ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma.

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.

Dapansutrile OLT1177 suppresses foreign body response inflammation while preserving vascularisation of implanted materials.

Mitigating inflammation associated with the foreign body response (FBR) remains a significant challenge in enhancing the performance of implantable medical devices. Current anti-inflammatory approaches aim to suppress implant fibrosis, the major outcome of the FBR, but also inadvertently inhibit beneficial immune signalling necessary for tissue healing and vascularization. In a previous study, we demonstrated the feasibility of 'selective' immunosuppression targeting the NLRP3 inflammasome using the small molecule inhibitor MCC950, leading to reduced implant fibrosis without compromising healing and leading to enhanced vascularization. However, the clinical potential of MCC950 is severely limited due to its failure to pass Phase I clinical safety trials. This has triggered substantial efforts to develop safer analogues of NLRP3 inhibitors. Dapansutrile (OLT1177) is emerging as a leading candidate amongst current NLRP3 inhibitors, demonstrating both safety and effectiveness in a growing number of clinical indications and Phase 2 trials. While the anti-inflammatory effects of OLT1177 have been shown, validation of these effects in the context of implanted materials and the FBR have not yet been demonstrated. In this study, we show OLT1177 possesses beneficial effects on key cell types which drive FBR outcomes, including macrophages, fibroblasts, and smooth muscle cells. Evaluation of OLT1177 in a 28 day subcutaneous implantation model showed OLT1177 reduced fibrotic capsule formation while promoting implant vascularization. Mechanistic studies revealed that this occurred through activation of early pro-angiogenic markers while suppressing late-stage anti-angiogenic markers. These findings establish OLT1177 as a promising therapeutic approach for mitigating implant fibrosis while supporting vascularisation, suggesting a highly promising selective immunosuppressive strategy for the FBR warranting further research to explore its optimal integration into medical materials and devices.

Investigating the Interrelationships Among Mental Health, Substance Use Disorders, and Suicidal Ideation Among Lesbian, Gay, and Bisexual Adults in the United States: Population-Based Statewide Survey Study.

BACKGROUND: Mental health disparities have been documented among lesbian, gay, and bisexual (LGB) adults in the United States. Substance use disorders and suicidal ideation have been identified as important health concerns for this population. However, the interrelationships among these factors are not well understood. OBJECTIVE: This study aims to investigate the interrelationships among mental health, substance use disorders, and suicidal ideation among LGB adults in the United States using a population-based statewide survey. METHODS: Our study was an observational cross-sectional analysis, and the data for this study were collected from a sample of LGB adults who participated in the statewide survey. The survey collected information on mental health, substance use disorders, and suicidal ideation using validated measures. Descriptive statistics and inferential data analysis were conducted to explore the interrelationships among these factors. RESULTS: The results showed that LGB adults who reported higher levels of depression and drug abuse and dependence also reported higher levels of suicidal tendency and mental illness. Inferential data analysis using χ2 tests revealed significant differences in depression score (χ22=458.241; P<.001), drug abuse and dependence score (χ22=226.946; P<.001), suicidal tendency score (χ22=67.795; P<.001), and mental illness score (χ22=363.722; P<.001) among the 3 sexual identity groups. Inferential data analysis showed significant associations between sexual identity and mental health outcomes, with bisexual individuals reporting the highest levels of depression, drug abuse and dependence, suicidal tendency, and mental illness. CONCLUSIONS: This study provides important insights into the interrelationships among mental health, substance use disorders, and suicidal ideation among LGB adults in the United States. The findings underscore the need for targeted interventions and research aimed at addressing the mental health needs of sexual minority populations. Future research should aim to better understand the underlying mechanisms driving these disparities and develop culturally sensitive and tailored interventions that meet the unique needs of LGB individuals. Reducing stigma and discrimination against sexual minority populations is also crucial to improving their mental health outcomes.

Evaluation of ketoclomazone and its analogues as inhibitors of 1-deoxy-d-xylulose 5-phosphate synthases and other thiamine diphosphate (ThDP)-dependent enzymes.

