A dedicated hypothalamic oxytocin circuit controls aversive social learning.

To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.

Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility.

Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF. These three CFAP47 variants were absent in human control population genome databases and were predicted to be deleterious by multiple bioinformatic tools. CFAP47 encodes a cilia- and flagella-associated protein that is highly expressed in testis. Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47. Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene. All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes. We also generated a Cfap47-mutated mouse model, the adult males of which were sterile and presented with reduced sperm motility and abnormal flagellar morphology and movement. However, fertility could be rescued by the use of intra-cytoplasmic sperm injections (ICSIs). Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested. These findings will provide important guidance for genetic counseling and assisted reproduction treatments.

Effects of carbonization temperature and time on the characteristics of carbonized sludge.

To investigate the influence of carbonization process parameters on the characteristics of municipal sludge carbonization products, this study selected carbonization temperatures of 300-700 °C and carbonization times of 0.5-1.5 h to carbonize municipal sludge. The results showed that with an increase in temperature and carbonization time, the sludge was carbonized more completely, and the structure and performance characteristics of the sludge changed significantly. Organic matter was continuously cracked, the amorphous nature of the material was reduced, its morphology was transformed into an increasing number of regular crystalline structures, and the content of carbon continued to decrease, from the initial 52.85 to 38.77%, while the content of inorganic species consisting continued to increase. The conductivity was reduced by 87.8%, and the degree of conversion of salt ions into their residual and insoluble states was significant. Natural water absorption in the sludge decreased from 8.13 to 1.29%, and hydrophobicity increased. The dry-basis higher calorific value decreased from 8,703 to 3,574 kJ/kg. Heavy metals were concentrated by a factor of 2-3, but the content of the available state was very low. The results of this study provide important technological support for the selection of suitable carbonization process conditions and for resource utilization.

Bioinformatics approach reveals the critical role of the NOD-like receptor signaling pathway in COVID-19-associated multiple sclerosis syndrome.

Multiple sclerosis (MS) is a kind of central nervous system (CNS) autoimmune disease, which mainly damages nerves, the brain, and the spinal cord. Recently, several clinical cases reported the relativity between Coronavirus Disease 2019 (COVID-19) and the development of MS, but the mechanism of how COVID-19 affects the occurrence of MS was still not clear. It is bioinformatics technology that we use to explore the potential association at the gene level. The genetic information related to the two diseases was collected from the DisGNET platform for functional protein network analysis and used STRING to identify the complete gene set. The protein-protein interaction (PPI) network was analyzed by STRING. Finally, in the GEO database, we selected peripheral blood mononuclear cell (PBMC) RNA sequencing data (GSE164805, GSE21942) from COVID-19 patients and MS patients to verify the potential cross mechanism between the two diseases. The similar gene set of immune or inflammation existed between the patients with COVID-19 and ones with MS, including L2RA, IFNG, IL1B, NLRP3, and TNF. Interaction network analysis among proteins revealed that IL1B, P2RX7, IFNB1, IFNB1, TNF, and CASP1 enhanced the network connectivity between the combined gene set of COVID-19 and MS associated with NOD-like receptor (NLR) signaling. The involvement of NLR signaling in both diseases was further confirmed by comparing peripheral blood monocyte samples from COVID-19 and MS patients. Activation of NLR signaling was found in both COVID-19 and MS. The PBMC samples analyses also indicated the involvement of the NLR signaling pathway. Taken together, our data analyses revealed that the NLR signaling pathway might play a critical role in the COVID-19-related MS.

Quantity and variety of fruit and vegetable intake in midlife and cognitive impairment in late life: a prospective cohort study.

