Prolonged exposure to bacterial toxins downregulated expression of toll-like receptors in mesenchymal stromal cell-derived osteoprogenitors

<p>Abstract</p> <p>Background</p> <p>Human mesenchymal stromal cells (MSCs, also known as mesenchymal stem cells) are multipotent cells with potential therapeutic value. Owing to their osteogenic capability, MSCs may be clinically applied for facilitating osseointegration in dental implants or orthopedic repair of bony defect. However, whether wound infection or oral microflora may interfere with the growth and osteogenic differentiation of human MSCs remains unknown. This study investigated whether proliferation and osteogenic differentiation of MSCs would be affected by potent gram-positive and gram-negative derived bacterial toxins commonly found in human settings.</p> <p>Results</p> <p>We selected lipopolysaccharide (LPS) from <it>Escherichia coli </it>and lipoteichoic acid (LTA) from <it>Streptococcus pyogenes </it>as our toxins of choice. Our findings showed both LPS and LTA did not affect MSC proliferation, but prolonged LPS challenge upregulated the osteogenic differentiation of MSCs, as assessed by alkaline phosphatase activity and calcium deposition. Because toll-like receptors (TLRs), in particularly TLR4 and TLR2, are important for the cellular responsiveness to LPS and LTA respectively, we evaluated their expression profiles serially from MSCs to osteoblasts by quantitative PCR. We found that during osteogenic differentiation, MSC-derived osteoprogenitors gradually expressed TLR2 and TLR4 by Day 12. But under prolonged incubation with LPS, MSC-derived osteoprogenitors had reduced TLR2 and TLR4 gene expression. This peculiar response to LPS suggests a possible adaptive mechanism when MSCs are subjected to continuous exposure with bacteria.</p> <p>Conclusion</p> <p>In conclusion, our findings support the potential of using human MSCs as a biological graft, even under a bacterial toxin-rich environment.</p

A Decade of Progress in Deep Brain Stimulation of the Subcallosal Cingulate for the Treatment of Depression

Major depression contributes significantly to the global disability burden. Since the first clinical study of deep brain stimulation (DBS), over 406 patients with depression have now undergone this neuromodulation therapy, and 30 animal studies have investigated the efficacy of subgenual cingulate DBS for depression. In this review, we aim to provide a comprehensive overview of the progress of DBS of the subcallosal cingulate in humans and the medial prefrontal cortex, its rodent homolog. For preclinical animal studies, we discuss the various antidepressant-like behaviors induced by medial prefrontal cortex DBS and examine the possible mechanisms including neuroplasticity-dependent/independent cellular and molecular changes. Interestingly, the response rate of subcallosal cingulate Deep brain stimulation marks a milestone in the treatment of depression. DBS among patients with treatment-resistant depression was estimated to be approximately 54% across clinical studies. Although some studies showed its stimulation efficacy was limited, it still holds great promise as a therapy for patients with treatment-resistant depression. Overall, further research is still needed, including more credible clinical research, preclinical mechanistic studies, precise selection of patients, and customized electrical stimulation paradigms

More than a piece of cake:Noun classifier processing in primary progressive aphasia

INTRODUCTION: Clinical understanding of primary progressive aphasia (PPA) has been primarily derived from Indo-European languages. Generalizing certain linguistic findings across languages is unfitting due to contrasting linguistic structures. While PPA patients showed noun classes impairments, Chinese languages lack noun classes. Instead, Chinese languages are classifier language, and how PPA patients manipulate classifiers is unknown. METHODS: We included 74 native Chinese speakers (22 controls, 52 PPA). For classifier production task, participants were asked to produce the classifiers of high-frequency items. In a classifier recognition task, participants were asked to choose the correct classifier. RESULTS: Both semantic variant (sv) PPA and logopenic variant (lv) PPA scored significantly lower in classifier production task. In classifier recognition task, lvPPA patients outperformed svPPA patients. The classifier production scores were correlated to cortical volume over left temporal and visual association cortices. DISCUSSION: This study highlights noun classifiers as linguistic markers to discriminate PPA syndromes in Chinese speakers. Highlights: Noun classifier processing varies in the different primary progressive aphasia (PPA) variants. Specifically, semantic variant PPA (svPPA) and logopenic variant PPA (lvPPA) patients showed significantly lower ability in producing specific classifiers. Compared to lvPPA, svPPA patients were less able to choose the accurate classifiers when presented with choices. In svPPA, classifier production score was positively correlated with gray matter volume over bilateral temporal and left visual association cortices in svPPA. Conversely, classifier production performance was correlated with volumetric changes over left ventral temporal and bilateral frontal regions in lvPPA. Comparable performance of mass and count classifier were noted in Chinese PPA patients, suggesting a common cognitive process between mass and count classifiers in Chinese languages.</p

COVID-19 vaccine effectiveness against the Omicron variant of SARS-CoV-2 in multimorbidity: A territory-wide case-control study

Multimorbidity entails a higher risk of SARS-CoV-2 infection and COVID-19 complications. We examined vaccine effectiveness (VE) stratified by multimorbidity using a case-control study of territory-wide electronic health records in Hong Kong. Cases of infection (testing positive), hospitalization, and mortality were identified from January to March 2022. Controls were matched by age, sex, outpatient attendance/hospitalization date, and Charlson Comorbidity Index. We demonstrated a consistently good VE among people with increased multimorbidity burden; even more so than among those with minimal such burden. There was also a significantly greater VE after a third dose of BNT162b2 or CoronaVac against infection. The difference in VE between those with multimorbidity and those without was less pronounced for hospitalization, and such difference for COVID-19-related mortality was negligible. In conclusion, VE of both examined vaccines against SARS-CoV-2 infection among people with more complex multimorbidity burden is significant. Further vaccine roll-out should prioritize people with multimorbidity

OPCML Is a Broad Tumor Suppressor for Multiple Carcinomas and Lymphomas with Frequently Epigenetic Inactivation

Background: Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction. Methodology/Principal Findings: Semi-quantitative RT-PCR showed frequent OPCML silencing in NPC and other common tumors, with no homozygous deletion detected by multiplex differential DNA-PCR. Instead, promoter methylation of OPCML was frequently detected in multiple carcinoma cell lines (nasopharyngeal, esophageal, lung, gastric, colon, liver, breast, cervix, prostate), lymphoma cell lines (non-Hodgkin and Hodgkin lymphoma, nasal NK/T-cell lymphoma) and primary tumors, but not in any non-tumor cell line and seldom weakly methylated in normal epithelial tissues. Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing. We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated. Ecotopic expression of OPCML led to significant inhibition of both anchorage-dependent and -indendent growth of carcinoma cells with endogenous silencing. Conlusions/Significance: Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies. © 2008 Cui et al.published_or_final_versio

Milk Consumption Across Life Periods in Relation to Lower Risk of Nasopharyngeal Carcinoma: A Multicentre Case-Control Study

Background: The much higher incidence of nasopharyngeal carcinoma (NPC) in men suggests sex hormones as a risk factor, and dairy products contain measurable amounts of steroid hormones. Milk consumption has greatly increased in endemic regions of NPC. We investigated the association between NPC and milk consumption across life periods in Hong Kong.Methods: A multicentre case-control study included 815 histologically confirmed NPC incident cases and 1,502 controls who were frequency-matched on age and sex at five major hospitals in Hong Kong in 2014–2017. Odds ratios (ORs) of NPC (cases vs. controls) for milk consumption at different life periods were estimated by unconditional logistic regression, adjusting for sex, age, socioeconomic status score, smoking and alcohol drinking status, exposure to occupational hazards, family history of cancer, IgA against Epstein-Barr virus viral capsid antigen, and total energy intake.Results: Compared with abstainers, lower risks of NPC were consistently observed in regular users (consuming ≥5 glasses of milk [fresh and powdered combined] per month) across four life periods of age 6–12 (adjusted OR 0.74, 95% CI 0.54–0.86), 13–18 (0.68, 0.55–0.84), 19–30 (0.68, 0.55–0.84), and 10 years before recruitment (0.72, 0.59–0.87). Long-term average milk consumption of ≤2.5, &gt;2.5, and ≤12.5, &gt;12.5 glasses per month yielded adjusted OR (95% CI) of 1.00 (0.80–1.26), 0.98 (0.81–1.18), 0.95 (0.76–1.18), and 0.55 (0.43–0.70), respectively (all P-values for trend &lt; 0.05).Conclusion: Consumption of milk across life periods was associated with lower risks of NPC. If confirmed to be causal, this has important implications for dairy product consumption and prevention of NPC

Long-term effects of coronavirus disease 2019 on diabetes complications and mortality in people with diabetes:Two cohorts in the UK and Hong Kong

AIM: To evaluate the long-term associations between coronavirus disease 2019 (COVID-19) and diabetes complications and mortality, in patients with diabetes. MATERIALS AND METHODS: People with diabetes diagnosed with COVID-19 infection (exposed group), from 16 March 2020 to 31 May 2021 from the UK Biobank (UKB cohort; n = 2456), and from 1 April 2020 to 31 May 2022 from the electronic health records in Hong Kong (HK cohort; n = 80 546), were recruited. Each patient was randomly matched with participants with diabetes but without COVID-19 (unexposed group), based on age and sex (UKB, n = 41 801; HK, n = 391 849). Patients were followed for up to 18 months until 31 August 2021 for UKB, and up to 28 months until 15 August 2022 for HK. Characteristics between cohorts were further adjusted with Inverse Probability Treatment Weighting. Long-term association of COVID-19 with multi-organ disease complications and all-cause mortality after 21 days of diagnosis was evaluated by Cox regression. RESULTS: Compared with uninfected participants, patients with COVID-19 infection with diabetes were consistently associated with higher risks of cardiovascular diseases (coronary heart disease [CHD]: hazard ratio [HR] [UKB]: 1.6 [95% confidence interval {CI}: 1.0, 2.4], HR [HK]: 1.2 [95% CI: 1.0, 1.5]; and stroke: HR [UKB]: 2.0 [95% CI: 1.1, 3.6], HR [HK]: 1.5 [95% CI: 1.3, 1.8]), microvascular disease (end stage renal disease: HR [UKB]: 2.1 [95% CI: 1.1, 4.0], HR [HK]: 1.2 [95% CI: 1.1, 1.4]) and all-cause mortality (HR [UKB]: 4.6 [95% CI: 3.8, 5.5], HR [HK]: 2.6 [95% CI: 2.5, 2.8]), in both cohorts. CONCLUSIONS: COVID-19 infection is associated with long-term increased risks of diabetes complications (especially cardiovascular complications, and mortality) in people with diabetes. Monitoring for signs/symptoms of developing these long-term complications post-COVID-19 infection in the infected patient population of people with diabetes may be beneficial in minimizing their morbidity and mortality

Nrf2 Expression Is Regulated by Epigenetic Mechanisms in Prostate Cancer of TRAMP Mice

Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a transcription factor which regulates the expression of many cytoprotective genes. In the present study, we found that the expression of Nrf2 was suppressed in prostate tumor of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice. Similarly, the expression of Nrf2 and the induction of NQO1 were also substantially suppressed in tumorigenic TRAMP C1 cells but not in non-tumorigenic TRAMP C3 cells. Examination of the promoter region of the mouse Nrf2 gene identified a CpG island, which was methylated at specific CpG sites in prostate TRAMP tumor and in TRAMP C1 cells but not in normal prostate or TRAMP C3 cells, as shown by bisulfite genomic sequencing. Reporter assays indicated that methylation of these CpG sites dramatically inhibited the transcriptional activity of the Nrf2 promoter. Chromatin immunopreceipitation (ChIP) assays revealed increased binding of the methyl-CpG-binding protein 2 (MBD2) and trimethyl-histone H3 (Lys9) proteins to these CpG sites in the TRAMP C1 cells as compared to TRAMP C3 cells. In contrast, the binding of RNA Pol II and acetylated histone H3 to the Nrf2 promoter was decreased. Furthermore, treatment of TRAMP C1 cells with DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5-aza) and histone deacetylase (HDAC) inhibitor trichostatin A (TSA) restored the expression of Nrf2 as well as the induction of NQO1 in TRAMP C1 cells. Taken together, these results indicate that the expression of Nrf2 is suppressed epigenetically by promoter methylation associated with MBD2 and histone modifications in the prostate tumor of TRAMP mice. Our present findings reveal a novel mechanism by which Nrf2 expression is suppressed in TRAMP prostate tumor, shed new light on the role of Nrf2 in carcinogenesis and provide potential new directions for the detection and prevention of prostate cancer

Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases

Automatic Morphological Subtyping Reveals New Roles of Caspases in Mitochondrial Dynamics

Morphological dynamics of mitochondria is associated with key cellular processes related to aging and neuronal degenerative diseases, but the lack of standard quantification of mitochondrial morphology impedes systematic investigation. This paper presents an automated system for the quantification and classification of mitochondrial morphology. We discovered six morphological subtypes of mitochondria for objective quantification of mitochondrial morphology. These six subtypes are small globules, swollen globules, straight tubules, twisted tubules, branched tubules and loops. The subtyping was derived by applying consensus clustering to a huge collection of more than 200 thousand mitochondrial images extracted from 1422 micrographs of Chinese hamster ovary (CHO) cells treated with different drugs, and was validated by evidence of functional similarity reported in the literature. Quantitative statistics of subtype compositions in cells is useful for correlating drug response and mitochondrial dynamics. Combining the quantitative results with our biochemical studies about the effects of squamocin on CHO cells reveals new roles of Caspases in the regulatory mechanisms of mitochondrial dynamics. This system is not only of value to the mitochondrial field, but also applicable to the investigation of other subcellular organelle morphology