TMEM16A regulates satellite cell mediated skeletal muscle regeneration by ensuring a moderate level of caspase 3 activity.

It has been documented that caspase 3 activity is necessary for skeletal muscle regeneration, but how its activity is regulated is largely unknown. Our previous report shows that intracellular TMEM16A, a calcium activated chloride channel, significantly regulates caspase 3 activity in myoblasts during skeletal muscle development. By using a mouse line with satellite cell (SC)-specific deletion of TMEM16A, we examined the role of TMEM16A in regulating caspase 3 activity in SC (or SC-derived myoblast) as well as skeletal muscle regeneration. The mutant animals displayed apparently impaired regeneration capacity in adult muscle along with enhanced ER stress and elevated caspase 3 activity in Tmem16a-/- SC derived myoblasts. Blockade of either excessive ER stress or caspase 3 activity by small molecules significantly restored the inhibited myogenic differentiation of Tmem16a-/- SCs, indicating that excessive caspase 3 activity resulted from TMEM16A deletion contributes to the impaired muscle regeneration and the upstream regulator of caspase 3 was ER stress. Our results revealed an essential role of TMEM16A in satellite cell mediated skeletal muscle regeneration by ensuring a moderate level of caspase 3 activity.

A genome-wide association study identifies candidate genes for sleep disturbances in depressed individuals.

OBJECTIVE: This study aimed to identify candidate loci and genes related to sleep disturbances in depressed individuals and clarify the co-occurrence of sleep disturbances and depression from the genetic perspective. METHODS: The study subjects (including 58,256 self-reported depressed individuals and 6,576 participants with PHQ-9 score ≥ 10, respectively) were collected from the UK Biobank, which were determined based on the Patient Health Questionnaire (PHQ-9) and self-reported depression status, respectively. Sleep related traits included chronotype, insomnia, snoring and daytime dozing. Genome-wide association studies (GWASs) of sleep related traits in depressed individuals were conducted by PLINK 2.0 adjusting age, sex, Townsend deprivation index and 10 principal components as covariates. The CAUSALdb database was used to explore the mental traits associated with the candidate genes identified by the GWAS. RESULTS: GWAS detected 15 loci significantly associated with chronotype in the subjects with self-reported depression, such as rs12736689 at RNASEL (P = 1.00 × 10- 09), rs509476 at RGS16 (P = 1.58 × 10- 09) and rs1006751 at RFX4 (P = 1.54 × 10- 08). 9 candidate loci were identified in the subjects with PHQ-9 ≥ 10, of which 2 loci were associated with insomnia such as rs115379847 at EVC2 (P = 3.50 × 10- 08), and 7 loci were associated with daytime dozing, such as rs140876133 at SMYD3 (P = 3.88 × 10- 08) and rs139156969 at ROBO2 (P = 3.58 × 10- 08). Multiple identified genes, such as RNASEL, RGS16, RFX4 and ROBO2 were reported to be associated with chronotype, depression or cognition in previous studies. CONCLUSION: Our study identified several candidate genes related to sleep disturbances in depressed individuals, which provided new clues for understanding the biological mechanism underlying the co-occurrence of depression and sleep disorders.

Uncovering the cellular and omics characteristics of natural killer cells in the bone marrow microenvironment of patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy and the most frequently acute leukemia of stem cell precursors and the myeloid derivatives in adult. Longitudinal studies have indicated the therapeutic landscape and drug resistance for patients with AML are still intractable, which largely attribute to the deficiency of detailed information upon the pathogenesis. METHODS: In this study, we compared the cellular phenotype of resident NK cells (rAML-NKs, rHD-NKs) and expanded NK cells (eAML-NKs, eHD-NKs) from bone marrow of AML patients (AML) and healthy donors (HD). Then, we took advantage of the co-culture strategy for the evaluation of the in vitro cytotoxicity of NK cells upon diverse tumor cell lines (e.g., K562, Nalm6, U937). With the aid of RNA-sequencing (RNA-SEQ) and bioinformatics analyses (e.g., GOBP analysis, KEGG analysis, GSEA, volcano plot), we verified the similarities and differences of the omics features between eAML-NKs and eHD-NKs. RESULTS: Herein, we verified the sharp decline in the content of total resident NK cells (CD3-CD56+) in rAML-NKs compared to rHD-NKs. Differ from the expanded eHD-NKs, eAML-NKs revealed decline in diverse NK cell subsets (NKG2D+, CD25+, NKp44+, NKp46+) and alterations in cellular vitality but conservations in cytotoxicity. According to transcriptomic analysis, AML-NKs and HD-NKs showed multifaceted distinctions in gene expression profiling and genetic variations. CONCLUSIONS: Collectively, our data revealed the variations in the cytobiological and transcriptomic features between AML-NKs and HD-NKs in bone marrow environment. Our findings would benefit the further development of novel biomarkers for AML diagnosis and NK cell-based cytotherapy in future.

