Astragaloside IV promotes cerebral tissue restoration through activating AMPK- mediated microglia polarization in ischemic stroke rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragaloside IV (AS), a key active ingredient obtained from Chinese herb Astragalus mongholicus Bunge, exerts potent neuroprotective and anti-inflammatory effects for treating neurodegenerative diseases. However, mechanisms of AS on improvement of ischemic brain tissue repair remain unclear. AIM OF THE STUDY: This research aims at using magnetic resonance imaging (MRI) to noninvasively determine whether AS facilitates brain tissue repair, and investigating whether AS exerts brain remodeling through adenosine monophosphate-activated protein kinase (AMPK) metabolic signaling regulating key glycolytic enzymes and energy transporters, thereby impacting microglia polarization. MATERIALS AND METHODS: Ischemic stroke model in male Sprague-Dawley rats were induced through permanent occlusion of the middle cerebral artery (MCAO). Infarct volume, the alterations of brain microstructure and nerve fibers reorganization were examined by multi-parametric MRI. The pathological damages of myelinated axons and microglia polarization surrounding infarct tissue were detected using pathological techniques. Furthermore, M1/M2 microglia polarization associated protein, glycolytic rate-limiting enzymes, energy transporters and AMPK/ mammalian target of rapamycin (mTOR)/ hypoxia inducible factor-1α (HIF-1α) signal were examined both in ischemic stroke rats and BV2 microglia treated with lipopolysaccharide (LPS) + interferon-γ (IFN-γ) by western blotting. RESULTS: MRI revealed that AS obviously decreased infarct volume, relieved brain microstructure damage and improved nerve fibers reorganization in ischemic stroke rats. Histological tests supported MRI findings. Notably, AS promoted microglia M2 and reduced M1 polarization, induced the AMPK activation accompanied with decreased levels of phosphorylated mTOR and HIF-1α. Moreover, AS suppressed the expression of glycolytic rate-limiting enzymes and energy transporters in ischemic stroke rats and BV2 microglia. In contrast, these beneficial effects were greatly blocked by AMPK inhibitor compound C. CONCLUSION: Overall, these results collectively suggested that AS facilitated tissue remodeling that may be partially through modulating polarization of microglia in AMPK- dependent metabolic pathways after ischemic stroke.

Schisandrin A alleviates renal fibrosis by inhibiting PKCß and oxidative stress.

BACKGROUND: Renal fibrosis is a common pathway that drives the advancement of numerous kidney maladies towards end-stage kidney disease (ESKD). Suppressing renal fibrosis holds paramount clinical importance in forestalling or retarding the transition of chronic kidney diseases (CKD) to renal failure. Schisandrin A (Sch A) possesses renoprotective effect in acute kidney injury (AKI), but its effects on renal fibrosis and underlying mechanism(s) have not been studied. STUDY DESIGN: Serum biochemical analysis, histological staining, and expression levels of related proteins were used to assess the effect of PKCß knockdown on renal fibrosis progression. Untargeted metabolomics was used to assess the effect of PKCß knockdown on serum metabolites. Unilateral Ureteral Obstruction (UUO) model and TGF-ß induced HK-2 cells and NIH-3T3 cells were used to evaluate the effect of Schisandrin A (Sch A) on renal fibrosis. PKCß overexpressed NIH-3T3 cells were used to verify the possible mechanism of Sch A. RESULTS: PKCß was upregulated in the UUO model. Knockdown of PKCß mitigated the progression of renal fibrosis by ameliorating perturbations in serum metabolites and curbing oxidative stress. Sch A alleviated renal fibrosis by downregulating the expression of PKCß in kidney. Treatment with Sch A significantly attenuated the upregulated proteins levels of FN, COL-I, PKCß, Vimentin and α-SMA in UUO mice. Moreover, Sch A exhibited a beneficial impact on markers associated with oxidative stress, including MDA, SOD, and GSH-Px. Overexpression of PKCß was found to counteract the renoprotective efficacy of Sch A in vitro. CONCLUSION: Sch A alleviates renal fibrosis by inhibiting PKCß and attenuating oxidative stress.

Buyang Huanwu Decoction promotes neurovascular remodeling by modulating astrocyte and microglia polarization in ischemic stroke rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu Decoction (BYHWD), one of the most commonly utilized traditional Chinese medicine prescription for treatment of cerebral ischemic stroke. However, the understanding of BYHWD on neurovascular repair following cerebral ischemia is so far limited. AIM OF THE STUDY: This research investigated the influence of BYHWD on neurovascular remodeling by magnetic resonance imaging (MRI) technology and revealed the potential neurovascular repair mechanism underlying post-treatment with BYHWD after ischemic stroke. MATERIALS AND METHODS: Male Sprague-Dawley rats were utilized as an ischemic stroke model by permanent occlusion of the middle cerebral artery (MCAO). BYHWD was intragastrically administrated once daily for 30 days straight. Multimodal MRI was performed to detect brain tissue injuries, axonal microstructural damages, cerebral blood flow and intracranial vessels on the 30th day after BYHWD treatment. Proangiogenic factors, axonal/synaptic plasticity-related factors, energy transporters and adenosine monophosphate-activated protein kinase (AMPK) signal pathway were evaluated using western blot. Double immunofluorescent staining and western blot were applied to evaluate astrocytes and microglia polarization. RESULTS: Administration of BYHWD significantly alleviated infarct volume and brain tissue injuries and ameliorated microstructural damages, accompanied with improved axonal/synaptic plasticity-related factors, axonal growth guidance factors and decreased axonal growth inhibitors. Meanwhile, BYHWD remarkably improved cerebral blood flow, cerebral vascular signal and promoted the expression of proangiogenic factors. Particularly, treatment with BYHWD obviously suppressed astrocytes A1 and microglia M1 polarization accompanied with promoted astrocyte A2 and microglia M2 polarization. Furthermore, BYHWD effectively improved energy transporters. Especially, BYHWD markedly increased expression of phosphorylated AMPK, cyclic AMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) accompanied by inactivation of the NF-κB. CONCLUSION: Taken together, these findings identified that the beneficial roles of BYHWD on neurovascular remodeling were related to AMPK pathways -mediated energy transporters and NFκB/CREB pathways.

High-temperature magnetically topological candidate material Mn3Bi2Te6.

The Mn-Bi-Te family displaying magnetism and non-trivial topological properties has received extensive attention. Here, we predict that the antiferromagnetic structure of Mn3Bi2Te6with three MnTe layers is energetically stable and the magnetic energy difference of Mn-Mn is enhanced four times compared with that in the single MnTe layer of MnBi2Te4. The predicted Néel transition point is raised to 102.5 K, surpassing the temperature of liquid nitrogen. The topological properties show that with the variation of the MnTe layer from a single layer to three layers, the system transforms from a non-trivial topological phase to a trivial topological phase. Interestingly, the ferromagnetic state of Mn3Bi2Te6is a topological semimetal and it exhibits a topological transition from trivial to non-trivial induced by the magnetic transition. Our results enrich the Mn-Bi-Te family system, offer a new platform for studying topological phase transitions, and pave a new way to improve the working temperature of magnetically topological devices.

A novel prognostic nomogram for adult acute lymphoblastic leukemia: a comprehensive analysis of 321 patients.

The cure rate of acute lymphoblastic leukemia (ALL) in adolescents and adults remains poor. This study aimed to establish a prognostic model for ≥14-year-old patients with ALL to guide treatment decisions. We retrospectively analyzed the data of 321 ALL patients between January 2017 and June 2020. Patients were randomly (2:1 ratio) divided into either the training or validation set. A nomogram was used to construct a prognostic model. Multivariate Cox analysis of the training set showed that age > 50 years, white blood cell count > 28.52×109/L, and MLL rearrangement were independent risk factors for overall survival (OS), while platelet count >37×109/L was an independent protective factor. The nomogram was established according to these independent prognostic factors in the training set, where patients were grouped into two categories: low-risk (≤13.15) and high-risk (>13.15). The survival analysis, for either total patients or sub-group patients, showed that both OS and progression-free survival (PFS) of low-risk patients was significantly better than that of high-risk patients. Moreover, treatment analysis showed that both OS and progression-free survival (PFS) of ALL with stem cell transplantation (SCT) were significantly better than that of ALL without SCT. Further stratified analysis showed that in low-risk patients, the OS and PFS of patients with SCT were significantly better than those of patients without SCT. In contrast, in high-risk patients, compared with non-SCT patients, receiving SCT can only significantly prolong the PFS, but it does not benefit the OS. We established a simple and effective prognostic model for ