Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice.

The pathophysiology of autism spectrum disorders (ASDs) is causally linked to postsynaptic scaffolding proteins, as evidenced by numerous large-scale genomic studies [1, 2] and in vitro and in vivo neurobiological studies of mutations in animal models [3, 4]. However, due to the distinct phenotypic and genetic heterogeneity observed in ASD patients, individual mutation genes account for only a small proportion (<2%) of cases [1, 5]. Recently, a human genetic study revealed a correlation between de novo variants in FERM domain-containing-5 (FRMD5) and neurodevelopmental abnormalities [6]. In this study, we demonstrate that deficiency of the scaffolding protein FRMD5 leads to neurodevelopmental dysfunction and ASD-like behavior in mice. FRMD5 deficiency results in morphological abnormalities in neurons and synaptic dysfunction in mice. Frmd5-deficient mice display learning and memory dysfunction, impaired social function, and increased repetitive stereotyped behavior. Mechanistically, tandem mass tag (TMT)-labeled quantitative proteomics revealed that FRMD5 deletion affects the distribution of synaptic proteins involved in the pathological process of ASD. Collectively, our findings delineate the critical role of FRMD5 in neurodevelopment and ASD pathophysiology, suggesting potential therapeutic implications for the treatment of ASD.

Extending the CWM approach to intraspecific trait variation: how to deal with overly optimistic standard tests?

Community weighted means (CWMs) are widely used to study the relationship between community-level functional traits and environment. For certain null hypotheses, CWM-environment relationships assessed by linear regression or ANOVA and tested by standard parametric tests are prone to inflated Type I error rates. Previous research has found that this problem can be solved by permutation tests (i.e., the max test). A recent extension of the CWM approach allows the inclusion of intraspecific trait variation (ITV) by the separate calculation of fixed, site-specific, and intraspecific CWMs. The question is whether the same Type I error rate inflation exists for the relationship between environment and site-specific or intraspecific CWM. Using simulated and real-world community datasets, we show that site-specific CWM-environment relationships have also inflated Type I error rate, and this rate is negatively related to the relative ITV magnitude. In contrast, for intraspecific CWM-environment relationships, standard parametric tests have the correct Type I error rate, although somewhat reduced statistical power. We introduce an ITV-extended version of the max test, which can solve the inflation problem for site-specific CWM-environment relationships and, without considering ITV, becomes equivalent to the "original" max test used for the CWM approach. We show that this new ITV-extended max test works well across the full possible magnitude of ITV on both simulated and real-world data. Most real datasets probably do not have intraspecific trait variation large enough to alleviate the problem of inflated Type I error rate, and published studies possibly report overly optimistic significance results.

The impact of vedolizumab therapy on extraintestinal manifestations in patients with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Extraintestinal manifestations (EIMs) pose a significant threat in inflammatory bowel disease (IBD) patients. Vedolizumab (VDZ) primarily affects the gastrointestinal tract. However, its impact on EIMs remains uncertain. Therefore, we conducted this meta-analysis to examine the effects of VDZ on EIMs during treatment. METHODS: Relevant studies were identified by conducting thorough searches across electronic databases, including PubMed, Ovid Embase, Medline, and Cochrane CENTRAL. Primary outcomes focused on the proportion of patients with resolution for pre-existing EIMs in IBD patients receiving VDZ. Secondary outcomes included the proportion of patients with EIM exacerbations and new onset EIMs during VDZ treatment. RESULTS: Our meta-analysis encompassed 21 studies. The proportion of patients with resolution of pre-existing EIMs in VDZ-treated IBD patients was 39% (150/386; 95% confidence interval [CI] 0.31-0.48). The proportion of patients with EIM exacerbations occurred at a rate of 28% (113/376; 95% CI 0.05-0.50), while new onset EIMs had a rate of 15% (397/2541; 95% CI 0.10-0.20). Subgroup analysis revealed a 40% (136/337) proportion of patients with resolution for articular-related EIMs and a 50% (9/18) rate for erythema nodosum. Exacerbation rates for arthritis/arthralgia, erythema nodosum/pyoderma gangrenosum, and aphthous stomatitis during VDZ use were 28% (102/328), 18% (7/38), and 11% (3/28), respectively. The incidence rate of newly developed EIMs during treatment was 11% (564/4839) for articular-related EIMs, with other EIMs below 2%. CONCLUSION: VDZ demonstrates efficacy in skin-related EIMs like erythema nodosum and joint-related EIMs including arthritis, arthralgia, spondyloarthritis, and peripheral joint diseases. Some joint and skin-related EIMs may experience exacerbation during VDZ therapy.