There is limited evidence on fruit and vegetable intake in relation to cognitive function. This study aimed to evaluate the associations of quantity and variety in fruit and vegetable intake in midlife with cognitive impairment in late life. We used data from 16 737 participants of the Singapore Chinese Health Study, a population-based cohort study. The participants provided dietary data at recruitment at median age of 52·5 (range: 45-74) years and also participated in the third follow-up interview 20 years later at median age of 72·2 (range: 61-96) years. Quantity and variety of fruits and vegetables consumed at baseline were measured using a validated FFQ. Cognitive impairment at the third follow-up was defined using a Singapore-modified version of Mini-Mental State Examination. About 14·3 % participants had cognitive impairment. In multivariable logistic regression models, comparing extreme quartiles for intake of fruits and vegetables combined, the OR (95 % CI) associated with cognitive impairment was 0·83 (95 % CI: 0·73, 0·95; P-trend = 0·006) for quantity and 0·76 (95 % CI: 0·67, 0·87; P-trend< 0·001) for variety scores. Independently, those with increased variety of fruit intake or higher quantity of vegetable intake also had significantly 22 % and 15 % reduced odds of cognitive impairment, respectively. Finally, compared with those with low intake for both quantity and variety, those with both high quantity and variety for fruits and vegetables had 23 % reduction in odds of cognitive impairment. In conclusion, increase in quantity and variety of fruits and vegetables in midlife may reduce the risk of cognitive impairment in late life.

Dietary total antioxidant capacity and mortality outcomes: the Singapore Chinese Health Study.

PURPOSE: To evaluate the relations of dietary total antioxidant capacity (DTAC) with mortality outcomes in a Chinese population. METHODS: The study included 62,063 participants from the Singapore Chinese Health Study. The participants were 45-74 years at baseline (1993-1998) when dietary data were collected with a validated 165-item food frequency questionnaire. The DTAC was derived using two widely adopted scores of integrated dietary consumption of antioxidant nutrients, i.e., the Comprehensive Dietary Antioxidant Index (CDAI) and Vitamin C Equivalent Antioxidant Capacity (VCEAC). We used Cox proportional hazard model to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations with adjustment for potential confounders. RESULTS: During 1,212,318 person-years of follow-up, 23,397 deaths [cardiovascular diseases (CVD): 7523; respiratory diseases: 4696; and cancer: 7713] occurred. In multivariable models, the HR (95% CI) comparing participants in the highest vs. lowest quartile of CDAI was 0.85 (0.82, 0.88) for all-cause mortality, 0.82 (0.76, 0.88) for CVD mortality, 0.76 (0.70, 0.83) for respiratory disease mortality (all P-trend < 0.001), and 0.94 (0.88, 1.00) for cancer mortality (P-trend = 0.16). Similar associations were found with the VCEAC index. Higher intakes of the DTAC components, i.e., vitamin C, vitamin E, carotenoids, and flavonoids, were all associated with lower mortality risk. CONCLUSION: Diet with a higher antioxidant capacity in midlife was associated with a lower risk of all-cause, cardiovascular and respiratory disease mortality in the Singapore Chinese population, supporting the public health recommendation of consuming more plant-based foods that are rich in antioxidant nutrients.

Association of sugar-sweetened beverage and artificially sweetened beverage intakes with mortality: an analysis of US National Health and Nutrition Examination Survey.

PURPOSE: Current evidence on the associations between sugar-sweetened beverage (SSB) intakes and mortality is inconsistent, whereas the evidence on artificially sweetened beverages (ASBs) was sparse. We aimed to investigate the associations of SSB and ASB intakes with mortality in a nationally representative sample of US adults. METHODS: Participants from the National Health and Nutrition Examination Survey (NHANES, 1999-2014; n = 31,402) were linked to the US mortality registry by the end of 2015. SSB and ASB intakes were collected using 24-h dietary recalls. Cox proportional hazard regression models were used to assess the associations of intakes of SSBs, ASBs, and added sugar from SSBs with mortality with adjustment for demographic, lifestyle, comorbidity, and dietary factors. RESULTS: After a mean follow-up of 7.9 years, 3878 deaths were identified. The multivariate-adjusted hazard ratios (95% confidence intervals) associated with each additional serving/d of SSB were 1.05 (1.01-1.09) for all-cause mortality and 1.11 (1.03-1.21) for heart disease mortality. Hazard ratios (95% confidence intervals) comparing the extreme quintiles of added sugar intakes from SSBs were 1.22 (1.05-1.42) for all-cause mortality and 1.45 (1.06-1.97) for heart disease mortality. No significant relationship was found between SSB intakes and cancer mortality or between high ASB intakes and mortality. Substituting one serving/d of SSB by an equivalent amount of ASBs, unsweetened coffees and teas, and plain water was associated with a 4-7% lower risk of all-cause mortality. CONCLUSION: Higher SSB intakes were associated with higher risks of all-cause mortality and heart disease mortality. High ASB intakes were not significantly associated with mortality. ASBs, unsweetened coffees and teas, and plain water might be optional alternatives for reducing SSB intakes.

