial body that never melted. Measurements of gravity will be obtained via the X-band telecommunication system on the Psyche spacecraft, collected from progressively lower mapping altitudes. Orbital gravity will allow an estimate of G M to better than 0.001 km3 s−2. A spherical harmonic model of gravity to degree and order 10 will be achievable and, in concert with spherical harmonic data sets from topography and magnetometry, as well as surface composition data, will provide information regarding the spatial and radial distribution of mass that will be used to constrain the origin and evolution of (16) Psyche. [ABSTRACT FROM AUTHOR]

As the COVID-19 pandemic shut down most face-to-face instructions and services in higher education, universities struggled to continue teaching and serving students. In particular, student services like academic advising were significantly impacted, as most advising is conducted in person. The use of synchronous communication technology was suddenly increased to continue advising students, employing Remote Academic Advising (RAA). Three researchers at a state university in the southeast USA conducted a case study to understand the experiences of using RAA by academic advisors. The study included 11 academic advisors from different academic colleges and areas who were engaged in RAA to provide advising service to students during the 2020–2021 academic year. Four themes emerged after a reiterative process of coding and analysing the interview responses. The four themes were a slow transition to using RAA, RAA can also be relational, RAA can promote more awareness of mental health and RAA should be part of regular advising practice. The discussion section includes recommendations for advancing RAA as regular practice through a concerted effort of promotion, leadership and effective use of RAA with synchronous communication technology among the advising community on campus. [ABSTRACT FROM AUTHOR]

With the increasing internationalization of its securities market, China has recently introduced Article 2(4) of the 2019 Securities Law, in order to deal with the important issue of extraterritorial jurisdiction over cross-border securities transactions. While it represents an important development, the provision is couched in very broad terms, bringing uncertainties and difficulties to its application in practice. This article proposes a phased reform agenda for improvement: in the short run, the effect test under Article 2(4) should be clarified with more guidance; in the long run, China should go beyond the effect test to consider other relevant tests such as the conduct test and the transactional test. The recent high-profile case of Luckin Coffee is carefully studied to show the factors that China may consider in applying Article 2(4), including the test of national interests, the principle of international comity, and the issue of judicial recourse constraints. [ABSTRACT FROM AUTHOR]

Objectives: To identify location and severity of intraoperative pathology at time of arthroscopic surgery for femoroacetabular impingement (FAI) as risk factors for conversion to total hip arthroplasty (THA) utilizing long-term follow-up (minimum 10 years). Methods: Retrospective study of prospectively collected data of adult patients (> 18 years) who underwent hip arthroscopy for FAI between 1998 and 2011 with minimum follow-up of 10 years. Location and severity of pathology at time of arthroscopic surgery were assessed as risk factors for later conversion to a primary outcome of THA. Patients with radiographic evidence of hip dysplasia and previous history of hip surgery were excluded. Patients were then grouped according to whether they had underwent THA. Differences in continuous variables including age, BMI, and center edge angle (CEA) were analyzed with independent t tests. Differences in categorical variables including type of treatment (debridement or repair), deformity (CAM vs pincer vs combined), Outerbridge grade, location of most severe chondral wear (anterosuperior acetabulum, posterosuperior acetabulum, femoral head), presence of chondral flap, and degree of chondrolabral degeneration (as measured by Beck classification) were analyzed with the Pearson's Chi-squared test. For variables with greater than two levels (chondrolabral degeneration, etc.) adjusted residuals were calculated to determine which comparisons were statistically different, with a value of >2 indicating a lack of fit with the null hypothesis of difference. A multivariable logistic regression model was constructed to estimate the influence of the exact location and severity of pathology on risk for conversion to THA. Model results are reported as odds ratios (OR) with corresponding 95% confidence intervals. Results: A total of 109 patients with a mean age of 39.41 ± 11.43 years and minimum follow-up of 10 years were eligible for inclusion in this study. The average follow-up was 12.29 ± 2.53 years. Average body mass index (BMI) was 26.19 ± 4.07 while average center edge angle (CEA) was 39.53 ± 7.24. 67 (61.5%) patients underwent debridement while 42 (38.5%) patients underwent labral repair. 32 (29.4%) patients subsequently converted to THA. BMI (1.7% difference, p = 0.072), CEA (0.3% difference, p = 0.832), sex (0.2% difference, p = 0.991), procedure type (11.8% difference, p = 0.565), and presence of a chondral flap (6.3% difference, p = 0.685) were not significantly associated with conversion to THA. FAI type, Outerbridge grade, chondrolabral junction degeneration, and location of most severe degenerative change were statistically significant, with adjusted residuals greater than 2 (Table 1). A multivariable logistic regression model demonstrated age (OR=1.08, 95% CI 1.03-1.14, p = 0.002), Grade 4 chondrolabral degeneration (OR = 3.26, 95% CI 1.16-9.17, p = 0.025) and combined FAI type (OR = 4.32, 95% CI 1.38 - 13.56, p = 0.012) as significant risk factors for conversion to THA. Conclusions: Grade 4 degeneration of the chondrolabral junction as well as combined FAI type and older age are significant risk factors for conversion to THA after arthroscopic treatment of FAI at minimum 10-years of follow-up. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular management and risk stratification of patients is an important issue in clinics. Patients who have experienced an adverse cardiac event are concerned for their future and want to know the survival probability. Methods: We trained eight state-of-the-art CNN models using polar maps of myocardial perfusion imaging (MPI), gender, lung/heart ratio, and patient age for 5-year survival prediction after an adverse cardiac event based on a cohort of 862 patients who had experienced adverse cardiac events and stress/rest MPIs. The CNN model outcome is to predict a patient's survival 5 years after a cardiac event, i.e., two classes, either yes or no. Results: The best accuracy of all the CNN prediction models was 0.70 (median value), which resulted from ResNet-50V2, using image as the input in the baseline experiment. All the CNN models had better performance after using frequency spectra as the input. The accuracy increment was about 7~9%. Conclusions: This is the first trial to use pure rest/stress MPI polar maps and limited clinical data to predict patients' 5-year survival based on CNN models and deep learning. The study shows the feasibility of using frequency spectra rather than images, which might increase the performance of CNNs. [ABSTRACT FROM AUTHOR]