Most pathogenic bacteria, apicomplexan parasites and plants rely on the methylerythritol phosphate (MEP) pathway to obtain precursors of isoprenoids. 1-Deoxy-d-xylulose 5-phosphate synthase (DXPS), a thiamine diphosphate (ThDP)-dependent enzyme, catalyses the first and rate-limiting step of the MEP pathway. Due to its absence in humans, DXPS is considered as an attractive target for the development of anti-infectious agents and herbicides. Ketoclomazone is one of the earliest reported inhibitors of DXPS and antibacterial and herbicidal activities have been documented. This study investigated the activity of ketoclomazone on DXPS from various species, as well as the broader ThDP-dependent enzyme family. To gain further insights into the inhibition, we have prepared analogues of ketoclomazone and evaluated their activity in biochemical and computational studies. Our findings support the potential of ketoclomazone as a selective antibacterial agent.

Successful Intentional Replantation of a Severely Compromised Tooth Using 3 Types of Phototherapy: A Case Report.

Background: Intentional replantation (IR) is an emerging and cost-effective last-resort treatment for persistent apical periodontitis. Adjunctive phototherapy for IR aims to improve the management of challenging cases by enhancing disinfection, stimulating healing and promoting regeneration. Objective: We report a novel phototherapy-assisted IR protocol conducted on a compromised lateral incisor with an extensive periapical infection (Ø > 10 mm) in a 68-year-old diabetic male. Methods: The IR protocol involved pre- and postoperative photobiomodulation (660 nm, 0.2 J/cm2, 60 sec/site), antimicrobial photodynamic therapy of the root surface (660 nm, 0.6 J/cm2, 30 sec, methylene blue photosensitizer), and Er:YAG root and socket debridement (2940 nm, 21 J/cm2, 30 sec). The total time from extraction to replantation was 14 min 35 sec. Results: The tooth at 3.5-year follow-up remained clinically functional with radiographic resolution of the infection indicating a successful reimplantation. Conclusions: This case report demonstrated that an adjunctive phototherapy IR protocol can effectively treat a compromised tooth with extensive periapical infection.

Perceived Well-Being among Adults with Diabetes and Hypertension: A National Study.

Perceived health and distresses are associated with the practice of lifestyle modifications, which increases the risk of diabetes and hypertension-related complications. This study aimed to define the characteristics and distribution of perceived health and distresses across the states between people with diabetes and hypertension. Data were derived from a national survey of US adults aged ≥18 years who were interviewed via phone call. Perceived health and distresses were assessed through corresponding questions. An amount of 333,316 respondents (43,911 with diabetes and 130,960 with hypertension) were included in the analysis; 61.8% of people with diabetes and 74.5% of people with hypertension reported having good or better health, while residents in the Southwest region perceived poor health statuses and more distresses. Education level (diabetes: odds ratio [OR] = 0.47-0.79, hypertension: OR = 0.42-0.76), employment status level (diabetes: OR = 1.40-2.22, hypertension: OR = 1.56-2.49), and household income (diabetes: OR = 0.22-0.65, hypertension: OR = 0.15-0.78) were significant factors associated with poorly perceived health among people with diabetes and hypertension, and the use of technology and strategies for policymakers are suggested to improve the perceived health status in this regard.

Intimate Partner Violence Among Lesbian, Gay, and Bisexual Adults: A Cross-Sectional Survey in Hong Kong.

Purpose: This study investigated the prevalence rates of various types of intimate partner violence (IPV) among lesbian, gay, and bisexual (LGB) adults in Hong Kong and examined the associations between IPV and different addictive behavior and mental health problems. Methods: A total of 759 LGB adults completed an online cross-sectional survey between November 2021 and February 2022. Data on past-year IPV and LGB-specific tactics (whether perpetrated or experienced by participants), addictive behavior, anxiety, depression, and demographics were collected and analyzed with descriptive statistics and logistic regressions. Results: Psychological aggression was the most common type of IPV within an LGB relationship (22.1%), followed by physical assault (10.8%) and IPV-related injury (4.1%). LGB-specific tactics were experienced by 39.0% of the LGB adults. Depression, anxiety, and frequent gambling were significantly associated with specific types of IPV and LGB-specific tactics. Conclusion: IPV was prevalent in the LGB population. Findings on correlates provided insights for future development of IPV detection and intervention.

A Classification-Based Adaptive Segmentation Pipeline: Feasibility Study Using Polycystic Liver Disease and Metastases from Colorectal Cancer CT Images.