Consumption of dietary nuts in midlife and risk of cognitive impairment in late-life: the Singapore Chinese Health Study.

BACKGROUND: evidence from prospective studies investigating the association between consumption of nuts in midlife and risk of cognitive impairment in late life is limited. METHODS: this study analysed data from 16,737 participants in a population-based cohort, the Singapore Chinese Health Study. Intake of nuts was assessed using a validated food-frequency questionnaire at baseline (1993-1998), when participants were 45-74 years old (mean age = 53.5 years). Cognitive function was tested using the Singapore modified Mini-Mental State Examination during the third follow-up visit (2014-2016), when participants were 61-96 years old (mean age = 73.2 years). Cognitive impairment was defined using education-specific cut-off points. Logistic regression models were used to estimate the odds ratio (OR) and the 95% confidence interval (CI) for the association between intake and risk of cognitive impairment. RESULTS: cognitive impairment was identified in 2,397 (14.3%) participants. Compared with those who consumed <1 serving/month of nuts, participants who consumed 1-3 servings/month, 1 serving/week and ≥2 servings/week had 12% (95% CI 2-20%), 19% (95% CI 4-31%) and 21% (2-36%) lower risk of cognitive impairment, respectively (P-trend = 0.01). Further adjustment for intake of unsaturated fatty acids attenuated the association to non-significance. Mediation analysis showed that the 50.8% of the association between nuts and risk of cognitive impairment was mediated by the intake of total unsaturated fatty acids (P < 0.001). CONCLUSION: higher intake of nuts in midlife was related to a lower risk of cognitive impairment in late life, which was partly mediated by unsaturated fatty acids.

A molecularly distinct subset of glioblastoma requires serum-containing media to establish sustainable bona fide glioblastoma stem cell cultures.

Glioblastoma (GBM) is the most frequent and deadly primary malignant brain tumor. Hallmarks are extensive intra-tumor and inter-tumor heterogeneity and highly invasive growth, which provide great challenges for treatment. Efficient therapy is lacking and the majority of patients survive less than 1 year from diagnosis. GBM progression and recurrence is caused by treatment-resistant glioblastoma stem cells (GSCs). GSC cultures are considered important models in target identification and drug screening studies. The current state-of-the-art method, to isolate and maintain GSC cultures that faithfully mimic the primary tumor, is to use serum-free (SF) media conditions developed for neural stem cells (NSCs). Here we have investigated the outcome of explanting 218 consecutively collected GBM patient samples under both SF and standard, serum-containing media conditions. The frequency of maintainable SF cultures (SFCs) was most successful, but for a subgroup of GBM specimens, a viable culture could only be established in serum-containing media, called exclusive serum culture (ESC). ESCs expressed nestin and SOX2, and displayed all functional characteristics of a GSC, that is, extended proliferation, sustained self-renewal and orthotopic tumor initiation. Once adapted to the in vitro milieu they were also sustainable in SF media. Molecular analyses showed that ESCs formed a discrete group that was most related to the mesenchymal GBM subtype. This distinct subgroup of GBM that would have evaded modeling in SF conditions only provide unique cell models of GBM inter-tumor heterogeneity.

FOXA1-induced circOSBPL10 potentiates cervical cancer cell proliferation and migration through miR-1179/UBE2Q1 axis.