Causal relationship between gut microbiota and rheumatoid arthritis: a two-sample Mendelian randomisation study.

OBJECTIVES: To assess whether there is a bidirectional causal relationship between the composition of gut microbiota and rheumatoid arthritis (RA), and to identify specific pathogenic bacterial taxa via the Mendelian randomisation (MR) analysis. METHODS: We acquired single nucleotide polymorphisms (SNPs) associated with the composition of gut microbiota (n=18,340) and with RA (n=331,313) from publicly available genome-wide association studies (GWAS). The genome-wide threshold was 1 × 10-5 in the forward MR analysis and was 5 × 10-8 in the reverse MR analysis. Inverse variance weighted (IVW) was the main method to analyse causality, and MR results were verified by several sensitivity analyses including weighted median, MR Egger, and MR Pleiotropy Residual Sum and Outlier (PRESSO). RESULTS: The IVW method suggested that eight taxa were positively correlated with RA, including: MollicutesRF9 (pIVW <0.01), Alphaproteobacteria (pIVW <0.01), Betaproteobacteria (p IVW =0.04), Bacteroidaceae (pIVW <0.01), Adlercreutzia (pIVW <0.01), Bacteroides (pIVW <0.01), Butyricimonas (p IVW =0.03) and Holdemanella (pIVW =0.03). Six bacterial taxa were negatively correlated with RA, including Desulfovibrionales (pIVW = 0.01), Methanobacteriales (pIVW <0.01), Methanobacteria (PIVW <0.01), Desulfovibrionaceae (pIVW <0.01), Methanobacteriaceae (pIVW <0.01) and Butyrivibrio (pIVW =0.02). Heterogeneity (p>0.05) and pleiotropy (p>0.05) analysis confirmed the robustness of the MR results. CONCLUSIONS: We identified some specific bacterial taxa that were causally associated with the risk of RA, providing new insights into prevention and diagnosis of RA.

Procalcitonin and C-reactive protein as diagnostic biomarkers in COVID-19 and Non-COVID-19 sepsis patients: a comparative study.

