Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on the surface of T cells. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). However, the mechanism of intracellular trafficking and plasma membrane presentation of PD-1 remains unclear. METHODS: Multiple databases of lung cancer patients were integratively analyzed to screen Rab proteins and potential immune-related signaling pathways. Imaging and various biochemical assays were performed in Jurkat T cells, splenocytes, and human peripheral blood mononuclear cells (PBMCs). Rab37 knockout mice and specimens of lung cancer patients were used to validate the concept. RESULTS: Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37 small GTPase to sustain T cell exhaustion, thereby leading to poor patient outcome. PD-1 colocalized with Rab37-specific vesicles of T cells in a GTP-dependent manner whereby Rab37 mediated dynamic trafficking and membrane presentation of PD-1. However, glycosylation mutant PD-1 delayed cargo recruitment to the Rab37 vesicles, thus stalling membrane presentation. Notably, T cell proliferation and activity were upregulated in tumor-infiltrating T cells from the tumor-bearing Rab37 knockout mice compared to those from wild type. Clinically, the multiplex immunofluorescence-immunohistochemical assay indicated that patients with high Rab37+/PD-1+/TIM3+/CD8+ tumor infiltrating T cell profile correlated with advanced tumor stages and poor overall survival. Moreover, human PBMCs from patients demonstrated high expression of Rab37, which positively correlated with elevated levels of PD-1+ and TIM3+ in CD8+ T cells exhibiting reduced tumoricidal activity. CONCLUSIONS: Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37high/PD-1high/TIM3high in tumor-infiltrating CD8+ T cells is a biomarker for poor prognosis in lung cancer patients.

Linking chronic stress to insomnia symptoms in older adults: The role of stress co-occurrence during the pandemic.

Studies examining the associations of chronic stressors with sleep health in older adults have shown conflicting results. While the COVID-19 pandemic increased perceived stress at the population level, less is known about chronic stressors experienced by older adults in the context of the COVID-19 pandemic and its impact on sleep health in an aging population. This study aims to examine the association of older adults' chronic stress with insomnia symptoms during the first year of the COVID-19 pandemic. A cross-sectional analysis was performed using early-release COVID-19 data from the Health and Retirement Study. Data on chronic stressors and insomnia symptoms in older adults (N = 2021; mean age = 68.8) were examined. Co-occurrence network analysis, latent class analysis, Rao-Scott χ2 tests, and multivariable logistic regression were used to characterize the co-occurrence of chronic stressors and associations with insomnia symptoms. The most common co-occurring chronic stressors during the first year of the COVID-19 pandemic were self-health issues, family-health issues, and financial stress. Older adults experiencing frequent stress co-occurrence had 91% higher odds of difficulty initiating sleep (p < 0.001), 40% higher odds of frequent nocturnal awakening (p = 0.028), and 83% higher odds of nonrestorative sleep (p < 0.001). However, adjustment for health risk factors and COVID-19 concerns attenuated the effects, leaving strongest association for difficulty initiating sleep (odds ratio = 1.51, p = 0.010). Frequent stress co-occurrence plays an important role linking chronic stress to insomnia symptoms in an aging population. Ongoing research is needed to examine the lingering effects of frequent stress co-occurrence on older adults' sleep health in the post COVID-19 era.

Relationship between resilience and self-care in people with chronic conditions: A systematic review and meta-analysis.