BACKGROUND: Recently, extensive evidence has clarified the crucial role of circular RNAs (circRNAs) as a pro-tumor or anti-cancer participant in human malignancies. A new circRNA derived from oxysterol binding protein like 10 (OSBPL10) (circOSBPL10) has not been researched in cervical cancer (CC) yet. METHODS: The expression of molecules was analyzed by RT-qPCR or western blot. Several functional assays were applied to explore the biological influence of circOSBPL10 on CC. The interaction between RNAs was estimated via luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. RESULTS: CircOSBPL10 characterized with cyclic structure was revealed to possess elevated expression in CC cells. CircOSBPL10 downregulation elicited suppressive impacts on CC cell proliferation and migration. Interestingly, circOSBPL10 regulated CC progression by interacting with microRNA-1179 (miR-1179). Moreover, ubiquitin conjugating enzyme E2 Q1 (UBE2Q1) targeted by miR-1179 was positively regulated by circOSBPL10 in CC. Furthermore, enhanced UBE2Q1 expression or suppressed miR-1179 level countervailed the repressive effect of circOSBPL10 depletion on the malignant phenotypes of CC cells. Moreover, forkhead box A1 (FOXA1) was confirmed to induce circOSBPL10 expression in CC cells. CONCLUSIONS: FOXA1-induced circOSBPL10 facilitates CC progression through miR-1179/UBE2Q1 axis, highlighting a strong potential for circOSBPL10 to serve as a promising therapeutic target in CC.

Midlife Dietary Intakes of Monounsaturated Acids, n-6 Polyunsaturated Acids, and Plant-Based Fat Are Inversely Associated with Risk of Cognitive Impairment in Older Singapore Chinese Adults.

BACKGROUND: Previous studies have shown inconsistent results for the relation between dietary fat intake and cognitive function in the elderly. Furthermore, prospective studies on this topic among the Chinese population are scarce. OBJECTIVES: We aimed to examine the association between midlife dietary fat intake and risk of cognitive impairment in the elderly. METHODS: Prospective cohort analysis was conducted among 16,736 participants from the Singapore Chinese Health Study. Dietary information was assessed by a validated FFQ at baseline (1993-1998) when participants aged 45-74 y (mean: 53.5; SD: 6.22). Cognitive impairment was identified using the Singapore modified Mini-Mental State Examination at the third follow-up visit (2014-2016) when participants aged 61-96 y (mean: 73.2; SD: 6.41). Multivariable logistic regression models were used to calculate ORs and 95% CIs. RESULTS: Cognitive impairment was presented in 2397 participants. When substituted for total carbohydrate, dietary fat intake was inversely related to cognitive impairment (OR comparing extreme quartiles: 0.80; 95% CI: 0.67, 0.94; P-trend = 0.003). The OR (95% CI) comparing extreme quartiles of specific dietary fats was 1.08 (0.89, 1.31; P-trend = 0.51) for SFAs, 0.80 (0.64, 0.99; P-trend = 0.02) for MUFAs, 0.84 (0.72, 0.99; P-trend = 0.02) for PUFAs, 0.92 (0.77, 1.09; P-trend = 0.49) for n-3 PUFAs, and 0.83 (0.70, 0.98; P-trend = 0.01) for n-6 PUFAs. An inverse association was found for plant-based fat (OR: 0.84; 95% CI: 0.72, 0.98; P-trend = 0.02), but not for animal-based fat (OR: 0.96; 95% CI: 0.81, 1.15; P-trend = 0.76). When substituted for SFAs, the OR (95% CI) was 0.77 (0.61, 0.97; P-trend = 0.02) for MUFAs and 0.82 (0.70, 0.95; P-trend = 0.003) for PUFAs. CONCLUSIONS: We found that substitution of total carbohydrate or SFAs with MUFAs and PUFAs, particularly n-6 PUFAs, was related to a lower risk of cognitive impairment in elderly Chinese participants. In addition, an inverse association with cognitive impairment was found for plant-based fat.

LGR5 promotes tumorigenicity and invasion of glioblastoma stem-like cells and is a potential therapeutic target for a subset of glioblastoma patients.

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient-derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5high ), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5-responding cultures could be identified by their significantly higher self-renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5high -ELDAhigh cultures were also significantly more malignant and invasive compared to the LGR5high -ELDAlow cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5-responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient-derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Meat consumption in midlife and risk of cognitive impairment in old age: the Singapore Chinese Health Study.