Unveiling adcyap1 as a protective factor linking pain and nerve regeneration through single-cell RNA sequencing of rat dorsal root ganglion neurons.

BACKGROUND: Severe peripheral nerve injury (PNI) often leads to significant movement disorders and intractable pain. Therefore, promoting nerve regeneration while avoiding neuropathic pain is crucial for the clinical treatment of PNI patients. However, established animal models for peripheral neuropathy fail to accurately recapitulate the clinical features of PNI. Additionally, researchers usually investigate neuropathic pain and axonal regeneration separately, leaving the intrinsic relationship between the development of neuropathic pain and nerve regeneration after PNI unclear. To explore the underlying connections between pain and regeneration after PNI and provide potential molecular targets, we performed single-cell RNA sequencing and functional verification in an established rat model, allowing simultaneous study of the neuropathic pain and axonal regeneration after PNI. RESULTS: First, a novel rat model named spared nerve crush (SNC) was created. In this model, two branches of the sciatic nerve were crushed, but the epineurium remained unsevered. This model successfully recapitulated both neuropathic pain and axonal regeneration after PNI, allowing for the study of the intrinsic link between these two crucial biological processes. Dorsal root ganglions (DRGs) from SNC and naïve rats at various time points after SNC were collected for single-cell RNA sequencing (scRNA-seq). After matching all scRNA-seq data to the 7 known DRG types, we discovered that the PEP1 and PEP3 DRG neuron subtypes increased in crushed and uncrushed DRG separately after SNC. Using experimental design scRNA-seq processing (EDSSP), we identified Adcyap1 as a potential gene contributing to both pain and nerve regeneration. Indeed, repeated intrathecal administration of PACAP38 mitigated pain and facilitated axonal regeneration, while Adcyap1 siRNA or PACAP6-38, an antagonist of PAC1R (a receptor of PACAP38) led to both mechanical hyperalgesia and delayed DRG axon regeneration in SNC rats. Moreover, these effects can be reversed by repeated intrathecal administration of PACAP38 in the acute phase but not the late phase after PNI, resulting in alleviated pain and promoted axonal regeneration. CONCLUSIONS: Our study reveals that Adcyap1 is an intrinsic protective factor linking neuropathic pain and axonal regeneration following PNI. This finding provides new potential targets and strategies for early therapeutic intervention of PNI.

Physiological, Metabolome and Gene Expression Analyses Reveal the Accumulation and Biosynthesis Pathways of Soluble Sugars and Amino Acids in Sweet Sorghum under Osmotic Stresses.

Water scarcity is a major environmental constraint on plant growth in arid regions. Soluble sugars and amino acids are essential osmolytes for plants to cope with osmotic stresses. Sweet sorghum is an important bioenergy crop and forage with strong adaptabilities to adverse environments; however, the accumulation pattern and biosynthesis basis of soluble sugars and amino acids in this species under osmotic stresses remain elusive. Here, we investigated the physiological responses of a sweet sorghum cultivar to PEG-induced osmotic stresses, analyzed differentially accumulated soluble sugars and amino acids after 20% PEG treatment using metabolome profiling, and identified key genes involved in the biosynthesis pathways of soluble sugars and amino acids using transcriptome sequencing. The results showed that the growth and photosynthesis of sweet sorghum seedlings were significantly inhibited by more than 20% PEG. After PEG treatments, the leaf osmotic adjustment ability was strengthened, while the contents of major inorganic osmolytes, including K+ and NO3-, remained stable. After 20% PEG treatment, a total of 119 and 188 differentially accumulated metabolites were identified in the stems and leaves, respectively, and the accumulations of soluble sugars such as raffinose, trehalose, glucose, sucrose, and melibiose, as well as amino acids such as proline, leucine, valine, serine, and arginine were significantly increased, suggesting that these metabolites should play key roles in osmotic adjustment of sweet sorghum. The transcriptome sequencing identified 1711 and 4978 DEGs in the stems, as well as 2061 and 6596 DEGs in the leaves after 20% PEG treatment for 6 and 48 h, respectively, among which the expressions of genes involved in biosynthesis pathways of sucrose (such as SUS1, SUS2, etc.), trehalose (including TPS6), raffinose (such as RAFS2 and GOLS2, etc.), proline (such as P5CS2 and P5CR), leucine and valine (including BCAT2), and arginine (such as ASS and ASL) were significantly upregulated. These genes should be responsible for the large accumulation of soluble sugars and amino acids under osmotic stresses. This study deepens our understanding of the important roles of individual soluble sugars and amino acids in the adaptation of sweet sorghum to water scarcity.

