Substances of health concern in home-distilled and commercial alcohols from Texas.

Objective: Poor distillation practices in the production of spirits have historically resulted in many instances of adverse health outcomes including death. Concern has focused on lead and copper contamination as well as unhealthy levels of methanol and glyphosate. This study assesses home-distilled and commercially distilled alcohols from Texas for these substances of concern, highlighting their potential risks to public health. Methods: Atomic absorption spectroscopy, gas chromatography, and enzyme-linked immunosorbent assay were employed to determine lead and copper, methanol, and glyphosate levels in 12 commercial and 36 home-distilled alcohol samples. Results: Our findings showed that 11 % of the home-distilled alcohols exceeded the U.S. Alcohol and Tobacco Tax and Trade Bureau's copper safety limits of 0.5 mg/L for wine. Additionally, 36 % of these samples surpassed the European Commission (EC)'s lead legal threshold of 0.15 mg/L set for wine products. Results from commercial alcohols indicated that no samples exceeded the same safety limits for copper, and 33 % exceeded the same legal threshold for lead. Both commercial and home-distilled alcohols exhibited methanol concentrations remarkably below the 0.35 % limit for brandy set by the U.S. Food and Drug Administration. Only two home-distilled samples contained detectable glyphosate concentrations well below 100 µg/L, the maximum residue level in beer and wine established by the EC. Conclusions: Our findings suggested that consumption of alcohol in Texas may pose potential health risks associated with the elevated content of lead and copper. There is a need for increased focus on alcohol as a potential source of exposure to heavy metals.

Sex Differences in Clustering Unhealthy Lifestyles Among Survivors of COVID-19: Latent Class Analysis.

BACKGROUND: The COVID-19 pandemic has underscored the significance of adopting healthy lifestyles to mitigate the risk of severe outcomes and long-term consequences. OBJECTIVE: This study focuses on assessing the prevalence and clustering of 5 unhealthy lifestyle behaviors among Vietnamese adults after recovering from COVID-19, with a specific emphasis on sex differences. METHODS: The cross-sectional data of 5890 survivors of COVID-19 in Vietnam were analyzed from December 2021 to October 2022. To examine the sex differences in 5 unhealthy lifestyle behaviors (smoking, drinking, unhealthy diet, physical inactivity, and sedentary behavior), the percentages were plotted along with their corresponding 95% CI for each behavior. Latent class analysis was used to identify 2 distinct classes of individuals based on the clustering of these behaviors: the "less unhealthy" group and the "more unhealthy" group. We examined the sociodemographic characteristics associated with each identified class and used logistic regression to investigate the factors related to the "more unhealthy" group. RESULTS: The majority of individuals (male participants: 2432/2447, 99.4% and female participants: 3411/3443, 99.1%) exhibited at least 1 unhealthy behavior, with male participants being more susceptible to multiple unhealthy behaviors. The male-to-female ratio for having a single behavior was 1.003, but it escalated to 25 for individuals displaying all 5 behaviors. Male participants demonstrated a higher prevalence of combining alcohol intake with sedentary behavior (949/2447, 38.8%) or an unhealthy diet (861/2447, 35.2%), whereas female participants tended to exhibit physical inactivity combined with sedentary behavior (1305/3443, 37.9%) or an unhealthy diet (1260/3443, 36.6%). Married male participants had increased odds of falling into the "more unhealthy" group compared to their single counterparts (odds ratio [OR] 1.45, 95% CI 1.14-1.85), while female participants exhibited lower odds (OR 0.65, 95% CI 0.51-0.83). Female participants who are underweight showed a higher likelihood of belonging to the "more unhealthy" group (OR 1.11, 95% CI 0.89-1.39), but this was not observed among male participants (OR 0.6, 95% CI 0.41-0.89). In both sexes, older age, dependent employment, high education, and obesity were associated with higher odds of being in the "more unhealthy" group. CONCLUSIONS: The study identified notable sex differences in unhealthy lifestyle behaviors among survivors of COVID-19. Male survivors are more likely to engage in unhealthy behaviors compared to female survivors. These findings emphasize the importance of tailored public health interventions targeting sex-specific unhealthy behaviors. Specifically, addressing unhealthy habits is crucial for promoting post-COVID-19 health and well-being.

The ribosomal transcription units of five echinostomes and their taxonomic implications for the suborder Echinostomata (Trematoda: Platyhelminthes).