PURPOSE: Epidemiological studies directly investigating the association between different types of meat intake and cognitive impairment are limited. We, therefore, examined this association in the Singapore Chinese Health Study. METHODS: In total, 16,948 participants were included in analysis. Diet was measured by a 165-item semiquantitative food-frequency questionnaire at baseline (1993-1998) when participants were 45-74 years. Cognitive impairment was defined using a Singapore modified version of Mini-Mental State Examination during follow-up three visits (2014-2016) when participants were 61-96 years. Multivariable logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI). RESULTS: Cognitive impairment was present in 2443 (14.4%) participants. Compared to the lowest quartile, the highest quartile of red meat intake was associated with increased risk of cognitive impairment (OR 1.16, 95% CI 1.01-1.32, P for trend = 0.009), while the corresponding value for poultry intake was 0.89 (95% CI 0.78-1.02, P for trend = 0.10). Higher fresh fish/shellfish was associated with a lower risk of cognitive impairment (OR 0.88, 95% CI 0.77-1.00, P for trend = 0.03), while preserved fish/shellfish intake was associated with a higher risk (OR 1.19, 95% CI 1.04-1.36, P for trend = 0.01). CONCLUSION: This study found that a higher intake of red meat in midlife was associated with increased likelihood of cognitive impairment in later life, while substitution of red meat intake with poultry or fresh fish/shellfish was associated with reduced risk.

Product Selectivity Controlled by Nanoporous Environments in Zeolite Crystals Enveloping Rhodium Nanoparticle Catalysts for CO2 Hydrogenation.

Supported rhodium nanoparticles (NPs) are well-known for catalyzing methanation in CO2 hydrogenation. Now we demonstrate that the selectivity in this process can be optimized for CO production by choice of molecular sieve crystals as supports. The NPs are enveloped within the crystals with controlled nanopore environments that allow tuning of the catalytic selectivity to minimize methanation and favor the reverse water-gas shift reaction. Pure silica MFI (S-1)-fixed rhodium NPs exhibited maximized CO selectivity at high CO2 conversions, whereas aluminosilicate MFI zeolite-supported rhodium NPs displayed high methane selectivity under the equivalent conditions. Strong correlations were observed between the nanoporous environment and catalytic selectivity, indicating that S-1 minimizes hydrogen spillover and favors fast desorption of CO to limit deep hydrogenation. Materials in this class appear to offer appealing opportunities for tailoring selective supported catalysts for a variety of reactions.

Chrysin inhibit human melanoma A375.S2 cell migration and invasion via affecting MAPK signaling and NF-κB signaling pathway in vitro.

Numerous evidences have shown that chrysin induced cytotoxic effects via induced cell cycle arrest and induction of cell apoptosis in human cancer cell lines, however, no information showed that chrysin inhibited skin cancer cell migration and invasion. In this study, we investigated anti-metastasis mechanisms of chrysin in human melanoma cancer A375.S2 cells in vitro. Under sub-lethal concentrations of chrysin (0, 5, 10, and 15 µM) which inhibits cell mobility, migration and invasion of A375.S2 cells that were assayed by wound healing and Transwell filter. That chrysin inhibited MMP-2 activity in A375.S2 cells was investigated by gelatin zymography assay. Western blotting was used to examine protein expression and results indicated that chrysin inhibited the expression of GRB2, SOS-1, PKC, p-AKT (Thr308), NF-κBp65, and NF-κBp50 at 24 and 48 hours treatment, but only at 10-15 µM of chrysin decreased Ras, PI3K, p-c-Jun, and Snail only at 48 hours treatment and only decrease p-AKT(Ser473) at 24 hours treatment. Furthermore, chrysin (5-15 µM) decreased the expression of uPA, N-cadherin and MMP-1 at 24 and 48 hours treatment but only decreased MMP-2 and VEGF at 48 hours treatment at 10-15 µM and 5-15 µM of chrysin, respectively, however, increased E-cadherin at 5-15 µM treatment. Results of confocal laser microscopy systems indicated that chrysin inhibited expression of NF-κBp65 in A375.S2 cells. Based on these observations, we suggest that chrysin can be used in anti-metastasis of human melanoma cells in the future.