Development and validation of a nomogram to predict non-response to 5-aminosalicylic acid in patients with ulcerative colitis.

BACKGROUND: there are some patients with ulcerative colitis (UC) who have non-response (NR) to 5-aminosalicylic acid (5-ASA). To promote individualized treatment in UC patients, it is crucial to identify valid predictors to estimate NR to 5-ASA. Therefore, this study aimed to identify the predictive value of clinical and biochemical markers and to construct a nomogram model predicting NR to 5-ASA in patients with UC. METHODS: data of patients diagnosed with UC in the First Hospital of China Medical University between January 2012 and December 2020 were retrospectively analyzed. Primary outcome was the proportion of NR to 5-ASA. Multivariable logistic regression was used to construct prediction models. Area under the curve (AUC), calibration and decision curve analyses (DCA) were assessed in the validation cohort. RESULTS: of 284 UC patients who were treatment-naive, 86 (30.3 %) had NR to 5-ASA. Univariate regression analysis showed that disease classification (DC) (p = 0.008), monocytes (MONO) (p = 0.041), platelet distribution width (PDW) (p = 0.027), serum total cholesterol (TC) (p = 0.031) and α1 globulin (p < 0.001) were strongly associated with NR to 5-ASA. Receiver operating characteristics (ROC) analysis indicated the AUC was 0.852, it showed that this model has a good degree of discrimination. The DCA curve showed that the predicted probability is 0.0-96.0 %. CONCLUSION: this study developed a predictive model with good discrimination and calibration, and high clinical validity, which can effectively estimate the risk of NR to 5-ASA. DC, MONO, PDW, TC and α1 globulin can be used as predictors for NR to 5-ASA in UC patients.

Excellent Switchable Properties, Broad-Band Emission, Ferroelectricity, and High Tc in a Two-Dimensional Hybrid Perovskite: (4,4-DCA)2PbBr4 Exploited by H/F Substitution.

Switchable materials have gained significant attention due to their potential applications in data storage, sensors, and switching devices. Two-dimensional (2D) hybrid perovskites have demonstrated promising prospects for designing switchable materials, where the dynamic motion of the organic components coupled with the distortion of the inorganic framework provides the driving force for triggering multifunctional switchable properties. Herein, through the H/F substitution strategy, we report a polar 2D hybrid lead-based perovskite, (4,4-DCA)2PbBr4 (4,4-DCA = 4,4-difluorocyclohexylammonium) (1), which exhibits dual-stable behavior in a dielectric and second harmonic generation (SHG) response during the reversible phase transition process near the high Curie temperature Tc ∼ 409 K. The phase transition temperature is significantly increased by 41 K compared to the corresponding non-fluorinated (CHA)2PbBr4 (CHA = cyclohexylammonium). Remarkably, the material shows rare broad-band yellow emission under UV excitation, attributed to the induction of self-trapped exciton emission by the distortion of the [PbBr6]4- octahedra, as confirmed by the first-principles analysis. 1 also exhibited ferroelectricity with a saturation polarization value and a small coercive field. This study provides a new insight into the modification of multifunctional switchable materials through the H/F substitution strategy.

Design, Synthesis and Antitumor Activity of FAK/PLK1 Dual Inhibitors with Quinazolinone as the Skeleton.

Febrifugine is a kind of quinazolinone compound with high biological activity from a Chinese herb called Chang Shan (Dichroa febrifuga). Febrifugine and its derivatives possess extensive biological activities, some of which exhibited anti-tumor activities as FAK inhibitors. However, they are not very effective at inhibiting tumor metastasis, perhaps because tumors gain energy through compensatory activation of other signaling pathways that promote cell migration and invasion. Therefore, seventeen novel febrifugine derivatives with quinazolinone skeleton were designed, synthesized and acted as potential FAK/PLK1 dual inhibitors. These compounds were determined by 1 H-NMR, 13 C-NMR and MS. Most of the compounds exhibited good inhibitory activity against cancer cell lines by computer-assisted screening, antitumor activity test and FAK/PLK1 inhibitory activity test, wherein compound 3b was screened as a high-efficiency lead compound.