Five newly obtained nuclear ribosomal transcription unit (rTU) sequences from Echinostomatidae and Echinochasmidae are presented. The inter- and intrafamilial relationships of these and other families in the suborder Echinostomata are also analyzed. The sequences obtained are the complete rTU of Artyfechinostomum malayanum (9,499 bp), the near-complete rTU of Hypoderaeum conoideum (8,076 bp), and the coding regions (from 5'-terminus of 18S to 3'-terminus of 28S rRNA gene) in Echinostoma revolutum (6,856 bp), Echinostoma miyagawai (6,854 bp), and Echinochasmus japonicus (7,150 bp). Except for the longer first internal transcribed spacer (ITS1) in Echinochasmus japonicus, all genes and spacers were almost identical in length. Comprehensive maximum-likelihood phylogenies were constructed using the PhyML software package. The datasets were either the concatenated 28S + 18S rDNA sequences (5.7-5.8 kb) from 60 complete rTUs of 19 families or complete 28S sequences only (about 3.8-3.9 kb) from 70 strains or species of 22 families. The phylogenetic trees confirmed Echinostomatoidea as monophyletic. Furthermore, a detailed phylogeny constructed from alignments of 169 28S D1-D3 rDNA sequences (1.1-1.3 kb) from 98 species of 50 genera of 10 families, including 154 echinostomatoid sequences (85 species/42 genera), clearly indicated known generic relationships within Echinostomatidae and Echinochasmidae and relationships of families within Echinostomata and several other suborders. Within Echinostomatidae, Echinostoma, Artyfechinostomum, and Hypoderaeum appeared as monophyletic, while Echinochasmus (Echinochasmidae) was polyphyletic. The Echinochasmidae are a sister group to the Psilostomidae. The datasets provided here will be useful for taxonomic reappraisal as well as studies of evolutionary and population genetics in the superfamily Echinostomatoidea, the sole superfamily in the suborder Echinostomata.

Design and Synthesis of l-1'-Homologated Adenosine Derivatives as Potential Anti-inflammatory Agents.

Inflammatory responses are fundamental protective warning mechanisms. However, in certain instances, they contribute significantly to the development of several chronic diseases such as cancer. Based on previous studies of truncated 1'-homologated adenosine derivatives, l-nucleosides and their nucleobase-modified quinolone analogues were designed, synthesized, and evaluated for anti-inflammatory activities. The target molecules were synthesized via the key intramolecular cyclization of monotosylate and Mitsunobu condensation from the natural product, d-ribose. All compounds tested and showed potent anti-inflammatory activities, as indicated by their inhibition of LPS-induced IL-1ß secretion from the RAW 264.7 macrophages. Gene expressions of pro-inflammatory cytokines showed that all compounds, except 3a and 3b, significantly reduced LPS-induced IL-1ß and IL-6 mRNA expressions. The half-maximal inhibitory concentrations (IC50) of 2g and 2h against IL-1ß were 1.08 and 2.28 µM, respectively. In contrast, only 2d, 2g, and 3d effectively reversed LPS-induced TNFα mRNA expression. Our mechanistic study revealed that LPS-induced phosphorylation of NF-κB was significantly downregulated by all compounds tested, providing evidence that the NF-κB signaling pathway is involved in their anti-inflammatory activities. Among the compounds tested, 2g and 2h had the most potent anti-inflammatory effects, as shown by the extent of decrease in pro-inflammatory gene expression, protein secretion, and NF-κB phosphorylation. These findings suggest that the l-truncated 1'-homologated adenosine skeleton and its nucleobase-modified analogues have therapeutic potential as treatments for various human diseases by mediating inflammatory processes.

CRISPR screen identifies CEBPB as contributor to dyskeratosis congenita fibroblast senescence via augmented inflammatory gene response.

Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder caused by underlying telomere/telomerase-related mutations. Cells from these patients offer an opportunity to study telomere-related aging and senescence. Our previous work has found that telomere shortening stimulates DNA damage responses (DDRs) and increases reactive oxygen species (ROS), thereby promoting entry into senescence. This work also found that telomere elongation via TERT expression, the catalytic component of the telomere-elongating enzyme telomerase, or p53 shRNA could decrease ROS by disrupting this telomere-DDR-ROS pathway. To further characterize this pathway, we performed a CRISPR/Cas9 knockout screen to identify genes that extend life span in DC cells. Of the cellular clones isolated due to increased life span, 34% had a guide RNA (gRNA) targeting CEBPB, while gRNAs targeting WSB1, MED28, and p73 were observed multiple times. CEBPB is a transcription factor associated with activation of proinflammatory response genes suggesting that inflammation may be present in DC cells. The inflammatory response was investigated using RNA sequencing to compare DC and control cells. Expression of inflammatory genes was found to be significantly elevated (P < 0.0001) in addition to a key subset of these inflammation-related genes [IL1B, IL6, IL8, IL12A, CXCL1 (GROa), CXCL2 (GROb), and CXCL5]. which are regulated by CEBPB. Exogenous TERT expression led to downregulation of RNA/protein CEBPB expression and the inflammatory response genes suggesting a telomere length-dependent mechanism to regulate CEBPB. Furthermore, unlike exogenous TERT and p53 shRNA, CEBPB shRNA did not significantly decrease ROS suggesting that CEBPB's contribution in DC cells' senescence is ROS independent. Our findings demonstrate a key role for CEBPB in engaging senescence by mobilizing an inflammatory response within DC cells.

Effect of paediatric early warning systems (PEWS) implementation on clinical deterioration event mortality among children with cancer in resource-limited hospitals in Latin America: a prospective, multicentre cohort study.

BACKGROUND: Paediatric early warning systems (PEWS) aid in the early identification of clinical deterioration events in children admitted to hospital. We aimed to investigate the effect of PEWS implementation on mortality due to clinical deterioration in children with cancer in 32 resource-limited hospitals across Latin America. METHODS: Proyecto Escala de Valoración de Alerta Temprana (Proyecto EVAT) is a quality improvement collaborative to implement PEWS in hospitals providing childhood cancer care. In this prospective, multicentre cohort study, centres joining Proyecto EVAT and completing PEWS implementation between April 1, 2017, and May 31, 2021, prospectively tracked clinical deterioration events and monthly inpatient-days in children admitted to hospital with cancer. De-identified registry data reported between April 17, 2017, and Nov 30, 2021, from all hospitals were included in analyses; children with limitations on escalation of care were excluded. The primary outcome was clinical deterioration event mortality. Incidence rate ratios (IRRs) were used to compare clinical deterioration event mortality before and after PEWS implementation; multivariable analyses assessed the correlation between clinical deterioration event mortality and centre characteristics. FINDINGS: Between April 1, 2017, and May 31, 2021, 32 paediatric oncology centres from 11 countries in Latin America successfully implemented PEWS through Proyecto EVAT; these centres documented 2020 clinical deterioration events in 1651 patients over 556 400 inpatient-days. Overall clinical deterioration event mortality was 32·9% (664 of 2020 events). The median age of patients with clinical deterioration events was 8·5 years (IQR 3·9-13·2), and 1095 (54·2%) of 2020 clinical deterioration events were reported in male patients; data on race or ethnicity were not collected. Data were reported per centre for a median of 12 months (IQR 10-13) before PEWS implementation and 18 months (16-18) after PEWS implementation. The mortality rate due to a clinical deterioration event was 1·33 events per 1000 patient-days before PEWS implementation and 1·09 events per 1000 patient-days after PEWS implementation (IRR 0·82 [95% CI 0·69-0·97]; p=0·021). In the multivariable analysis of centre characteristics, higher clinical deterioration event mortality rates before PEWS implementation (IRR 1·32 [95% CI 1·22-1·43]; p<0·0001), being a teaching hospital (1·18 [1·09-1·27]; p<0·0001), not having a separate paediatric haematology-oncology unit (1·38 [1·21-1·57]; p<0·0001), and having fewer PEWS omissions (0·95 [0·92-0·99]; p=0·0091) were associated with a greater reduction in clinical deterioration event mortality after PEWS implementation; no association was found with country income level (IRR 0·86 [95% CI 0·68-1·09]; p=0·22) or clinical deterioration event rates before PEWS implementation (1·04 [0·97-1·12]; p=0·29). INTERPRETATION: PEWS implementation was associated with reduced clinical deterioration event mortality in paediatric patients with cancer across 32 resource-limited hospitals in Latin America. These data support the use of PEWS as an effective evidence-based intervention to reduce disparities in global survival for children with cancer. FUNDING: American Lebanese Syrian Associated Charities, US National Institutes of Health, and Conquer Cancer Foundation. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Treatment-related mortality in children with cancer in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Approximately 90% of children with cancer live in low-income and middle-income countries (LMICs), where 5-year survival is lower than 20%. Treatment-related mortality in high-income countries is approximately 3-5%; however, in LMICs, treatment-related mortality has been reported in up to 45% of children with cancer. This study aimed to systematically explore the burden of treatment-related mortality in children with cancer in LMICs and to explore the association between country income level and treatment-related mortality. METHODS: For this systematic review and meta-analysis we identified articles published between Jan 1, 2010, and June 22, 2021, describing treatment-related mortality in paediatric patients (aged 0-21 years) with cancer in LMICs. We searched PubMed, Trip, Web of Science, Embase, and the WHO Global Metric Index databases. The search was limited to full-text articles and excluded case reports (<10 patients) and haematopoietic stem-cell transplantation recipients. Two reviewers independently screened studies for eligibility, extracted data from included publications, and evaluated data quality. Random and mixed-effects models were used to estimate treatment-related mortality burden and trends. The Cochran-Q statistic was used to assess heterogeneity between studies. This study is registered on PROSPERO (CRD42021264849). FINDINGS: Of 13 269 identified abstracts, 501 studies representing 68 351 paediatric patients with cancer were included. The treatment-related mortality estimate was 6·82% (95% CI 5·99-7·64), accounting for 30·9% of overall mortality (4437 of 14 358 deaths). Treatment-related mortality was inversely related to country income. Treatment-related mortality was 14·19% (95% CI 9·65-18·73) in low-income countries, 9·21% (7·93-10·49) in lower-middle-income countries, and 4·47% (3·42-5·53) in upper-middle-income countries (Cochran-Q 42·39, p<0·0001). In upper-middle-income countries, the incidence of treatment-related mortality decreased over time (slope -0·002, p=0·0028); however, outcomes remained unchanged in low-income (p=0·21) and lower-middle-income countries (p=0·16). INTERPRETATION: Approximately one in 15 children receiving cancer treatment in LMICs die from treatment-related complications. Although treatment-related mortality has decreased in upper-middle-income countries over time, it remains unchanged in LMICs. There is an urgent need for targeted supportive care interventions to reduce global disparities in childhood cancer survival. FUNDING: American Lebanese Syrian Associated Charities and National Cancer Institute.