BACKGROUND: Living with chronic condition(s) is difficult, due in part to the complexities of effective disease self-care. Self-care has been considered a challenging process according to the literature which describes multiple barriers patients with chronic conditions experience. Resilience has the potential to buffer the adversities of daily self-care and maintain physical and emotional well-being. No systematic review and meta-analysis have been conducted to synthesise and quantify the relationship between resilience and self-care across chronic conditions. AIMS: (1) To examine how the definitions and measurements of self-care and resilience align with the middle-range theory of self-care of chronic illness (i.e. self-care maintenance, self-care monitoring, and self-care management) and 3 Rs of resilience process from the society-to-cells framework (i.e. resistance, recovery and rebound) across different chronic conditions; and (2) to examine whether and the degree to which resilience is correlated with self-care across different chronic conditions. DESIGN: Systematic review and meta-analysis, following PRISMA guidelines. METHODS: PubMed, CINAHL, SocINDEX and PsychINFO were searched for quantitative studies published from January 2000 through July 2020. Descriptive data were summarised using numerical counting to provide an overview of the study characteristics. Definitions and measurements of self-care and resilience were synthesised narratively based on self-care and resilience theories. Numerical data with Pearson's product-moment correlation among observational studies were examined using meta-analysis. RESULTS: This review included 20 articles, involving 9,269 individuals across 11 chronic conditions. Despite self-care and resilience being defined and operationalised in a variety of ways, most definitions shared some underlying core constructs. Meta-analysis showed a positive relationship between resilience and self-care across chronic conditions. Findings from interventional studies indicated a bidirectional relationship between resilience and self-care. CONCLUSIONS: Overall, resilience was positively associated with self-care in people with chronic conditions. Longitudinal and experimental studies are needed to better understand the causal relationship between resilience and self-care. RELEVANT TO CLINICAL PRACTICE: Resilience has the potential to buffer the adversities of daily self-care and maintain physical and emotional well-being. The positive relationship between resilience and self-care found in this review provides preliminary evidence for clinicians to not only focus on reducing barriers and risk factors of self-care but also to improve or increase patients' resilience through various evidence-based interventions.

Autophagy drives plasticity and functional polarization of tumor-associated macrophages.

Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and are key cells in regulating tumor development, metastasis, immune responses, inflammation, and chemoresistance. In response to TME stimulation, circulating monocytes are recruited and differentiated as TAMs. Most TAMs are defined as alternatively activated (M2) phenotype to create immunosuppressive TME and support tumor progression. In contrast, classically activated (M1) TAMs can produce pro-inflammatory cytokines and enhance immune responses against tumor development. Autophagy is a conserved catabolic process to control cellular homeostasis and biological function. Emerging evidence reveals crucial contribution of autophagy in modulating TAM plasticity and functional polarization in TME. In this review, we introduce the current understanding of autophagy-regulated TAM function in development of cancer. We focus on how autophagy modulates antigen presentation, LC3-associated phagocytosis, cytokine secretion, inflammasome regulation, recruitment, differentiation, and polarization of TAMs and suggest strategies for potential therapeutics by targeting autophagy in TAMs. We expect this review can provide a new notion of future cancer immunotherapy.

Recent advances in conventional and unconventional vesicular secretion pathways in the tumor microenvironment.

All cells in the changing tumor microenvironment (TME) need a class of checkpoints to regulate the balance among exocytosis, endocytosis, recycling and degradation. The vesicular trafficking and secretion pathways regulated by the small Rab GTPases and their effectors convey cell growth and migration signals and function as meditators of intercellular communication and molecular transfer. Recent advances suggest that Rab proteins govern conventional and unconventional vesicular secretion pathways by trafficking widely diverse cargoes and substrates in remodeling TME. The mechanisms underlying the regulation of conventional and unconventional vesicular secretion pathways, their action modes and impacts on the cancer and stromal cells have been the focus of much attention for the past two decades. In this review, we discuss the current understanding of vesicular secretion pathways in TME. We begin with an overview of the structure, regulation, substrate recognition and subcellular localization of vesicular secretion pathways. We then systematically discuss how the three fundamental vesicular secretion processes respond to extracellular cues in TME. These processes are the conventional protein secretion via the endoplasmic reticulum-Golgi apparatus route and two types of unconventional protein secretion via extracellular vesicles and secretory autophagy. The latest advances and future directions in vesicular secretion-involved interplays between tumor cells, stromal cell and host immunity are also described.

Relationship of Cognitive and Social Engagement to Health and Psychological Outcomes in Community-Dwelling Older Adults.

BACKGROUND: Cognitive and social engagement is an important yet underdocumented aspect of older adult engagement and function. OBJECTIVE: The purpose of this study was to examine relationships between cognitive and social engagement and health and psychological outcomes in a cohort of community-dwelling older adults aged approximately 55-70 years. METHODS: Analysis of data from the Wisconsin Registry for Alzheimer's Prevention, a multiwave cohort study with 1,582 participants, using a 1:1 prospective case-control design to examine whether lower cognitive and social engagement at Visit 4 (baseline) is associated with worse health and psychological outcomes at Visit 5 (2 years after Visit 4). Wisconsin Registry for Alzheimer's Prevention participants were included in this study if they had complete data on cognitive and social engagement and self-rated health at both visits. RESULTS: After matching potential covariates using propensity scores, participants with low cognitive and social engagement (cases) at baseline continued to have significantly lower cognitive and social engagement than the controls (participants with high cognitive and social engagement at baseline) at Visit 5, and they had lower self-rated health and higher surgery rate. Depressive symptoms, cognitive status, and hospitalization at Visit 5 did not significantly differ between cases and controls. DISCUSSION: This study provides evidence supporting cognitive and social engagement as an important marker of early decline in activity engagement that may indicate a potential later decline in functional, psychological, and health outcomes.

Gender Differences in the Relationship Between Financial Stress and Metabolic Abnormalities.

BACKGROUND: Financial stress is associated with higher prevalence of metabolic abnormalities and cardiovascular disease, but the extent to which this association differs by type of metabolic abnormalities or gender is unclear. OBJECTIVES: The study aims were (a) to examine the association between financial stress and the prevalence of common metabolic abnormalities and (b) to test the association for gender differences. METHODS: A cross-sectional secondary analysis was conducted using data from the Retirement and Sleep Trajectories study, an ancillary study of the Wisconsin Sleep Cohort study. Composite indicator structural equation alpha modeling with a stacking approach was applied in the data analysis. RESULTS: After controlling for covariates, financial stress was positively associated with the prevalence of abdominal obesity, metabolic syndrome, and dyslipidemia, with significant gender differences. Among men, financial stress was positively associated with the prevalence of hypertriglyceridemia. Among women, financial stress was positively associated with the prevalence of prediabetes, abdominal obesity, metabolic syndrome, and dyslipidemia. CONCLUSION: Men living with financial stress are more likely to have hypertriglyceridemia, a specific metabolic abnormality and risk factor for acute cardiovascular events. However, financial stress in women is associated with a broader array of metabolic abnormalities (e.g., dyslipidemia, prediabetes, abdominal obesity, metabolic syndrome), highlighting a potential risk of multiple chronic conditions later in life.

Does 24-h Activity Cycle Influence Plasma PCSK9 Concentration? A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Higher plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration has been associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Animal and human studies have examined the relationship between 24-h activity cycles (24-HAC) and PCSK9, but conflicting results exist. Therefore, this review aimed to examine the relationship between 24-HAC and plasma PCSK9 concentration in animals and humans.Three databases (PubMed, CINAHL, and Web of Science) were searched for eligible articles. Descriptive data were summarized using network meta-analysis. The effect size was estimated using pairwise meta-analysis. RECENT FINDINGS: The interventions designed to increase moderate to vigorous physical activities (MVPA) did not significantly change plasma PCSK9 concentration (Hedges' g = 0.137; p = 0.337). However, the effect was influenced by statin therapy and intervention delivery mode. Specifically, physical activity interventions in conjunction with statin therapy significantly increased plasma PCSK9 concentration (Hedges' g = 0.275; p = 0.007). Supervised exercise training significantly increased plasma PCSK9 concentration (Hedges' g = 0.630; p = 0.001), but physical activity counseling did not (p = 0.845). The effects of MVPA on plasma PCSK9 may be moderated by statin therapy, intervention delivery mode, or other potential unknown mechanistic factors. Thus, caution should be taken when using plasma PCSK9 as an outcome indicator for physical activity interventions aimed at decreasing the risk of ASCVD. Graphical abstract.

Correction to: Does 24-h Activity Cycle Influence Plasma PCSK9 Concentration? A Systematic Review and Meta-Analysis.

Due to typesetting mistake, an unknown image was accidentally captured as graphical abstract. This should be removed.

Biodistribution, pharmacokinetics and radioimmunotherapy of 188Re-cetuximab in NCI-H292 human lung tumor-bearing nude mice.

Background Cetuximab is a fully humanized IgG1 subclass monoclonal that binds specifically to the human epidermal growth factor receptor (EGFR). Although EGFR is expressed in normal cells, the overexpression of EGFR is detected in many human cancers, such as colon, rectum and lung tumors. In this study, cetuximab with a combination of radiotherapy nuclear 188Re achieved better therapeutic effect on lung cancer. Methods188Re-cetuximab administered by the i.v. route in human NCI-H292 lung tumor-bearing mice was investigated. NanoSPECT/CT images were taken to evaluate the distribution and tumor targeting of 188Re-cetuximab in mice. The anti-tumor effect of 188Re-cetuximab was assessed by the tumor growth inhibition, survival ratio. Results For nanoSPECT/CT imaging, a significant uptake in tumor was observed at 24 and 48 h following the injection of 188Re-cetuximab. The anti-tumor effect of 188Re-cetuximab was assessed by tumor growth inhibition and the survival ratio. The tumor-bearing mice treated with 188Re-cetuximab showed a better mean tumor growth inhibition rate (MGI = 0.049) and longer median survival time and lifespan (62.50 d; 70.07%) than those treated with 188Re-perrhenate and cetuximab only by single injection. A synergistic effect of tumor growth inhibition was observed with the combination index exceeding one for 188Re-cetuximab (CI = 6.135 and 9.276). Conclusion The tumor targeting and localization of 188Re-cetuximab were confirmed in this study. Synergistic therapeutic efficacy was demonstrated for the radioimmunotherapy of 188Re-cetuximab. The results of this study reveal the potential advantage and benefit obtained from 188Re-cetuximab for diagnosis and therapy of oncology applications in the future.

A Population-Based Assessment of the Impact of 7- and 13-Valent Pneumococcal Conjugate Vaccines on Macrolide-Resistant Invasive Pneumococcal Disease: Emergence and Decline of Streptococcus pneumoniae Serotype 19A (CC320) With Dual Macrolide Resistance Mechanisms.

BACKGROUND: Macrolide efflux encoded by mef(E)/mel and ribosomal methylation encoded by erm(B) confer most macrolide resistance in Streptococcus pneumoniae. Introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in 2000 reduced macrolide-resistant invasive pneumococcal disease (MR-IPD) due to PCV7 serotypes (6B, 9V, 14, 19F, and 23F). METHODS: In this study, the impact of PCV7 and PCV13 on MR-IPD was prospectively assessed. A 20-year study of IPD performed in metropolitan Atlanta, Georgia, using active, population-based surveillance formed the basis for this study. Genetic determinants of macrolide resistance were evaluated using established techniques. RESULTS: During the decade of PCV7 use (2000-2009), MR-IPD decreased rapidly until 2002 and subsequently stabilized until the introduction of PCV13 in 2010 when MR-IPD incidence decreased further from 3.71 to 2.45/100000 population. In 2003, serotype 19A CC320 isolates containing both mef(E)/mel and erm(B) were observed and rapidly expanded in 2005-2009, peaking in 2010 (incidence 1.38/100000 population), accounting for 36.1% of MR-IPD and 11.7% of all IPD isolates. Following PCV13 introduction, dual macrolide-resistant IPD decreased 74.1% (incidence 0.32/100000 in 2013). However, other macrolide-resistant serotypes (eg, 15A and 35B) not currently represented in PCV formulations increased modestly. CONCLUSIONS: The selective pressures of widespread macrolide use and PCV7 and PCV13 introductions on S. pneumoniae were associated with changes in macrolide resistance and the molecular basis over time in our population. Durable surveillance and programs that emphasize the judicious use of antibiotics need to continue to be a focus of public health strategies directed at S. pneumoniae.

Down-regulation of CD53 expression in Epinephelus coioides under LPS, poly (I:C), and cytokine stimulation.

Tetraspanins are a group of cell surface molecules involved in cell adhesion, motility, metastasis, signal transduction, and immune cell activation. Members of the tetraspanin family include CD9, CD37, CD63, CD53, and others. However, few tetraspanins have been investigated in teleosts. In this study, we obtained the open reading frame of CD53 cDNA from orange spotted grouper (Epinephelus coioices), an economically important fish. The predicted amino acid structure contains four membrane-spanning domains and a conserved CCG motif. The amino acid identity between human and grouper CD53 was only 38%; however, both CD53 proteins share the same structure. Quantitative real-time PCR revealed that mRNA is abundant in immune organs, including the head and trunk kidneys, spleen, thymus, gill, and blood. Immunochemistry and immunofluorescence analyses further revealed that CD53 was majorly expressed in the leukocytes of various organs. Finally, mRNA and protein expression for CD53 was down-regulated in fish treated with immune stimulators, including LPS, Poly (I:C), Vibrio, recombinant grouper IL-6, and CCL4. Our results indicate that the expression of CD53 may play important roles in pathogen invasion and inflammation reaction.

Higher migraine risk in healthcare professionals than in general population: a nationwide population-based cohort study in Taiwan.

BACKGROUND: High stress levels and shift work probably trigger migraine in healthcare professionals (HCPs). However, the migraine risk differences between HCPs and the general population is unknown. METHODS: This nationwide population-based cohort study used Taiwan's National Health Insurance Research Database. Physicians (50,226), nurses (122,357), and other HCPs (pharmacists, technicians, dietitians, rehabilitation therapists, social workers, etc.) (45,736) were enrolled for the study cohort, and randomly selected non-HCPs (218,319) were enrolled for the comparison cohort. Conditional logistical regression analysis was used to compare the migraine risks. Comparisons between HCPs and between physician specialties were also done. RESULTS: Physicians, nurses, and other HCPs had higher migraine risks than did the general population (adjusted odds ratio [AOR]: 1.672; 95 % confidence interval [CI]: 1.468-1.905, AOR: 1.621; 95 % CI: 1.532-1.714, and AOR: 1.254; 95 % CI: 1.124-1.399, respectively) after stroke, hypertension, epilepsy, anxiety, depression, and insomnia had been adjusted for. Nurses and physicians had higher migraine risks than did other HCPs (AOR: 1.303; 95 % CI: 1.206-1.408, and AOR: 1.193; 95 % CI: 1.069-1.332, respectively). Obstetricians and gynecologists had a lower migraine risk than did other physician specialists (AOR: 0.550; 95 % CI: 0.323-0.937). CONCLUSION: HCPs in Taiwan had a higher migraine risk than did the general population. Heavy workloads, emotional stress, and rotating night shift sleep disturbances appear to be the most important risk factors. These findings should provide an important reference for promoting occupational health in HCPs in Taiwan.

Great leap forward famine exposure and urban-rural migration convolute the modern prevalence of diabetes in China.

BACKGROUND: Although evidence from birth cohort analysis has indicated the metabolic risk of early-life exposure to the Great Leap Forward Famine (GLFF) in China, three confounding effects, including the exposure windows, aging, and geographical variations in famine severity, have been brought to debates for a decade. This study aimed to address these confounding effects and extensively examine how GLFF exposure is associated with diabetes risk in mid-to-late life and its interaction with urban-rural migration. METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS) were analyzed with age-stratification and stepped wedge approaches. Weighted prevalence and multivariable logistic regression were used to investigate the effects of GLFF exposure and urban-rural migration on mid-to-late life diabetes risk and the interaction between GLFF exposure and urban-rural migration. Birth provinces were controlled as a fixed effect to account for variations in famine severity across provinces. RESULTS: Compared to those who were never exposed to GLFF, fetal GLFF exposure was associated with a higher risk of adult-onset diabetes after controlling for provinces, demographics, and health statuses. Yet, after adding the proxy of childhood growth environments into the model, fetal exposure to GLFF was not significantly associated with adult-onset diabetes risk (OR = 1.22, p = 0.10), compared to those who were never exposed to GLFF. Across the three age-stratification groups, static urban residents, in general, had a higher risk of diabetes compared to static rural residents. Interaction effects between GLFF exposure and urban-rural migration were insignificant across all three age-stratification groups. CONCLUSION: Fetal exposure to GLFF might have a traceable effect on adult-onset diabetes risk. Yet, the growth environment and urban lifestyle outweigh and further confound the impact of GLFF exposure on adult-onset diabetes risk.

Twelve Weeks of Daily Lentil Consumption Improves Fasting Cholesterol and Postprandial Glucose and Inflammatory Responses-A Randomized Clinical Trial.

Lentils have potential to improve metabolic health but there are limited randomized clinical trials evaluating their comprehensive impact on metabolism. The aim of this study was to assess the impact of lentil-based vs. meat-based meals on fasting and postprandial measures of glucose and lipid metabolism and inflammation. Thirty-eight adults with an increased waist circumference (male ≥ 40 inches and female ≥ 35 inches) participated in a 12-week dietary intervention that included seven prepared midday meals totaling either 980 g (LEN) or 0 g (CON) of cooked green lentils per week. Linear models were used to assess changes in fasting and postprandial markers from pre- to post-intervention by meal group. Gastrointestinal (GI) symptoms were assessed through a survey randomly delivered once per week during the intervention. We found that regular consumption of lentils lowered fasting LDL (F = 5.53, p = 0.02) and total cholesterol levels (F = 8.64, p < 0.01) as well as postprandial glucose (ß = -0.99, p = 0.01), IL-17 (ß = -0.68, p = 0.04), and IL-1ß (ß = -0.70, p = 0.03) responses. GI symptoms were not different by meal group and all symptoms were reported as "none" or "mild" for the duration of the intervention. Our results suggest that daily lentil consumption may be helpful in lowering cholesterol and postprandial glycemic and inflammatory responses without causing GI stress. This information further informs the development of pulse-based dietary strategies to lower disease risk and to slow or reverse metabolic disease progression in at-risk populations.

Artificial intelligence prediction of In-Hospital mortality in patients with dementia: A multi-center study.

BACKGROUND: Prediction of mortality is very important for care planning in hospitalized patients with dementia and artificial intelligence has the potential to serve as a solution; however, this issue remains unclear. Thus, this study was conducted to elucidate this matter. METHODS: We identified 10,573 hospitalized patients aged ≥ 45 years with dementia from three hospitals between 2010 and 2020 for this study. Utilizing 44 feature variables extracted from electronic medical records, an artificial intelligence (AI) model was constructed to predict death during hospitalization. The data was randomly separated into 70 % training set and 30 % testing set. We compared predictive accuracy among six algorithms including logistic regression, random forest, extreme gradient boosting (XGBoost), Light Gradient Boosting Machine (LightGBM), multilayer perceptron (MLP), and support vector machine (SVM). Additionally, another set of data collected in 2021 was used as the validation set to assess the performance of six algorithms. RESULTS: The average age was 79.8 years, with females constituting 54.5 % of the sample. The in-hospital mortality rate was 6.7 %. LightGBM exhibited the highest area under the curve (0.991) for predicting mortality compared to other algorithms (XGBoost: 0.987, random forest: 0.985, logistic regression: 0.918, MLP: 0.898, SVM: 0.897). The accuracy, sensitivity, positive predictive value, and negative predictive value of LightGBM were 0.943, 0.944, 0.943, 0.542, and 0.996, respectively. Among the features in LightGBM, the three most important variables were the Glasgow Coma Scale, respiratory rate, and blood urea nitrogen. In the validation set, the area under the curve of LightGBM reached 0.753. CONCLUSIONS: The AI prediction model demonstrates strong accuracy in predicting in-hospital mortality among patients with dementia, suggesting its potential implementation to enhance future care quality.

Heat-related illness and dementia: a study integrating epidemiological and experimental evidence.

BACKGROUND: Heat-related illness (HRI) is commonly considered an acute condition, and its potential long-term consequences are not well understood. We conducted a population-based cohort study and an animal experiment to evaluate whether HRI is associated with dementia later in life. METHODS: The Taiwan National Health Insurance Research Database was used in the epidemiological study. We identified newly diagnosed HRI patients between 2001 and 2015, but excluded those with any pre-existing dementia, as the study cohort. Through matching by age, sex, and the index date with the study cohort, we selected individuals without HRI and without any pre-existing dementia as a comparison cohort at a 1:4 ratio. We followed each cohort member until the end of 2018 and compared the risk between the two cohorts using Cox proportional hazards regression models. In the animal experiment, we used a rat model to assess cognitive functions and the histopathological changes in the hippocampus after a heat stroke event. RESULTS: In the epidemiological study, the study cohort consisted of 70,721 HRI patients and the comparison cohort consisted of 282,884 individuals without HRI. After adjusting for potential confounders, the HRI patients had a higher risk of dementia (adjusted hazard ratio [AHR] = 1.24; 95% confidence interval [CI]: 1.19-1.29). Patients with heat stroke had a higher risk of dementia compared with individuals without HRI (AHR = 1.26; 95% CI: 1.18-1.34). In the animal experiment, we found cognitive dysfunction evidenced by animal behavioral tests and observed remarkable neuronal damage, degeneration, apoptosis, and amyloid plaque deposition in the hippocampus after a heat stroke event. CONCLUSIONS: Our epidemiological study indicated that HRI elevated the risk of dementia. This finding was substantiated by the histopathological features observed in the hippocampus, along with the cognitive impairments detected, in the experimental heat stroke rat model.