Detection of Antibiotic Resistance in Feline-Origin ESBL Escherichia coli from Different Areas of China and the Resistance Elimination of Garlic Oil to Cefquinome on ESBL E. coli.

The development of drug-resistance in the opportunistic pathogen Escherichia coli has become a global public health concern. Due to the share of similar flora between pets and their owners, the detection of pet-origin antibiotic-resistant E. coli is necessary. This study aimed to detect the prevalence of feline-origin ESBL E. coli in China and to explore the resistance elimination effect of garlic oil to cefquinome on ESBL E. coli. Cat fecal samples were collected from animal hospitals. The E. coli isolates were separated and purified by indicator media and polymerase chain reaction (PCR). ESBL genes were detected by PCR and Sanger sequencing. The MICs were determined. The synergistic effect of garlic oil and cefquinome against ESBL E. coli was investigated by checkerboard assays, time-kill and growth curves, drug-resistance curves, PI and NPN staining, and a scanning electronic microscope. A total of 80 E. coli strains were isolated from 101 fecal samples. The rate of ESBL E. coli was 52.5% (42/80). The prevailing ESBL genotypes in China were CTX-M-1, CTX-M-14, and TEM-116. In ESBL E. coli, garlic oil increased the susceptibility to cefquinome with FICIs from 0.2 to 0.7 and enhanced the killing effect of cefquinome with membrane destruction. Resistance to cefquinome decreased with treatment of garlic oil after 15 generations. Our study indicates that ESBL E. coli has been detected in cats kept as pets. The sensitivity of ESBL E. coli to cefquinome was enhanced by garlic oil, indicating that garlic oil may be a potential antibiotic enhancer.

Impact of SARS-CoV-2 vaccination in inflammatory bowel disease patients with different biological agents: a systematic review and meta-analysis.

BACKGROUND: There are concerns regarding the effect of biological agents on SARS-CoV-2 vaccination in patients with inflammatory bowel disease (IBD). A systematic review and meta-analysis was performed about the serological responses, breakthrough infections and clinical relapse of IBD patients treated with biological agents following SARS-CoV-2 vaccination. METHODS: Electronic databases were searched to identify relevant studies. Primary outcomes were the pooled seroconversion rates, breakthrough infection rates and clinical relapse rates after SARS-CoV-2 vaccination in IBD patients treated with biological agents. Secondary outcomes were the comparison of seroconversion rates, breakthrough infection rates and clinical relapse rates in IBD patients treated with biological agents and control cohort after SARS-CoV-2 vaccination. RESULTS: Thirty-five studies were included in this meta-analysis. A high percentage of seroconversion (96.6%, 99% and 99.2%) was achieved in IBD patients treated with anti-TNF-α therapy, vedolizumab and ustekinumab after SARS-CoV-2 vaccination, respectively. The pooled breakthrough infection rate was 2.5% and 3.9% in IBD patients treated with anti-TNF-α therapy and vedolizumab, respectively. The breakthrough infection rate in IBD patients treated with anti-TNF-α therapy was significantly lower than control cohort (RR 0.178, 95% CI 0.084-0.378). The pooled clinical relapse rate in IBD patients treated with anti-TNF-α therapy, vedolizumab and ustekinumab was 6.9%, 5.4% and 5.3%, respectively. CONCLUSION: The overall seroconversion rate after SARS-CoV-2 vaccination in IBD patients treated with biological agents is high. The overall breakthrough infection rate and clinical relapse rate in IBD patients treated with biological agents were low.

Long-term clinical outcomes after the discontinuation of anti-TNF agents in patients with inflammatory bowel disease: a meta-analysis.