Automated segmentation tools often encounter accuracy and adaptability issues when applied to images of different pathology. The purpose of this study is to explore the feasibility of building a workflow to efficiently route images to specifically trained segmentation models. By implementing a deep learning classifier to automatically classify the images and route them to appropriate segmentation models, we hope that our workflow can segment the images with different pathology accurately. The data we used in this study are 350 CT images from patients affected by polycystic liver disease and 350 CT images from patients presenting with liver metastases from colorectal cancer. All images had the liver manually segmented by trained imaging analysts. Our proposed adaptive segmentation workflow achieved a statistically significant improvement for the task of total liver segmentation compared to the generic single-segmentation model (non-parametric Wilcoxon signed rank test, n = 100, p-value << 0.001). This approach is applicable in a wide range of scenarios and should prove useful in clinical implementations of segmentation pipelines.

Protocol to study immunodynamics in the tumor microenvironment using a tyramide signal amplification-based immunofluorescent multiplex panel.

Immunodynamics in the tumor microenvironment can be precisely examined by using multiple antigen identification approaches. Here, we present a protocol for capturing expression levels of multiple target proteins in the same specimen at single-cell resolution using a tyramide signal amplification-based immunofluorescent multiplexing system. We describe steps for tumor tissue microarray preparation, multiplex immunohistochemistry staining, image acquisition, and quantification. This protocol can quantify immune cells in tissues from patients or experimental disease models at a protein level. For complete details on the use and execution of this protocol, please refer to Chung et al. (2023),1 Tang et al. (2022),2 and Tang et al. (2022).3.

Exploring discrimination, social acceptance, and its impact on the psychological well-being of older men who have sex with men: A cross-sectional study.

BACKGROUND: The exploration of discrimination, social acceptance, and their impact on the psychological well-being of older men who have sex with men (MSM) is a critical area of study within the broader field of LGBTQ+ research. This demographic, comprising individuals who identify as both male and homosexual and are aged in the older spectrum of the population, faces unique challenges that intersect age, sexual orientation, and societal attitudes. Objectives This study aimed to explore the relationship between social acceptance and isolation with discrimination and the impact on the psychological well-being of older MSM. METHODS: A cross-sectional survey was administered among older MSM residing in three distinct regions: the People's Republic of China (PRC), Hong Kong, and Taiwan, with a total sample size of N = 453 participants, evenly distributed with N = 151 individuals from each region. The survey included the General Health Questionnaire-12 (GHQ-12), the Discrimination and Self-Stigma Evaluation Scale (DSSES), and the Perceived Acceptance Scale (PAS) which measures the perceived social acceptance from friends, mother, father, and family. The data were analyzed using descriptive statistics, ANOVA, and regression analysis. RESULTS: The mean scores of the GHQ-12 indicated that the participants had a moderate level of psychological distress, with a mean score of 6.38 (SD = 2.55). The DSSES mean score was 27.78 (SD = 8.73), indicating that participants experienced discrimination in their everyday lives. The PAS mean score was 3.08 (SD = 0.48), indicating that participants had a moderate level of perceived social acceptance. These results suggest that discrimination and social acceptance differ among older MSM in different areas in PRC, Hong Kong, and Taiwan. CONCLUSIONS: The study highlights the impact of discrimination and social acceptance on the psychological well-being of older MSM. The findings suggest that interventions aimed at reducing discrimination and promoting social acceptance may improve the psychological well-being of older MSM. These results have important implications for healthcare providers and policymakers in developing strategies to promote social acceptance and reduce discrimination towards older MSM.

Variation in temperature of peak trait performance constrains adaptation of arthropod populations to climatic warming.

The capacity of arthropod populations to adapt to long-term climatic warming is currently uncertain. Here we combine theory and extensive data to show that the rate of their thermal adaptation to climatic warming will be constrained in two fundamental ways. First, the rate of thermal adaptation of an arthropod population is predicted to be limited by changes in the temperatures at which the performance of four key life-history traits can peak, in a specific order of declining importance: juvenile development, adult fecundity, juvenile mortality and adult mortality. Second, directional thermal adaptation is constrained due to differences in the temperature of the peak performance of these four traits, with these differences expected to persist because of energetic allocation and life-history trade-offs. We compile a new global dataset of 61 diverse arthropod species which provides strong empirical evidence to support these predictions, demonstrating that contemporary populations have indeed evolved under these constraints. Our results provide a basis for using relatively feasible trait measurements to predict the adaptive capacity of diverse arthropod populations to geographic temperature gradients, as well as ongoing and future climatic warming.

Societal discrimination and mental health among transgender athletes: a systematic review and Meta-analysis.