Design, Synthesis, and Biological Activity of l-1'-Homologated Adenosine Derivatives.

On the basis of the previously reported polypharmacological profile of truncated d-1'-homologated adenosine derivatives [J. Med. Chem.2020, 63, 16012], the l-nucleoside analogues were synthesized using computer-aided design and evaluated for biological activity. The target molecules were synthesized from d-ribose via the key intramolecular cyclization of the monotosylate and Mitsunobu condensation. The peroxisome proliferator-activated receptor (PPAR) binding activities of l-nucleoside analogue 2d (K i = 4.3 µM for PPARγ and 1.0 µM for PPARδ) were significantly improved in comparison with those of the d-nucleoside compound 1 (11.9 and 2.7 µM, respectively). In addition, the l-nucleosides showed more potent adiponectin-secretion-promoting activity than the d-nucleoside analogues.

Acidic patch histone mutations and their effects on nucleosome remodeling.

Structural and biochemical studies have identified a histone surface on each side of the nucleosome disk termed 'the nucleosome acidic patch' that acts as a regulatory hub for the function of numerous nuclear proteins, including ATP-dependent chromatin complexes (remodelers). Four major remodeler subfamilies, SWI/SNF, ISWI, CHD, and INO80, have distinct modes of interaction with one or both nucleosome acidic patches, contributing to their specific remodeling outcomes. Genome-wide sequencing analyses of various human cancers have uncovered high-frequency mutations in histone coding genes, including some that map to the acidic patch. How cancer-related acidic patch histone mutations affect nucleosome remodeling is mainly unknown. Recent advances in in vitro chromatin reconstitution have enabled access to physiologically relevant nucleosomes, including asymmetric nucleosomes that possess both wild-type and acidic patch mutant histone copies. Biochemical investigation of these substrates revealed unexpected remodeling outcomes with far-reaching implications for alteration of chromatin structure. This review summarizes recent findings of how different remodeler families interpret wild-type and mutant acidic patches for their remodeling functions and discusses models for remodeler-mediated changes in chromatin landscapes as a consequence of acidic patch mutations.

The Functional Roles of Immune Cells in Primary Liver Cancer.

Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Incidence of liver cancer has been increasing in recent years, and the 5-year survival is <20%. HCC and CCA are often accompanied with a dense stroma coupled with infiltrated immune cells, which is referred to as the tumor microenvironment. Populations of specific immune cells, such as high density of CD163+ macrophages and low density of CD8+ T cells, are associated with prognosis and survival rates in both HCC and CCA. Immune cells in the tumor microenvironment can be a therapeutic target for liver cancer treatments. Previous studies have introduced immunotherapy using immune checkpoint inhibitors, pulsed dendritic cells, or transduced T cells, to enhance cytotoxicity of immune cells and inhibit tumor growth. This review summarizes current understanding of the roles of immune cells in primary liver cancer covering HCC and CCA.

Estradiol-dependent gene expression profile in the amygdala of young ovariectomized spontaneously hypertensive rats.

Estrogen plays a role in cardiovascular functions, emotional health, and energy homeostasis via estrogen receptors expressed in the brain. The comorbid relationship between rising blood pressure, a decline in mood and motivation, and body weight gain after menopause, when estrogen levels drop, suggests that the same brain area(s) contributes to protection from all of these postmenopausal disorders. The amygdala, a major limbic system nuclear complex known to express high estrogen receptor levels, is involved in the regulation of such physiological and psychological responses. We hypothesized that elevated estrogen levels contribute to premenopausal characteristics by activating specific genes and pathways in the amygdala. We examined the effect of 1 mo of estradiol treatment on the gene expression profile in the amygdala of ovariectomized young adult female spontaneously hypertensive rats. Estradiol substitution significantly decreased blood pressure, prevented body weight gain, and enhanced the voluntary physical activity of ovariectomized rats. In the amygdala of ovariectomized rats, estradiol treatment downregulated the expression of genes associated with estrogen signaling, cholinergic synapse, dopaminergic synapse, and long-term depression pathways. These findings indicate that the transcriptomic characteristics of the amygdala may be involved in estrogen-dependent regulation of blood pressure, physical activity motivation, and body weight control in young adult female spontaneously hypertensive rats.

Negative Impacts of COVID-19 Induced Lockdown on Changes in Eating Behavior, Physical Activity, and Mental Health as Modified by Digital Healthy Diet Literacy and eHealth Literacy.

Background: The COVID-19-induced lockdown has been implemented in many countries, which may cause unfavorable changes in lifestyles and psychological health. People's health literacy, healthy diet, and lifestyles play important roles in mitigating the negative impacts of the pandemic. Therefore, we aimed to examine associations of COVID-19 lockdown with changes in eating behavior, physical activity, and mental health; and the modification effects by digital healthy diet literacy (DDL) and eHealth literacy (eHEALS) on the associations. Methods: We conducted an observational study on 4,348 outpatients from 7th April to 31st May 2020. Data from 11 hospitals in Vietnam included demographic characteristics, DDL, eHEALS, eating behavior, physical activity, and mental health changes. Multiple logistic regression and interaction models were performed to examine associations. Results: Patients under lockdown had a lower likelihood of having "unchanged or healthier" eating behavior (odds ratio, OR, 0.38; 95% confidence interval, 95%CI, 0.29 to 0.51; p < 0.001), "unchanged or more" physical activity (OR, 0.79; 95% CI, 0.69 to 0.90; p < 0.001), and "stable or better" mental health (OR, 0.77; 95% CI, 0.67 to 0.89; p < 0.001), as compared to those after lockdown. In interaction models, as compared to patients after lockdown and with the lowest DDL score, those under lockdown and with a one-score increment of DDL had a higher likelihood of having "unchanged or healthier" eating behavior (OR, 1.05; 95% CI, 1.02 to 1.07; p < 0.001), and "stable or better" mental health (OR, 1.02; 95% CI, 1.01 to 1.04; p < 0.001). Similarly, as compared to patients after lockdown and with the lowest eHEALS score, those under lockdown and with a one-score increment of eHEALS had a higher likelihood of having an "unchanged or more" physical activity (OR, 1.03; 95% CI, 1.01 to 1.05; p < 0.001). Conclusion: The COVID-19 lockdown measure could negatively affect eating behavior, physical activity, and mental health among outpatients. Better DDL and eHEALS were found to mitigate the negative impacts of the lockdown, which may empower outpatients to maintain healthy lifestyles and protect mental health. However, this study holds several limitations that may undermine the certainty of reported findings.

Fear, anxiety and depression among pregnant women during COVID-19 pandemic: impacts of healthy eating behaviour and health literacy.