BACKGROUND: This study aimed to assess and compare procalcitonin (PCT) and C-reactive protein (CRP) levels between COVID-19 and non-COVID-19 sepsis patients. Additionally, we evaluated the diagnostic efficiency of PCT and CRP in distinguishing between Gram-positive (GP) and Gram-negative (GN) bacterial infections. Moreover, we explored the associations of PCT with specific pathogens in this context. METHODS: The study included 121 consecutive sepsis patients who underwent blood culture testing during the COVID-19 epidemic. PCT and CRP were measured, and reverse transcriptase-polymerase chain reaction (RT-PCR) was employed for the detection of COVID-19 nucleic acid. The Mann-Whitney U-test was used to compare PCT and CRP between the COVID-19 and non-COVID-19 groups. Receiver operating characteristic (ROC) curves were generated to compare PCT and CRP levels in the GN group versus the GP group for assessing the diagnostic efficiency. The kruskal-Wallis H test was applied to assess the impact of specific pathogen groups on PCT concentrations. RESULTS: A total of 121 sepsis patients were categorized into a COVID-19 group (n = 25) and a non-COVID-19 group (n = 96). No significant differences in age and gender were observed between the COVID-19 and non-COVID-19 groups. The comparison of biomarkers between these groups showed no statistically significant differences. The optimal cut-off values for PCT and CRP in differentiating between GP and GN infections were 1.03 ng/mL and 34.02 mg/L, respectively. The area under the ROC curve was 0.689 (95% confidence interval (CI) 0.591-0.786) for PCT and 0.611 (95% CI 0.505-0.717) for CRP. The diagnostic accuracy was 69.42% for PCT and 58.69% for CRP. The study found a significant difference in PCT levels among specific groups of pathogens (P < 0.001), with the highest levels observed in Escherichia coli infections. The frequency of Staphylococcus spp. positive results was significantly higher (36.0%) in COVID-19 compared to non-COVID-19 sepsis patients (P = 0.047). CONCLUSION: Sepsis patients with COVID-19 revealed a significantly higher culture positivity for staphylococcus spp. than the non-COVID-19 group. Both PCT and CRP showed moderate diagnostic efficiency in differentiating between GP and GN bacterial infections. PCT showed potential utility in identifying E. coli infections compared to other pathogens.

Assessing the effect of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes.

Longitudinal changes in brain structure and lifestyle can affect sleep phenotypes. However, the influence of the interaction between longitudinal changes in brain structure and lifestyle on sleep phenotypes remains unclear. Genome-wide association study dataset of longitudinal changes in brain structure was obtained from published study. Phenotypic data of lifestyles and sleep phenotypes were obtained from UK Biobank cohort. Using genotype data from UK Biobank, we calculated polygenetic risk scores of longitudinal changes in brain structure phenotypes. Linear/logistic regression analysis was conducted to evaluate interactions between longitudinal changes in brain structure and lifestyles on sleep duration, chronotype, insomnia, snoring and daytime dozing. Multiple lifestyle × longitudinal changes in brain structure interactions were detected for 5 sleep phenotypes, such as physical activity×caudate_age2 for daytime dozing (OR = 1.0389, P = 8.84 × 10-3) in total samples, coffee intake×cerebellar white matter volume_age2 for daytime dozing (OR = 0.9652, P = 1.13 × 10-4) in females. Besides, we found 4 overlapping interactions in different sleep phenotypes. We conducted sex stratification analysis and identified one overlapping interaction between female and male. Our results support the moderate effects of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes, and deepen our understanding of the pathogenesis of sleep disorders.

Assessing the association of coffee consumption on the relationship of chronic pain with depression and anxiety.

BACKGROUND: A bidirectional relationship between chronic pain (CP) and mental disorders has been reported, and coffee was believed to be associated with both. However, the association of coffee in this bidirectional relationship remains unclear. We aim to analyze the association of coffee consumption on the relationship of CP with depression and anxiety. METHODS: A total of 376,813 participants from UK Biobank were included. We collected data on anxiety, depression and CP from objects of our study population. The association of coffee consumption on the relationship of CP with depression and anxiety was assessed through logistic/linear regression models. Moreover, seemingly unrelated estimation test (SUEST) was used to compare whether the coefficients differed in two different groups. RESULTS: We observed significant associations of coffee consumption in the interaction of CP with depression and anxiety, such as the association of multisite chronic pain (MCP) on self-reported depression (ßcoffee = 0.421, ßnon-coffee = 0.488, PSUEST = 0.001), and the association of MCP on generalized anxiety disorder-7 (GAD-7) scores (ßcoffee = 0.561, ßnon-coffee = 0.678, PSUEST = 0.004) were significantly different between coffee drinking and non-coffee drinking groups. Furthermore, in analysis stratified by gender, we found headache (ßmale = 0.392, ßfemale = 0.214, PSUEST = 0.022) and hip pain (ßmale = 0.480, ßfemale = 0.191, PSUEST = 0.021) had significant associations with self-reported depression between males and females groups in coffee drinkers. CONCLUSIONS: Our results suggested that coffee consumption has a significant association on the relationship of CP with depression and anxiety.

GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice.

The homeostasis of protein palmitoylation and depalmitoylation is essential for proper physiological functions in various tissues, in particular the central nervous system (CNS). The dysfunction of PPT1 (PPT1-KI, infantile neuronal ceroid lipofuscinosis [INCL] mouse model), which catalyze the depalmitoylation process, results in serious neurodegeneration accompanied by severe astrogliosis in the brain. Endeavoring to determine critical factors that might account for the pathogenesis in CNS by palm-proteomics, glial fibrillary acidic protein (GFAP) was spotted, indicating that GFAP is probably palmitoylated. Questions concerning if GFAP is indeed palmitoylated in vivo and how palmitoylation of GFAP might participate in neural pathology remain unexplored and are waiting to be investigated. Here we show that GFAP is readily palmitoylated in vitro and in vivo; specifically, cysteine-291 is the unique palmitoylated residue in GFAP. Interestingly, it was found that palmitoylated GFAP promotes astrocyte proliferation in vitro. Furthermore, we showed that PPT1 depalmitoylates GFAP, and the level of palmitoylated GFAP is overwhelmingly up-regulated in PPT1-knockin mice, which lead us to speculate that the elevated level of palmitoylated GFAP might accelerate astrocyte proliferation in vivo and ultimately led to astrogliosis in INCL. Indeed, blocking palmitoylation by mutating cysteine-291 into alanine in GFAP attenuate astrogliosis, and remarkably, the concurrent neurodegenerative pathology in PPT1-knockin mice. Together, these findings demonstrate that hyperpalmitoylated GFAP plays critical roles in regulating the pathogenesis of astrogliosis and neurodegeneration in the CNS, and most importantly, pinpointing that cysteine-291 in GFAP might be a valuable pharmaceutical target for treating INCL and other potential neurodegenerative diseases.

Assessing the interaction effects of brain structure longitudinal changes and life environmental factors on depression and anxiety.

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome-wide association study datasets of 15 brain structure longitudinal changes (N = 15,640) were obtained from the published study. Genotype and phenotype-related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change-related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex-specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta = -.003, p = .018 for depression; beta = -003, p = .008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta = .088, p = .002 for depression; beta = .070, p = .008 for anxiety). We also observed sex-specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta = -.004, p = .020 for depression; beta = -.005, p = .002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety.

Combined effects of inflammation and coronavirus disease 2019 (COVID-19) on the risks of anxiety and depression: A cross-sectional study based on UK Biobank.

Infection-induced perturbation of immune homeostasis could promote psychopathology. Psychiatric sequelae have been observed after previous coronavirus outbreaks. However, limited studies were conducted to explore the potential interaction effects of inflammation and coronavirus disease 2019 (COVID-19) on the risks of anxiety and depression. In this study, first, polygenic risk scores (PRS) were calculated for eight COVID-19 clinical phenotypes using individual-level genotype data from the UK Biobank. Then, linear regression models were developed to assess the effects of COVID-19 PRS, C-reactive protein (CRP), systemic immune inflammation index (SII), and their interaction effects on the Generalized Anxiety Disorder-7 (GAD-7, 104 783 individuals) score and the Patient Health Questionnaire-9 (PHQ-9, 104 346 individuals) score. Several suggestive interactions between inflammation factors and COVID-19 clinical phenotypes were detected for PHQ-9 score, such as CRP/SII × Hospitalized/Not_Hospitalized in women group and CRP × Hospitalized/Unscreened in age >65 years group. For GAD-7 score, we also found several suggestive interactions, such as CRP × Positive/Unscreened in the age ≤65 years group. Our results suggest that not only COVID-19 and inflammation have important effects on anxiety and depression but also the interactions of COVID-19 and inflammation have serious risks for anxiety and depression.

Oral micronized progesterone versus vaginal progesterone for luteal phase support in fresh embryo transfer cycles: a multicenter, randomized, non-inferiority trial.