BACKGROUND: Discrimination and inequality have been identified as significant problems faced by transgender individuals in sports participation. However, uncertainties remain regarding the effectiveness of interventions aimed at promoting equality. OBJECTIVES: This systematic review and meta-analysis aimed to examine the experiences of transgender athletes in sports, focusing on mental health issues and factors contributing to inequality among transgender and other sexual minorities. METHODS: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched 10 electronic databases, including PubMed, Google Scholar, and Web of Science, to identify eligible studies published between 2005 and 2022. The search yielded 1430 articles, of which only 12 studies met the inclusion criteria for this review. RESULTS: The meta-analysis of the 12 studies included in this review revealed that transgender athletes faced social discrimination and inequality in sports participation, resulting in mental health problems and higher rates of suicide. From a cohort of 21,565 participants in the studies, 7152 (33%) were subjected to discrimination in sports participation and healthcare, with a rate of 0.61 (95% confidence interval [CI]: 0.35, 0.81). However, transgender athletes who felt welcomed and embraced by their respective teams accounted for 0.39 (95% CI: 0.19, 0.65). These results indicated significant differences between how transgender athletes are treated in healthcare settings and when participating in sports. CONCLUSION: The study findings underscore the need for policies, cultural research, and interventions to address discrimination and inequality faced by transgender athletes in sports participation. Promoting equality and safeguarding the rights of transgender athletes can mitigate the risk of mental health problems and increase physical activity among sexual minorities.

Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage-Myofibroblast Transition in Non-Small-Cell Lung Carcinoma.

Macrophage-myofibroblast transition (MMT) is a newly discovered pathway for mass production of pro-tumoral cancer-associated fibroblasts (CAFs) in non-small cell lung carcinoma (NSCLC) in a TGF-ß1/Smad3 dependent manner. Better understanding its regulatory signaling in tumor microenvironment (TME) may identify druggable target for the development of precision medicine. Here, by dissecting the transcriptome dynamics of tumor-associated macrophage at single-cell resolution, a crucial role of a hematopoietic transcription factor Runx1 in MMT formation is revealed. Surprisingly, integrative bioinformatic analysis uncovers Runx1 as a key regulator in the downstream of MMT-specific TGF-ß1/Smad3 signaling. Stromal Runx1 level positively correlates with the MMT-derived CAF abundance and mortality in NSCLC patients. Mechanistically, macrophage-specific Runx1 promotes the transcription of genes related to CAF signatures in MMT cells at genomic level. Importantly, macrophage-specific genetic deletion and systemic pharmacological inhibition of TGF-ß1/Smad3/Runx1 signaling effectively prevent MMT-driven CAF and tumor formation in vitro and in vivo, representing a potential therapeutic target for clinical NSCLC.

Thiamine analogues featuring amino-oxetanes as potent and selective inhibitors of pyruvate dehydrogenase.

Pyruvate dehydrogenase complex (PDHc) is suppressed in some cancer types but overexpressed in others. To understand its contrasting oncogenic roles, there is a need for selective PDHc inhibitors. Its E1-subunit (PDH E1) is a thiamine pyrophosphate (TPP)-dependent enzyme and catalyses the first and rate-limiting step of the complex. In a recent study, we reported a series of ester-based thiamine analogues as selective TPP-competitive PDH E1 inhibitors with low nanomolar affinity. However, when the ester linker was replaced with an amide for stability reasons, the binding affinity was significantly reduced. In this study, we show that an amino-oxetane bioisostere of the amide improves the affinity and maintains stability towards esterase-catalysed hydrolysis.

Mitigating Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: Ameliorating Sexual Function and Psychological Well-Being in Older Men.

This study aimed to investigate the prevalence of lower urinary tract symptoms (LUTS) in older men (N= 3056) with benign prostatic hyperplasia (BPH) and its effects on their sexual function and mental health. Descriptive, correlation, and regression analyses were used to explore the relationships between prostate and lower urinary tract health and psychological well-being. Better prostate and lower urinary tract health positively affected psychological well-being, and sexual function also had a positive influence. LUTS have an adverse impact on sexual function and mental health. Early intervention is crucial for mitigating the negative impact of LUTS on the quality of life in older men. Addressing prostate and lower urinary tract health issues through appropriate interventions may improve psychological well-being. Health care professionals must consider the adverse effects of BPH and LUTS on sexual function and mental health, and implement interventions to enhance the overall quality of life in older men.