BACKGROUND: there are concerns regarding the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). A systematic review and meta-analysis were performed to evaluate the risk of relapse after discontinuation of anti-TNF agent in patients, and the response to retreatment with the same anti-TNF agent. METHODS: electronic databases were searched to identify relevant studies. Primary outcomes were the pooled percentage of relapses after the withdrawal of anti-TNF agents. Secondary outcomes were the pooled percentage of the response to retreatment with the same anti-TNF agent after relapse. RESULTS: thirty-seven studies were included in this meta-analysis. The overall risk of relapse after discontinuation of anti-TNF agent was 43 % for ulcerative colitis (UC) and 43 % for Crohn's disease (CD). In UC, the relapse rate was 37 % at 1-2 year, and 58 % at 3-5 years. In CD, the relapse rate was 38 % at 1-2 year, 53 % at 3-5 years, and 49 % at more than five years. When clinical remission was the only criterion for stopping anti-TNF agent, the relapse rate was 42 % in UC and 45 % in CD, which decreased to 40 % in UC and 36 % in CD when clinical remission and endoscopic healing were required. Retreatment with the same anti-TNF agent induced remission again in 78 % of UC patients and 76 % of CD patients. CONCLUSION: our meta-analysis showed that a high proportion of IBD patients will relapse after discontinuation of anti-TNF agent. The response to retreatment with the same anti-TNF agent is generally favorable in patients who relapse.

Reply: SARS-CoV-2 vaccination in inflammatory bowel disease patients with different biological agents.

We thank Dr Mungmunpuntipantip and colleague for their interest and thoughtful comments on our publication. The authors have highlighted several important considerations for the impact of SARS-CoV-2 vaccination in inflammatory bowel disease (IBD) patients with different biological agents. We fully agree with the author's point of view, and we also point out the limitations in our meta-analysis.

[Comparison of Disease Burden Factors of Thyroid Cancer Between China and the World From 1990 to 2019].

Objective To compare the prevalence and disease burden of thyroid cancer and their trends between China and the globe from 1990 to 2019.Methods With the global disease burden data in 2019,Joinpoint was used to predict the trends of the disease burden of thyroid cancer in China and the globe from 1990 to 2019,and logarithmic linear model was used to test the predicted trends.The R language was used for predictive analysis and graphic plotting of the disease burden from 2020 to 2035.Results From 1990 to 2019,the standardized incidence rate and the standardized mortality rate of thyroid cancer in China were lower than those in the globe.The standardized incidence rate in China and the globe showed an increasing trend(with the increases of 102.65% and 40.65%,respectively),while the standardized mortality rate showed a decreasing trend(with the decreases of 7.63% and 4.91%,respectively).Compared with those of the female population,the standardized incidence and mortality rates of the Chinese male population increased significantly from 1990 to 2019(the rates of change in the male population were 48.65% and 214.60%,respectively;and the rates of change in the female population were -39.01% and 60.44%,respectively).China's overall standardized years of life lost(YLL),years lived with disability(YLD),and disability-adjusted life years(DALY)rates during the 30-year period were lower than the global average.The Chinese and global populations showed the standardized YLL rate decreasing by 16.61% and 6.88% and the standardized DALY rate decreasing by 10.77% and 3.65%,respectively,while the rates of standardized YLD increased by 128.91% and 46.89%,respectively.The magnitude of DALY in China and the world was mainly influenced by YLL.The standardized incidence,mortality,and DALY rates of the Chinese male population were gradually approaching the global levels.From 1990 and 2019,thyroid cancer showed a higher mortality rate in the population with the age ≥ 75 years and a higher incidence rate in the population with the age <75 years.It is projected that from 2020 to 2035,the standardized incidence rates in China and the world will increase by 36.66% and 21.15%,respectively;the standardized mortality rates will decrease by 20.19% and 3.46%,respectively;and the standardized DALY rate is expected to decrease by 7.08% in China and increase by 4.35% in the world.Conclusions From 1990 to 2019,China's standardized incidence rate of thyroid cancer increased and had a higher increase than the global level,and the standardized mortality rate decreased,with a slightly higher decrease than the global level.However,the increases in the standardized incidence rate and mortality rate of this disease in China's ≥75 years male population were severe.Although China's disease burden of thyroid cancer showed a decreasing trend in line with the global trend as a whole,the disease burden in the Chinese males was higher than that in the females.Specifically,the disease burden due to premature death was predominant,and the burden in specific populations requires policy attention.

C1632 suppresses the migration and proliferation of non-small-cell lung cancer cells involving LIN28 and FGFR1 pathway.