INTRODUCTION: The COVID-19 pandemic has been influencing people's psychological health, especially in pregnant women. We aimed to examine associated factors of fear of COVID-19, anxiety and depression among pregnant women during the pandemic where the impacts of healthy eating behaviour (HES) and health literacy (HL) were emphasized. METHODS: A cross-sectional study was conducted between 14 February 2020 and 31 May 2020 in 18 health centres and hospitals across Vietnam. Data of 518 pregnant women were analysed, including socio-demographics, pregnant-related factors, HES, HL, health-related behaviours, fear of COVID-19 scale (FCoV-19S), anxiety (using the generalized anxiety disorder (GAD-7)) and depression (using the patient health questionnaire with 9 items (PHQ-9)). Regression analysis was utilized to explore the associations. RESULTS: Pregnant women with higher scores of HES and HL had lower likelihood of anxiety (odds ratio, OR, 0.79; 95% confidence interval (95%CI), 0.73, 0.87; p < .001; and OR, 0.94; 95%CI, 0.90, 0.99; p = .018) and depression (OR, 0.84; 95%CI, 0.78, 0.91; p < .001; and OR, 0.96; 95%CI, 0.91, 0.99; p = .044), respectively. Pregnant women being employed had a lower FCoV-19S score (regression coefficient, B, -1.46; 95%CI, -2.51, -0.40; p = .007). Besides, other significant predictors of anxiety were eating healthier during the pandemic, unchanged or more physical activity, elevated gestational age and smoking. Other significant predictors of depression were eating healthier during the pandemic, elevated gestational age and smoking. CONCLUSIONS: Among others, HES and HL had positive impacts on protecting pregnant women against anxiety and depression. Improving HES and HL should be addressed as a strategic approach to improve reproductive health during the pandemic.KEY MESSAGEThe COVID-19 pandemic influences antenatal mental disorders with the higher level as opposed to that before the pandemic.Healthy eating behaviour and better health literacy (HL) had critical roles in lowering prenatal anxiety and depression during the COVID-19 crisis.Strategic approaches for improving healthy eating and HL should be recommended for protecting pregnant women from mental health problems during the pandemic.

Single and Combinative Impacts of Healthy Eating Behavior and Physical Activity on COVID-19-like Symptoms among Outpatients: A Multi-Hospital and Health Center Survey.

BACKGROUND: Healthy eating and physical activity are effective non-pharmacological approaches to boost immune function and contain the pandemic. We aimed to explore the associations and interactions between physical activity and healthy eating behavior with COVID-19-like symptoms (Slike-CV19S). METHODS: A cross-sectional study was conducted on 3947 outpatients, from 14 February to 2 March 2020, at nine health facilities in Vietnam. Data collection included sociodemographic characteristics, healthy eating behavior (using the healthy eating score (HES) questionnaire), physical activity (using the short form international physical activity questionnaire), and Slike-CV19S. The associations and interactions were tested using logistic regression models. RESULTS: Frequent intake of fruits (OR = 0.84; p = 0.016), vegetables (OR = 0.72; p = 0.036), and fish (OR = 0.43; p < 0.001) were associated with a lower Slike-CV19S likelihood, as compared with infrequent intake. Patients with higher HES levels (OR = 0.84; p = 0.033 for medium HES; OR = 0.77; p = 0.006 for high HES) or being physically active (OR = 0.69; p < 0.001) had a lower Slike-CV19S likelihood, as compared to those with low HES or physical inactivity, respectively. Patients with medium HES who were physically active (OR = 0.69; p = 0.005), or with high HES and physically active (OR = 0.58; p < 0.001), had a lower Slike-CV19S likelihood, as compared to those with low HES and physical inactivity. CONCLUSIONS: Healthy eating behavior and physical activity showed single and combinative impacts on protecting people from Slike-CV19S. Strategic approaches are encouraged to improve healthy behaviors, which may further contribute to containing the pandemic.

CD40LG mutations in Vietnamese patients with X-linked hyper-IgM syndrome; catastrophic anti-phospholipid syndrome as a new complication.

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects. METHODS: We identified three patients with XHIGM in Ho Chi Minh City, Vietnam. Whole-exome sequencing, immunological analyses and western blot were performed to investigate phenotypic and genotypic features. RESULTS: Despite showing symptoms typical of XHIGM, including recurrent sinopulmonary infections, oral ulcers and otitis media, the diagnosis was significantly delayed. One patient developed anti-phospholipid syndrome, which has been documented for the first time in XHIGM syndrome. Two patients had elevated IgM levels and all of them had low IgG levels. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non-frameshift deletion c.436_438delTAC, stop-gain c.654C>A). Due to these mutations, the CD40 ligand was not expressed in any of the three patients, as demonstrated by western blot analysis. CONCLUSION: This is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy.