STUDY QUESTION: Does oral micronized progesterone result in a non-inferior ongoing pregnancy rate compared to vaginal progesterone gel as luteal phase support (LPS) in fresh embryo transfer cycles? SUMMARY ANSWER: The ongoing pregnancy rate in the group administered oral micronized progesterone 400 mg per day was non-inferior to that in the group administered vaginal progesterone gel 90 mg per day. WHAT IS KNOWN ALREADY: LPS is an integrated component of fresh IVF, for which an optimal treatment regimen is still lacking. The high cost and administration route of the commonly used vaginal progesterone make it less acceptable than oral micronized progesterone; however, the efficacy of oral micronized progesterone is unclear owing to concerns regarding its low bioavailability after the hepatic first pass. STUDY DESIGN, SIZE, DURATION: This non-inferiority randomized trial was conducted in eight academic fertility centers in China from November 2018 to November 2019. The follow-up was completed in April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1310 infertile women who underwent their first or second IVF cycles were enrolled. On the day of hCG administration, the patients were randomly assigned to one of three groups for LPS: oral micronized progesterone 400 mg/day (n = 430), oral micronized progesterone 600 mg/day (n = 440) or vaginal progesterone 90 mg/day (n = 440). LPS was started on the day of oocyte retrieval and continued till 11-12 weeks of gestation. The primary outcome was the rate of ongoing pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention-to-treat analysis, the rate of ongoing pregnancy in the oral micronized progesterone 400 mg/day group was non-inferior to that of the vaginal progesterone gel group [35.3% versus 38.0%, absolute difference (AD): -2.6%; 95% CI: -9.0% to 3.8%, P-value for non-inferiority test: 0.010]. There was insufficient evidence to support the non-inferiority in the rate of ongoing pregnancy between the oral micronized progesterone 600 mg/day group and the vaginal progesterone gel group (31.6% versus 38.0%, AD: -6.4%; 95% CI: -12.6% to -0.1%, P-value for non-inferiority test: 0.130). In addition, we did not observe a statistically significant difference in the rate of live births between the groups. LIMITATIONS, REASONS FOR CAUTION: The primary outcome of our trial was the ongoing pregnancy rate; however, the live birth rate may be of greater clinical interest. Although the results did not show a difference in the rate of live births, they should be confirmed by further trials with larger sample sizes. In addition, in this study, final oocyte maturation was triggered by hCG, and the findings may not be extrapolatable to cycles with gonadotropin-releasing hormone agonist triggers. WIDER IMPLICATIONS OF THE FINDINGS: Oral micronized progesterone 400 mg/day may be an alternative to vaginal progesterone gel in patients reluctant to accept the vaginal route of administration. However, whether a higher dose of oral micronized progesterone is associated with a poorer pregnancy rate or a higher rate of preterm delivery warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant from the National Natural Science Foundation of China (82071718). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the number ChiCTR1800015958. TRIAL REGISTRATION DATE: May 2018. DATE OF FIRST PATIENT'S ENROLMENT: November 2018.

Exome-wide screening identifies novel rare risk variants for major depression disorder.

Despite thousands of common genetic loci of major depression disorders (MDD) have been identified by GWAS to date, a large proportion of genetic variation predisposing to MDD remains unaccounted for. By utilizing the newly released UK Biobank 200,643 exome dataset, we conducted an exome-wide association study to identify rare risk variants contributing to MDD. After quality control, 120,033 participants with MDD polygenic risk scores (PRS) values were included. The individuals with lower 30% quantile of the PRS value were filtered for case and control selecting. Then the cases were set as the individuals with upper 10% quantile of the PHQ depression score and lower 10% quantile were set as controls. Finally, 1612 cases and 1612 controls were included in this study. The variants were annotated by ANNOVRA software. After exclusions, 34,761 qualifying variants, including 148 frameshift variant, 335 non-frameshift variant, 33,758 nonsynonymous, 91 start-loss, 393 stop-gain, 36 stop-loss variants were imported into the SKAT R-package to perform single variants, gene-based burden and robust burden tests with minor allele frequency (MAF) < 0.01. Single variant association testing identified one variant, rs4057749 (P = 5.39 × 10-9), within OR8B4 gene at an exome-wide significance level. The gene-based burden test of the exonic variants identified genome-wide significant associations in OR8B4 (PSKAT = 6.23 × 10-5, PSKAT Robust = 4.49 × 10-5), TRAPPC11 (PSKAT = 0.014, PSKAT Robust = 0.015), SBK3 (PSKAT = 0.020, PSKAT Robust = 0.025) and TNRC6B (PSKAT = 0.026, PSKAT Robust = 0.036). We identified multiple novel rare risk variants contributing to MDD in the individuals with lower PRS of MDD. The findings can help to broaden the genetic insights of the MDD pathogenesis.