Tetrandrine inhibits human brain glioblastoma multiforme GBM 8401 cancer cell migration and invasion in vitro.

Tetrandrine (TET) has been reported to induce anti-cancer activity in many human cancer cells and also to inhibit cancer cell migration and invasion. However, there are no reports to show TET inhibits cell migration and invasion in human brain glioblastoma multiforme GBM 8401 cells. In this study, we investigated the anti-metastasis effects of TET on GBM 8401 cells in vitro. Under sub-lethal concentrations (from 1, 5 up to 10 µM), TET significantly inhibited cell mobility, migration and invasion of GBM 8401 cells that were assayed by wound healing and Transwell assays. Gelatin zymography assay showed that TET inhibited MMP-2 activity in GBM 8401 cells. Western blotting results indicated that TET inhibited several key metastasis-related proteins, such as p-EGFR(Tyr1068) , SOS-1, GRB2, Ras, p-AKT(Ser473) and p-AKT(Thr308) , NF-κB-p65, Snail, E-cadherin, N-cadherin, NF-κB, MMP-2 and MMP-9 that were significant reduction at 24 and 48 hours treatment by TET. TET reduced MAPK signaling associated proteins such as p-JNK1/2 and p-c-Jun in GBM 8401 cells. The electrophoretic mobility shift (EMSA) assay was used to investigate NF-κB and DNA binding was reduced by TET in a dose-dependently. Based on these findings, we suggested that TET could be used in anti-metastasis of human brain glioblastoma multiforme GBM 8401 cells in the future.

Oncogenic signaling is dominant to cell of origin and dictates astrocytic or oligodendroglial tumor development from oligodendrocyte precursor cells.

Stem cells, believed to be the cellular origin of glioma, are able to generate gliomas, according to experimental studies. Here we investigated the potential and circumstances of more differentiated cells to generate glioma development. We and others have shown that oligodendrocyte precursor cells (OPCs) can also be the cell of origin for experimental oligodendroglial tumors. However, the question of whether OPCs have the capacity to initiate astrocytic gliomas remains unanswered. Astrocytic and oligodendroglial tumors represent the two most common groups of glioma and have been considered as distinct disease groups with putatively different origins. Here we show that mouse OPCs can give rise to both types of glioma given the right circumstances. We analyzed tumors induced by K-RAS and AKT and compared them to oligodendroglial platelet-derived growth factor B-induced tumors in Ctv-a mice with targeted deletions of Cdkn2a (p16(Ink4a-/-), p19(Arf-/-), Cdkn2a(-/-)). Our results showed that glioma can originate from OPCs through overexpression of K-RAS and AKT when combined with p19(Arf) loss, and these tumors displayed an astrocytic histology and high expression of astrocytic markers. We argue that OPCs have the potential to develop both astrocytic and oligodendroglial tumors given loss of p19(Arf), and that oncogenic signaling is dominant to cell of origin in determining glioma phenotype. Our mouse data are supported by the fact that human astrocytoma and oligodendroglioma display a high degree of overlap in global gene expression with no clear distinctions between the two diagnoses.

Development of a Nomogram Model to Predict the Risk of Stricture Recurrence after Urethroplasty: A Retrospective Study.

OBJECTIVE: A retrospective study was performed to analyse the influencing factors of stricture recurrence after urethroplasty and to establish a predictive nomogram model. METHODS: The clinical data of patients who underwent urethroplasty in our hospital from January 2021 to June 2023 were retrospectively analysed. Depending on whether stenosis occurs six months after surgery, the patients were divided into recurrence and nonrecurrence groups. Logistic regression analysis was performed on the indicators with statistically significant differences between the two groups in single factor analysis to analyse the influencing factors of postoperative recurrence risk of stricture. X64.4.1.3 version R language and external source packages were used to build the nomogram model. The nomogram was internally validated through 10-fold cross-validation, and C-index was calculated. The area under the curve (AUC) of the receiver operating characteristic curve was employed to evaluate the results of the internal validation. RESULTS: Amongst 105 patients who underwent urethroplasty in our hospital, 15 patients with recurrence were included in the recurrence group, and 90 patients without recurrence were included in the nonrecurrence group. The length of stricture segment, history of urethroplasty and smoking history within 3 months before surgery were risk factors for stricture recurrence, with odds ratio (OR) values of 1.874 (95% CI: 1.103-5.725), 1.670 (95% CI: 1.105-2.904) and 1.740 (95% CI: 1.456-5.785), respectively. The constructed nomogram obtained an average AUC of 0.842 and an average C-index of 0.794, calculated after 200 times of 10-fold cross-validation. CONCLUSIONS: From the data of this study, it can be deduced that the influencing factors of stricture recurrence after urethroplasty include the length of stricture segment, history of urethroplasty and smoking history of 3 months before surgery. Using the above factors as a basis to construct a predictive nomogram model is helpful to screen high-risk patients with recurrence of stricture after urethroplasty.