Photobiomodulation Response From 660 nm is Different and More Durable Than That From 980 nm.

BACKGROUND AND OBJECTIVES: Photobiomodulation (PBM) therapy uses light at various wavelengths to stimulate wound healing, grow hair, relieve pain, and more-but there is no consensus about optimal wavelengths or dosimetry. PBM therapy works through putative, wavelength-dependent mechanisms including direct stimulation of mitochondrial respiration, and/or activation of transmembrane signaling channels by changes in water activity. A common wavelength used in the visible red spectrum is ~660 nm, whereas recently ~980 nm is being explored and both have been proposed to work via different mechanisms. We aimed to gain more insight into identifying treatment parameters and the putative mechanisms involved. STUDY DESIGN/MATERIALS AND METHODS: Fluence-response curves were measured in cultured keratinocytes and fibroblasts exposed to 660 or 980 nm from LED sources. Metabolic activity was assessed using the MTT assay for reductases. ATP production, a major event triggered by PBM therapy, was assessed using a luminescence assay. To measure the role of mitochondria, we used an ELISA to measure COX-1 and SDH-A protein levels. The respective contributions of cytochrome c oxidase and ATP synthase to the PBM effects were gauged using specific inhibitors. RESULTS: Keratinocytes and fibroblasts responded differently to exposures at 660 nm (red) and 980 nm (NIR). Although 980 nm required much lower fluence for cell stimulation, the resulting increase in ATP levels was short-term, whereas 660 nm stimulation elevated ATP levels for at least 24 hours. COX-1 protein levels were increased following 660 nm treatment but were unaffected by 980 nm. In fibroblasts, SDH-A levels were affected by both wavelengths, whereas in keratinocytes only 660 nm light impacted SDH-A levels. Inhibition of ATP synthase nearly completely abolished the effects of both wavelengths on ATP synthesis. Interestingly, inhibiting cytochrome c oxidase did not prevent the rise in ATP levels in response to PBM treatment. CONCLUSION: To the best of our knowledge, this is the first demonstration of differing kinetics in response to PBM therapy at red versus NIR wavelength. We also found cell-type-specific differences in PBM therapy response to the two wavelengths studied. These findings confirm that different response pathways are involved after 660 and 980 nm exposures and suggest that 660 nm causes a more durable response. © 2021 Wiley Periodicals LLC.

Post-transcriptional regulation by the exosome complex is required for cell survival and forebrain development via repression of P53 signaling.

Fine-tuned gene expression is crucial for neurodevelopment. The gene expression program is tightly controlled at different levels, including RNA decay. N6-methyladenosine (m6A) methylation-mediated degradation of RNA is essential for brain development. However, m6A methylation impacts not only RNA stability, but also other RNA metabolism processes. How RNA decay contributes to brain development is largely unknown. Here, we show that Exosc10, a RNA exonuclease subunit of the RNA exosome complex, is indispensable for forebrain development. We report that cortical cells undergo overt apoptosis, culminating in cortical agenesis upon conditional deletion of Exosc10 in mouse cortex. Mechanistically, Exosc10 directly binds and degrades transcripts of the P53 signaling-related genes, such as Aen and Bbc3. Overall, our findings suggest a crucial role for Exosc10 in suppressing the P53 pathway, in which the rapid turnover of the apoptosis effectors Aen and Bbc3 mRNAs is essential for cell survival and normal cortical histogenesis.

Improved Noninvasive In Vivo Tracking of AAV-9 Gene Therapy Using the Perchlorate-Resistant Sodium Iodide Symporter from Minke Whale.

The sodium iodide symporter (NIS) is widely used as a reporter gene to noninvasively monitor the biodistribution and durability of vector-mediated gene expression via gamma scintigraphy, single-photon emission computed tomography (SPECT), and positron-emission tomography (PET). However, the approach is limited by background signal due to radiotracer uptake by endogenous NIS-expressing tissues. In this study, using the SPECT tracer pertechnetate (99mTcO4) and the PET tracer tetrafluoroborate (B18F4), in combination with the NIS inhibitor perchlorate, we compared the transport properties of human NIS and minke whale (Balaenoptera acutorostrata scammoni) NIS in vitro and in vivo. Based on its relative resistance to perchlorate, the NIS protein from minke whale appeared to be the superior candidate reporter gene. SPECT and PET imaging studies in nude mice challenged with NIS-encoding adeno-associated virus (AAV)-9 vectors confirmed that minke whale NIS, in contrast to human and endogenous mouse NIS, continues to function as a reliable reporter even when background radiotracer uptake by endogenous NIS is blocked by perchlorate.