Treatment Resistance in Schizophrenia Is Associated with Attention Deficit/Hyperactivity Disorder and Gut Microbiota: A Genetic Correlation and Mendelian Randomization Study.

INTRODUCTION: Observational studies highlight associations of common diseases with individual schizophrenia symptoms. However, it is unclear whether these diseases are associated with individual treatment-resistant schizophrenia (TRS). We aimed to explore the genetic associations between common immune diseases, metabolic diseases, psychiatric disorders, gut microbiota and TRS. METHODS: Genome-wide association study (GWAS) summary data of European participants (n = ∼456,327) included TRS, 11 psychiatric disorders, 23 immune and metabolic diseases, body mass index, height, and 211 gut microbiota. In this genetic correlation and two-sample Mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with common immune diseases, metabolic diseases, psychiatric disorders, and gut microbiota with TRS. RESULTS: LDSC revealed candidate associations between attention deficit/hyperactivity disorder (ADHD), schizophrenia, intestinal infectious diseases, obesity and TRS (genetic correlation range, 0.230-0.702; p < 0.05). Two-sample MR analyses suggested that ADHD was positively associated with TRS (estimate [SE] = 0.204 [0.073], p = 0.005), a finding that remained stable across statistical models. Besides, schizophrenia and genus Barnesiella levels were causally associated with TRS but not consistent across MR approaches. CONCLUSION: This study reports genetic correlations between ADHD, schizophrenia, intestinal infectious diseases, obesity and TRS. The study also found that genus Barnesiella was associated with TRS. These findings may have clinical implications, highlighting the possible strategy for TRS prevention.

Impact of Deep Margin Elevation Procedures Upon Periodontal Parameters: A Systematic Review.

INTRODUCTION: Deep margin elevation (DME) is an emerging technique attempting to minimize the need for surgical procedures (i.e., crown lengthening [CL]), deliver indirect restorations in one clinical session and reduce overall treatment time. The present study evaluated the impact of DME upon periodontal measurements based exclusively on human studies. METHODS: A literature search was performed by two independent reviewers in several databases including PubMed, EMBASE, and Cochrane Central up to March 2022. This review searched for randomized human trials, cohort (prospective/ retrospective) and/or case series studies using DME, reporting periodontal (i.e. marginal bone levels [MBL], probing depths [PD], bleeding on probing [BoP], recession [REC], clinical attachment level [CAL]), and the type of approach (non-surgical or surgical) with at least ⟩3 months of post-operative outcomes. RESULTS: None of the included studies reported MBL, REC or CAL, and thus, results were limited to PD and BoP. BoP was increased when the distance between restorative margin and alveolar bone was approximately ⟨2mm. Non-surgical and surgical DME approaches led to different outcomes in PD (0.26±0.77mm vs -0.39±0.85mm) and BoP (31.50% vs -22.33%). CONCLUSIONS: Limited findings of the present systematic review can be drawn and thus, the impact of DME upon the periodontium remains inconclusive.

Association between gut microbiota and longevity: a genetic correlation and mendelian randomization study.