Chemoresistance and migration represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients in clinic. In the present study, we report that the compound C1632 is preferentially distributed in the lung after oral administration in vivo with high bioavailability and limited inhibitory effects on CYP450 isoenzymes. We found that C1632 could simultaneously inhibit the expression of LIN28 and block FGFR1 signalling transduction in NSCLC A549 and A549R cells, resulting in significant decreases in the phosphorylation of focal adhesion kinase and the expression of matrix metalloproteinase-9. Consequently, C1632 effectively inhibited the migration and invasion of A549 and A549R cells. Meanwhile, C1632 significantly suppressed the cell viability and the colony formation of A549 and A549R cells by inhibiting DNA replication and inducing G0/G1 cell cycle arrest. Interestingly, compared with A549 cells, C1632 possesses the same or even better anti-migration and anti-proliferation effects on A549R cells, regardless of drug resistance. In addition, C1632 also displayed the capacity to inhibit the growth of A549R xenograft tumours in mice. Altogether, these findings reveal the potential of C1632 as a promising anti-NSCLC agent, especially for chemotherapy-resistant NSCLC treatment.

Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice.

Canagliflozin is an antidiabetic medicine that inhibits sodium-glucose cotransporter 2 (SGLT2) in proximal tubules. Recently, it was reported to have several noncanonical effects other than SGLT2 inhibiting. However, the effects of canagliflozin on skeletal muscle regeneration remain largely unexplored. Thus, in vivo muscle contractile properties recovery in mice ischemic lower limbs following gliflozins treatment was evaluated. The C2C12 myoblast differentiation after gliflozins treatment was also assessed in vitro. As a result, both in vivo and in vitro data indicate that canagliflozin impairs intrinsic myogenic regeneration, thus hindering ischemic limb muscle contractile properties, fatigue resistance recovery, and tissue regeneration. Mitochondrial structure and activity are both disrupted by canagliflozin in myoblasts. Single-cell RNA sequencing of ischemic tibialis anterior reveals a decrease in leucyl-tRNA synthetase 2 (LARS2) in muscle stem cells attributable to canagliflozin. Further investigation explicates the noncanonical function of LARS2, which plays pivotal roles in regulating myoblast differentiation and muscle regeneration by affecting mitochondrial structure and activity. Enhanced expression of LARS2 restores the differentiation of canagliflozin-treated myoblasts, and accelerates ischemic skeletal muscle regeneration in canagliflozin-treated mice. Our data suggest that canagliflozin directly impairs ischemic skeletal muscle recovery in mice by downregulating LARS2 expression in muscle stem cells, and that LARS2 may be a promising therapeutic target for injured skeletal muscle regeneration.

Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists.

RATIONALE: Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. To date no treatment strategies have been developed to regulate clinical VC. OBJECTIVE: The objective of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model. METHODS AND RESULTS: Young adult osteoprotegerin-deficient mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409-treated mice were paralleled by markedly lower alkaline phosphatase activity and a dramatic reduction in the expression of transcription factors, including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells isolated from human and mouse aortas. Calcification of smooth muscle cells induced by osteogenic medium was inhibited in the presence of GHRH or MR409, as evidenced by reduced alkaline phosphatase activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor-selective small interfering RNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A which in turn blocked nicotinamide adenine dinucleotide phosphate oxidase activity and reduced production of reactive oxygen species, thus blocking the phosphorylation of nuclear factor κB (p65), a key intermediate in the ligand of receptor activator for nuclear factor-κ B-Runx2/alkaline phosphatase osteogenesis program. A protein kinase A-selective small interfering RNA or the chemical inhibitor H89 abolished these beneficial effects of MR409. CONCLUSIONS: GHRH-A controls osteogenesis in smooth muscle cells by targeting cross talk between protein kinase A and nuclear factor κB (p65) and through the suppression of reactive oxygen species production that induces the Runx2 gene and alkaline phosphatase. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.

Trigonal Prismatic Cobalt(II) Single-Ion Magnets: Manipulating the Magnetic Relaxation Through Symmetry Control.