The interplay between mast cells, pineal gland, and circadian rhythm: Links between histamine, melatonin, and inflammatory mediators.

Our daily rhythmicity is controlled by a circadian clock with a specific set of genes located in the suprachiasmatic nucleus in the hypothalamus. Mast cells (MCs) are major effector cells that play a protective role against pathogens and inflammation. MC distribution and activation are associated with the circadian rhythm via two major pathways, IgE/FcεRI- and IL-33/ST2-mediated signaling. Furthermore, there is a robust oscillation between clock genes and MC-specific genes. Melatonin is a hormone derived from the amino acid tryptophan and is produced primarily in the pineal gland near the center of the brain, and histamine is a biologically active amine synthesized from the decarboxylation of the amino acid histidine by the L-histidine decarboxylase enzyme. Melatonin and histamine are previously reported to modulate circadian rhythms by pathways incorporating various modulators in which the nuclear factor-binding near the κ light-chain gene in B cells, NF-κB, is the common key factor. NF-κB interacts with the core clock genes and disrupts the production of pro-inflammatory cytokine mediators such as IL-6, IL-13, and TNF-α. Currently, there has been no study evaluating the interdependence between melatonin and histamine with respect to circadian oscillations in MCs. Accumulating evidence suggests that restoring circadian rhythms in MCs by targeting melatonin and histamine via NF-κB may be promising therapeutic strategy for MC-mediated inflammatory diseases. This review summarizes recent findings for circadian-mediated MC functional roles and activation paradigms, as well as the therapeutic potentials of targeting circadian-mediated melatonin and histamine signaling in MC-dependent inflammatory diseases.

Mast Cells Induce Ductular Reaction Mimicking Liver Injury in Mice Through Mast Cell-Derived Transforming Growth Factor Beta 1 Signaling.

BACKGROUND AND AIMS: Following liver injury, mast cells (MCs) migrate into the liver and are activated in patients with cholestasis. Inhibition of MC mediators decreases ductular reaction (DR) and liver fibrosis. Transforming growth factor beta 1 (TGF-ß1) contributes to fibrosis and promotes liver disease. Our aim was to demonstrate that reintroduction of MCs induces cholestatic injury through TGF-ß1. APPROACH AND RESULTS: Wild-type, KitW-sh (MC-deficient), and multidrug resistance transporter 2/ABC transporter B family member 2 knockout mice lacking l-histidine decarboxylase were injected with vehicle or PKH26-tagged murine MCs pretreated with 0.01% dimethyl sulfoxide (DMSO) or the TGF-ß1 receptor inhibitor (TGF-ßRi), LY2109761 (10 µM) 3 days before sacrifice. Hepatic damage was assessed by hematoxylin and eosin (H&E) and serum chemistry. Injected MCs were detected in liver, spleen, and lung by immunofluorescence (IF). DR was measured by cytokeratin 19 (CK-19) immunohistochemistry and F4/80 staining coupled with real-time quantitative PCR (qPCR) for interleukin (IL)-1ß, IL-33, and F4/80; biliary senescence was evaluated by IF or qPCR for p16, p18, and p21. Fibrosis was evaluated by sirius red/fast green staining and IF for synaptophysin 9 (SYP-9), desmin, and alpha smooth muscle actin (α-SMA). TGF-ß1 secretion/expression was measured by enzyme immunoassay and qPCR. Angiogenesis was detected by IF for von Willebrand factor and vascular endothelial growth factor C qPCR. In vitro, MC-TGF-ß1 expression/secretion were measured after TGF-ßRi treatment; conditioned medium was collected. Cholangiocytes and hepatic stellate cells (HSCs) were treated with MC-conditioned medium, and biliary proliferation/senescence was measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and qPCR; HSC activation evaluated for α-SMA, SYP-9, and collagen type-1a expression. MC injection recapitulates cholestatic liver injury characterized by increased DR, fibrosis/TGF-ß1 secretion, and angiogenesis. Injection of MC-TGF-ßRi reversed these parameters. In vitro, MCs induce biliary proliferation/senescence and HSC activation that was reversed with MCs lacking TGF-ß1. CONCLUSIONS: Our study demonstrates that reintroduction of MCs mimics cholestatic liver injury and that MC-derived TGF-ß1 may be a target in chronic cholestatic liver disease.