Plasticity of intragraft alloreactive T cell clones in human gut correlates with transplant outcomes.

The site of transition between tissue-resident memory (TRM) and circulating phenotypes of T cells is unknown. We integrated clonotype, alloreactivity, and gene expression profiles of graft-repopulating recipient T cells in the intestinal mucosa at the single-cell level after human intestinal transplantation. Host-versus-graft (HvG)-reactive T cells were mainly distributed to TRM, effector T (Teff)/TRM, and T follicular helper compartments. RNA velocity analysis demonstrated a trajectory from TRM to Teff/TRM clusters in association with rejection. By integrating pre- and post-transplantation (Tx) mixed lymphocyte reaction-determined alloreactive repertoires, we observed that pre-existing HvG-reactive T cells that demonstrated tolerance in the circulation were dominated by TRM profiles in quiescent allografts. Putative de novo HvG-reactive clones showed a transcriptional profile skewed to cytotoxic effectors in rejecting grafts. Inferred protein regulon network analysis revealed upstream regulators that accounted for the effector and tolerant T cell states. We demonstrate Teff/TRM interchangeability for individual T cell clones with known (allo)recognition in the human gut, providing novel insight into TRM biology.

A polymer coating applied to Salmonella prevents the binding of Salmonella-specific antibodies.

The use of Salmonella as a potential antitumor agent has been investigated, but innate immunity against this bacterium reduces the efficacy of its tumor-targeting and antitumor activities. The purpose of this study was to investigate the modulation of the tumor-targeting efficiency of Salmonella enterica serovar choleraesuis by modifying the immune response to these bacteria by coating them with poly(allylamine hydrochloride) (PAH), designated PAH-S.C. To evaluate this modulation, we used naïve mice and mice immunized with Salmonella to study the role of the preexisting immune response to the antitumor activity of PAH-S.C. When anti-Salmonella antibodies were present, the invasion activity, cytotoxicity, and gene transfer of Salmonella was significantly decreased, both in vitro and in vivo. Treatment with PAH-S.C. resulted in delayed tumor growth and enhanced survival in immunized mice. Furthermore, immunohistochemical studies of the tumors revealed the infiltration of neutrophils and macrophages in immunized mice treated with PAH-S.C. These results indicate that Salmonella encapsulation effectively circumvented the Salmonella-specific immune response.

The biofunction of orange-spotted grouper (Epinephelus coioides) CC chemokine ligand 4 (CCL4) in innate and adaptive immunity.

CC chemokine (motif) ligand 4 (CCL4) is indispensable to the chemoattraction of macrophages, natural killer cells, and lymphocytes in mammals; however, it has only been cloned in a limited number of fish species and information related to its biofunction remains ambiguous with regard to teleosts. To explore the role of teleost CCL4, we first evaluated the mRNA expression of the Epinephelus coioides CCL4 (gCCL4) gene in various organs under LPS and poly (I:C) stimulated; secondary, we evaluated the immune-related genes expression of fish under the recombinant gCCL4 protein stimulated. Our results revealed an increase in the mRNA of gCCL4 in immune organs immediately following stimulation by poly (I:C); however, in LPS stimulated fish, the expression did not increase until nearly 24 h after induction. In biofunction assays, recombinant gCCL4 was found to induce chemotactic activity in the peripheral blood leukocytes of groupers and up-regulate the gene expressions of grouper TNFA1 (TNF-α1), TNFA2 (TNF-α2), IFNG (IFN-γ), MX, TBX21 (T-bet), CD8 (α and ß chain). These findings indicate that grouper CCL4 attracts leukocytes, induces an inflammatory response, and drives lymphocyte differentiation into the Th1 pathway.