Tumour-associated macrophages: versatile players in the tumour microenvironment.

Tumour-Associated Macrophages (TAMs) are one of the pivotal components of the tumour microenvironment. Their roles in the cancer immunity are complicated, both pro-tumour and anti-cancer activities are reported, including not only angiogenesis, extracellular matrix remodeling, immunosuppression, drug resistance but also phagocytosis and tumour regression. Interestingly, TAMs are highly dynamic and versatile in solid tumours. They show anti-cancer or pro-tumour activities, and interplay between the tumour microenvironment and cancer stem cells and under specific conditions. In addition to the classic M1/M2 phenotypes, a number of novel dedifferentiation phenomena of TAMs are discovered due to the advanced single-cell technology, e.g., macrophage-myofibroblast transition (MMT) and macrophage-neuron transition (MNT). More importantly, emerging information demonstrated the potential of TAMs on cancer immunotherapy, suggesting by the therapeutic efficiency of the checkpoint inhibitors and chimeric antigen receptor engineered cells based on macrophages. Here, we summarized the latest discoveries of TAMs from basic and translational research and discussed their clinical relevance and therapeutic potential for solid cancers.

Analysis of CDPK1 targets identifies a trafficking adaptor complex that regulates microneme exocytosis in Toxoplasma.

Apicomplexan parasites use Ca2+-regulated exocytosis to secrete essential virulence factors from specialized organelles called micronemes. Ca2+-dependent protein kinases (CDPKs) are required for microneme exocytosis; however, the molecular events that regulate trafficking and fusion of micronemes with the plasma membrane remain unresolved. Here, we combine sub-minute resolution phosphoproteomics and bio-orthogonal labeling of kinase substrates in Toxoplasma gondii to identify 163 proteins phosphorylated in a CDPK1-dependent manner. In addition to known regulators of secretion, we identify uncharacterized targets with predicted functions across signaling, gene expression, trafficking, metabolism, and ion homeostasis. One of the CDPK1 targets is a putative HOOK activating adaptor. In other eukaryotes, HOOK homologs form the FHF complex with FTS and FHIP to activate dynein-mediated trafficking of endosomes along microtubules. We show the FHF complex is partially conserved in T. gondii, consisting of HOOK, an FTS homolog, and two parasite-specific proteins (TGGT1_306920 and TGGT1_316650). CDPK1 kinase activity and HOOK are required for the rapid apical trafficking of micronemes as parasites initiate motility. Moreover, parasites lacking HOOK or FTS display impaired microneme protein secretion, leading to a block in the invasion of host cells. Taken together, our work provides a comprehensive catalog of CDPK1 targets and reveals how vesicular trafficking has been tuned to support a parasitic lifestyle.

"I use salt. However, I also use soy sauce, oyster sauce, sometimes chili sauce and .": interviews with Australians of Chinese ancestry regarding reducing salt consumption for hypertension prevention.

BACKGROUND: High dietary salt consumption is a significant health issue in Chinese populations. This study identified the facilitators for and barriers to salt reduction for prevention of hypertension among Chinese Australians. METHODS: An inductive qualitative study with semi-structured interviews (n = 8) was conducted with convenience samples recruited from social media. Adults who a) were over 18 years old, b) were of Chinese ancestry and c) had lived in Australia for at least 6 months were eligible for participation. Interview transcripts were transcribed and analysed using content analysis. RESULTS: Four facilitators for and eight barriers to reducing salt consumption were synthesised from the narrative materials. The facilitators were: 1) individual perceptions of health benefits, 2) salt alternatives, 3) digital information and 4) increased awareness of negative health impacts from a high-salt diet. The barriers identified were: 1) negative physical changes not apparent, 2) inadequate salt-related health education, 3) hidden salt in food products, 4) inadequate food literacy, 5) pricing, 6) busy lifestyle, 7) low perceived susceptibility and 8) individual food taste preference and cooking habits. Peer and family influence had positive and negative effects on participants' likelihood of reducing salt consumption. CONCLUSIONS: The facilitators for and barriers to maintaining a low-salt diet in Chinese Australians were multifaceted and interrelated. Future salt-reduction strategies should focus on the health benefits of reduced salt consumption and practical interventions such as salt alternatives and education on low-salt food choices and cooking methods and changing perceptions about salt reduction to become a social norm in the Chinese community.