BACKGROUND: Longevity is one of the most complex phenotypes, and its genetic basis remains unclear. This study aimed to explore the genetic correlation and potential causal association between gut microbiota and longevity. RESULTS: Linkage disequilibrium score (LDSC) regression analysis and a bi-directional two-sample Mendelian Randomization (MR) analysis were performed to analyze gut microbiota and longevity-related traits. LDSC analysis detected four candidate genetic correlations, including Veillonella (genetic correlation = 0.5578, P = 4.67 × 10- 2) and Roseburia (genetic correlation = 0.4491, P = 2.67 × 10- 2) for longevity, Collinsella (genetic correlation = 0.3144, P = 4.07 × 10- 2) for parental lifespan and Sporobacter (genetic correlation = 0.2092, P = 3.53 × 10- 2) for healthspan. Further MR analysis observed suggestive causation between Collinsella and parental longevity (father's age at death) (weighted median: b = 1.79 × 10- 3, P = 3.52 × 10- 2). Reverse MR analysis also detected several causal effects of longevity-related traits on gut microbiota, such as longevity and Sporobacter (IVW: b = 7.02 × 10- 1, P = 4.21 × 10- 25). Statistical insignificance of the heterogeneity test and pleiotropy test supported the validity of the MR study. CONCLUSION: Our study found evidence that gut microbiota is causally associated with longevity, or vice versa, providing novel clues for understanding the roles of gut microbiota in aging development.

Dissecting the association between psychiatric disorders and neurological proteins: a genetic correlation and two-sample bidirectional Mendelian randomization study.

OBJECTIVES: The role of neurological proteins in the development of bipolar disorder (BD) and schizophrenia (SCZ) remains elusive now. The current study aims to explore the potential genetic correlations of plasma neurological proteins with BD and SCZ. METHODS: By using the latest genome-wide association study (GWAS) summary data of BD and SCZ (including 41,917 BD cases, 11,260 SCZ cases, and 396,091 controls) derived from the Psychiatric GWAS Consortium website (PGC) and a recently released GWAS of neurological proteins (including 750 individuals), we performed a linkage disequilibrium score regression (LDSC) analysis to detect the potential genetic correlations between the two common psychiatric disorders and each of the 92 neurological proteins. Two-sample Mendelian randomisation (MR) analysis was then applied to assess the bidirectional causal relationship between the neurological proteins identified by LDSC, BD and SCZ. RESULTS: LDSC analysis identified one neurological protein, NEP, which shows suggestive genetic correlation signals for both BD (coefficient = -0.165, p value = 0.035) and SCZ (coefficient = -0.235, p value = 0.020). However, those association did not remain significant after strict Bonferroni correction. Two sample MR analysis found that there was an association between genetically predicted level of NEP protein, BD (odd ratio [OR] = 0.87, p value = 1.61 × 10-6) and SCZ (OR = 0.90, p value = 4.04 × 10-6). However, in the opposite direction, there is no genetically predicted association between BD, SCZ, and NEP protein level. CONCLUSION: This study provided novel clues for understanding the genetic effects of neurological proteins on BD and SCZ.

Application of sodium bicarbonate in extraction and determination of synthetic colorant in processed grain products.

As the only standard of its kind, GB5009.35-2016 provides the determination of water-soluble synthetic colorants in processed grain products with high starch content for the purpose of food safety risk monitoring. However, it's only applicable to candy products and liquid foods as beverages, but not solid grain products. Extraction is a critical and essential step in the overall analytical process for determination. This paper provides an improved method for extraction of synthetic colorants in food products presenting high starch content. The samples were successively extracted with methanol-water (4:6, v/v) containing 2.7% sodium bicarbonate, and the target analytes were purified by solid phase extraction column. The obtained eluent was concentrated in constant volume, separated by ODS-SP C18 column and determined by diode array detector. The limits of detection were in the range of 2.21 ~ 8.62 ng/mL for 6 synthetic colors. The average recoveries at the spiked levels of 10, 30, 50 µg/kg varied in the range of 79.3 ~ 101.4% with RSD (n = 6) around 0.2 ~ 6.7%. The developed sodium bicarbonate based extraction method was successfully applied to speciation analysis of water soluble azo synthetic colorant in starchy food, such as millet, grits, brown rice, rice flour, cornmeal and cornflakes. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-021-05199-x.

Effects of bone marrow mesenchymal stem cells on repair and receptivity of damaged endometrium in rats.