Pregnancy induces maternal renal adaptations that include increased glomerular filtration rate and renal blood flow which can be compromised in obstetrical complications such as preeclampsia. Brown Norway (BN) rat pregnancies are characterized by placental insufficiency, maternal hypertension, and proteinuria. We hypothesized that BN pregnancies would show renal functional, anatomical, or molecular features of preeclampsia. We used the Sprague-Dawley (CD) rat as a model of normal pregnancy. Pregnancy increased the glomerular filtration rate by 50% in CD rats and 12.2% in BN rats compared to non-pregnancy, and induced proteinuria only in BN rats. BN pregnancies showed a decrease in maternal plasma calcitriol levels, which correlated with renal downregulation of 1-alpha hydroxylase and upregulation of 24-hydroxylase. RNA sequencing revealed that pregnancy induced 297 differentially expressed genes (DEGs) in CD rats and 174 DEGs in BN rats, indicating a 70% increased response to pregnancy in CD compared to BN rats. Pregnancy induced activation of innate immune pathways such as 'Role of Pattern Recognition Receptors', and 'Interferon signaling' with interferon regulatory factor 7 as a common upregulated upstream factor in both rat strains. Comparison of rat strain transcriptomic profiles revealed 475 DEGs at non-pregnancy and 569 DEGs at pregnancy with 205 DEGs shared at non-pregnancy (36%), indicating that pregnancy interacted with rat strain in regulating 64% of the DEGs. Pathway analysis revealed that pregnancy induced a switch in renal transcriptomics in BN rats from 'inhibition of renal damage' to 'acute phase reaction', 'recruitment of immune cells' and 'inhibition of 1,25-(OH)2-vitamin D synthesis'. Key upstream regulators included peroxisome-proliferator-activated receptor alpha (PPARA), platelet-derived growth factor B dimer (PDGF-BB), and NF-kB p65 (RELA). DNA methylome profiling by reduced representation bisulfite sequencing studies revealed that the DEGs did not correlate with changes in promoter methylation. In sum, BN rat kidneys respond to pregnancy-specific signals with an increase in pro-inflammatory gene networks and alteration of metabolic pathways including vitamin D deficiency in association with mild proteinuria and blunted GFR increase. However, the lack of glomerular endotheliosis and mild hypertension/proteinuria in pregnant BN rats limits the relevance of this rat strain for preeclampsia research. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroblastoma is a highly heterogeneous malignancy with a wide range of outcomes from spontaneous regression to fatal chemoresistant disease, as currently treated according to the risk stratification of the Children's Oncology Group (COG), resulting in some high COG risk patients receiving excessive treatment, due to lacking predictors for treatment response. Here, we sought to complement COG risk classification by using the tumor intracellular microbiome, which is part of the tumor's molecular signature. We determine that an intra-tumor microbial gene abundance score, namely M-score, separates the high COG-risk patients into two subpopulations (Mhigh and Mlow) with higher accuracy in risk stratification than the current COG risk assessment, thus sparing a subset of high COG-risk patients from being subjected to traditional high-risk therapies. Currently, most neuroblastoma patients are treated according to the Children's Oncology Group (COG) risk group assignment; however, neuroblastoma's heterogeneity renders only a few predictors for treatment response, resulting in excessive treatment. Here, we sought to couple COG risk classification with tumor intracellular microbiome, which is part of the molecular signature of a tumor. We determine that an intra-tumor microbial gene abundance score, namely M-score, separates the high COG-risk patients into two subpopulations (Mhigh and Mlow) with higher accuracy in risk stratification than the current COG risk assessment, thus sparing a subset of high COG-risk patients from being subjected to traditional high-risk therapies. Mechanistically, the classification power of M-scores implies the effect of CREB over-activation, which may influence the critical genes involved in cellular proliferation, anti-apoptosis, and angiogenesis, affecting tumor cell proliferation survival and metastasis. Thus, intracellular microbiota abundance in neuroblastoma regulates intracellular signals to affect patients' survival. [ABSTRACT FROM AUTHOR]