Two mononuclear trigonal prismatic Co(II) complexes [Co(tppm*)][BPh4]2 (1) and [Co(hpy)][BPh4]2·3CH2Cl2 (2) (tppm* = 6,6',6″-(methoxymethanetriyl)tris(2-(1H-pyrazol-1-yl)pyridine; hpy = tris(2,2'-bipyrid-6-yl)methanol) were synthesized by incorporating the Co(II) ions in two pocketing tripodal hexadentate ligands. Magnetic studies indicate similar uniaxial magnetic anisotropy while having distinct dynamic magnetic properties for two complexes, of which 1 exhibits clear hysteresis loops and Orbach process governed magnetic relaxation with an effective energy barrier (Ueff) of 192 cm-1, among the best examples in transition metallic SIMs, about 10 times larger than that of 2 (Ueff = 20 cm-1, extracted by fitting the data to an Orbach relaxation process but there is no real state at this energy). Such pronounced difference is ascribed to the dominant Raman process and quantum tunneling of magnetization (QTM) in 2 owing to the structural distortion and symmetry breaking, indicated by a nearly perfect trigonal prismatic geometry (D3 local symmetry) for 1 and a more distorted configuration for 2 (C3 local symmetry). Ab initio calculations predict strong axial anisotropy for 1 with minimal QTM probability, with the transverse component of anisotropy being estimated to be much higher for 2 than 1, leading to a 10-fold lower Ueff value than 1.

Clustering effects of health risk behavior on mental health and physical activity in Chinese adolescents.

PURPOSE: Risk behaviors are significantly impacting physical and psychological health among adolescents, resulting in a tremendous public health issue. The aim of this study is to examine the association of clustered risk behaviors with mental health and physical activity, and identify to what extent the clustering of various risk behaviors is associated with psychological health and physical activity in Chinese adolescents. METHODS: Students aged 16-18 years, male 16.2 ± 1.03, female 16.3 ± 1.56, were recruited from 30 high schools to complete an online questionnaire in fall semester 2017. A structured questionnaire, 2017 state and local youth risk behavior survey was revised, modified, and translated into Chinese. Five questions were designed to assess physical activity times of the last 7 days. Symptom checklist 90 (SCL-90) was used to investigate the mental health status of the participants. Statistical analyses were done employing chi-square tests, two step cluster analysis, logistic regression. RESULT: Results illustrate that girls report a significantly higher mean of being bullied in school, electronically bullied, feeling sad or hopeless, and trying cigarette smoking. Two-step cluster analysis and regression analysis find that alcohol use, smoking and sedentary behavior have significant effect on adolescent health. Logic regression demonstrated that risk behaviors have significantly associated with mental health and physical activity in specific cluster. CONCLUSION: This study finds that a specific behavior cluster has significant impact on mental health and physical activity among adolescents. Integrating risk behaviors cluster with factors can be employed to target high-risk adolescents who have poor physical and psychosocial health. The research suggest that more effective and feasible school intervention programs can be designed to promote adolescent health-related behavior in terms of those pathways.

Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs.

A growing body of evidence suggests type 2 diabetes mellitus (T2DM) is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanisms remain unclear, T2DM may exacerbate neurodegenerative processes. AMP-activated protein kinase (AMPK) signaling is an evolutionary preserved pathway that is important during homeostatic energy biogenesis responses at both the cellular and whole-body levels. Metformin, a ubiquitously prescribed anti-diabetic drug, exerts its effects by AMPK activation. However, while the roles of AMPK as a metabolic mediator are generally well understood, its performance in neuroprotection and neurodegeneration are not yet well defined. Given hyperglycemia is accompanied by an accelerated rate of advanced glycosylation end product (AGE) formation, which is associated with the pathogenesis of diabetic neuronal impairment and, inflammatory response, clarification of the role of AMPK signaling in these processes is needed. Therefore, we tested the hypothesis that metformin, an AMPK activator, protects against diabetic AGE induced neuronal impairment in human neural stem cells (hNSCs). In the present study, hNSCs exposed to AGE had significantly reduced cell viability, which correlated with elevated inflammatory cytokine expression, such as IL-1α, IL-1ß, IL-2, IL-6, IL-12 and TNF-α. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. In addition, metformin rescued the transcript and protein expression levels of acetyl-CoA carboxylase (ACC) and inhibitory kappa B kinase (IKK) in AGE-treated hNSCs. NF-κB is a transcription factor with a key role in the expression of a variety of genes involved in inflammatory responses, and metformin did prevent the AGE-mediated increase in NF-κB mRNA and protein levels in the hNSCs exposed to AGE. Indeed, co-treatment with metformin significantly restored inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) levels in AGE-treated hNSCs. These findings extend our understanding of the central role of AMPK in AGE induced inflammatory responses, which increase the risk of neurodegeneration in diabetic patients.