AIM: This study was to investigate whether bone marrow mesenchymal stem cells (BMSCs) can repair damaged endometrium in rats and its effect on endometrial receptivity. METHODS: A rat model of endometrial damage was established by heat injury. BMSCs were labeled with PKH26 and were transplanted into the right uterine cavity. The endometrial thickness and fertility testing were examined to assess the repair of damaged endometrium. The mass on trichrome staining was used to assess the endometrium fibrosis. The expression of integrin avß3 and leukemia inhibitory factor (LIF) in rat endometrium was used to evaluate the endometrial receptivity. RESULTS: After transplantation of BMSCs, the distribution of PKH26 positive cells was mainly on the damaged side in the endometrial tissues. Compared to control group, the endometrial tissue structure recovered after treatment with BMSCs. BMSCs transplantation improved the fertility of endometrial injury model rats. BMSCs decreased the area of endometrial fibrosis. The expression of integrin avß3 and LIF in endometrium was the stronger in BMSCs treatment group than control group. CONCLUSION: BMSCs can migrate to the endometrium and repair damaged endometrium and improve endometrium receptivity.

An R2R3-type MYB transcription factor, GmMYB29, regulates isoflavone biosynthesis in soybean.

Isoflavones comprise a group of secondary metabolites produced almost exclusively by plants in the legume family, including soybean [Glycine max (L.) Merr.]. They play vital roles in plant defense and have many beneficial effects on human health. Isoflavone content is a complex quantitative trait controlled by multiple genes, and the genetic mechanisms underlying isoflavone biosynthesis remain largely unknown. Via a genome-wide association study (GWAS), we identified 28 single nucleotide polymorphisms (SNPs) that are significantly associated with isoflavone concentrations in soybean. One of these 28 SNPs was located in the 5'-untranslated region (5'-UTR) of an R2R3-type MYB transcription factor, GmMYB29, and this gene was thus selected as a candidate gene for further analyses. A subcellular localization study confirmed that GmMYB29 was located in the nucleus. Transient reporter gene assays demonstrated that GmMYB29 activated the IFS2 (isoflavone synthase 2) and CHS8 (chalcone synthase 8) gene promoters. Overexpression and RNAi-mediated silencing of GmMYB29 in soybean hairy roots resulted in increased and decreased isoflavone content, respectively. Moreover, a candidate-gene association analysis revealed that 11 natural GmMYB29 polymorphisms were significantly associated with isoflavone contents, and regulation of GmMYB29 expression could partially contribute to the observed phenotypic variation. Taken together, these results provide important genetic insights into the molecular mechanisms underlying isoflavone biosynthesis in soybean.

Protective effect of acacetin in human periodontal ligament cells via regulation of autophagy and inflammation.

Our study investigated the effects of acacetin, a natural flavonoid compound, on the survival and expression of inflammatory related cytokines in lipopolysaccharide (LPS)-stimulated human periodontal ligament (PDL) cells. Treatment with acacetin significantly promoted survival and suppressed apoptosis in LPS-stimulated PDL cells in a dose-dependent manner, as shown by CCK-8 and flow cytometry assays, respectively. Moreover, ELISA assay showed that acacetin dose-dependently attenuated LPS-induced increases of TNF-α, IL-6 and IL-1ß in PDL cells. Western blot analysis showed that administration of acacetin dose-dependently increased the ratio of LC3II/LC3I, as well as the expression of beclin-1, as compared to LPS-stimulated PDL cells. Inhibition of autophagy by rapamycin, an autophagy inhibitor, increased the production of pro-inflammatory cytokines and decreased survival, abolishing the beneficial role of acacetin in LPS-stimulated PDL cells. In addition, the expression of GSK-3ß, a regulator of autophagy, was suppressed by administration with acacetin in a dose-dependent manner. Acacetin treatment promotes survival and suppresses inflammation in LPS-stimulated PDL cells via regulating autophagy and GSK-3ß signal in PDL cells, suggesting that acacetin may be a potential novel agent for the treatment of chronic periodontitis.