Beneficial impact of visual stimulation-based digital therapeutics on blood pressure control in non-hypertensive individuals.

Hypertension-related diseases occur in both hypertensive and non-hypertensive individuals. However, few studies to date have explored blood pressure (BP) control in non-hypertensive individuals. This before-after study aimed to examine the impact of visual stimulation-based digital therapeutics (VS-DTx) on BP and heart rate (HR). Eighty-three eligible non-hypertensive participants were included in this study. The McNemar test and Paired Samples Wilcoxon Signed Rank Test were employed to assess decline rates and differences in BP and HR between the control phase and the intervention (using VS-DTx) phase. Pairwise correlation analysis was used to analyze the correlation between the two phases. This study found the systolic BP (SBP) and mean arterial pressure (MAP) in the VS-DTx phase showed a downward trend (66.2% vs 49.3%; 68.7% vs 55.4%). The mean SBP decreased from 114.73 mm Hg to 111.18 mm Hg, and the mean MAP decreased from 87.96 mm Hg to 84.88 mm Hg in the VS-DTx phase. Paired Samples Wilcoxon Test showed differences in both ΔSBP (Z = -3.296; P < 0.01) and ΔMAP (Z = -2.386; P < 0.05) (Δ is defined as the difference between baseline and post-stimulus). The pairwise correlations analysis revealed that VS-DTx affected the MAP reduction (r = 0.33; P < 0.01) between the browsing digital devices phase and the VS-DTx phase. The results indicated that VS-DTx may have a certain effect on BP, including SBP and MAP. This study preliminarily explored the possible effects of VS-DTx on BP, providing certain useful insights for future research in digital BP management.

Life satisfaction components and all-cause and cause-specific mortality: A large prospective cohort study.

BACKGROUND: Which life satisfaction components could be a target of positive psychological interventions for longevity is largely unknown. We aimed to investigate association of the composite measure of life satisfaction and its individual components with mortality. METHODS: This cohort study included UK Biobank participants who responded to questions concerning five components of life satisfaction at baseline. We generated a composite score representing overall life satisfaction, ranging from 0 (lowest) to 5 (highest). The outcomes were all-cause and cause-specific mortality. We used multivariable Cox regression to estimate hazard ratios (HR) for the associations of interest. RESULTS: Among 165,842 eligible participants, 12,261 all-cause deaths were observed over a median of 12.9-year follow-up. Overall life satisfaction was inversely associated with all-cause mortality (adjusted HR 0.94 [95% CI: 0.93-0.95] per 1 score increment). Health satisfaction showed the strongest association with all-cause mortality, with a fully adjusted HR of 0.52 (95% CI: 0.49-0.55) for high/extreme satisfaction and 0.63 (95% CI: 0.59-0.66) for moderate satisfaction, compared with unsatisfaction (P-trend<0.001), independent of other satisfaction components, regardless of physical health and sociodemographics. The association for family, friendship, work and financial satisfaction was attenuated when adjusted for other life satisfaction components. Similar findings were observed for cause-specific mortality. LIMITATIONS: Observational study with single baseline measurement of life satisfaction precludes the ability to establish causal relationship. CONCLUSIONS: Higher overall life satisfaction was associated with lower mortality. As the major contributor to lower mortality regardless of physical health and sociodemographics, health satisfaction could be an important target of positive psychological interventions for longevity.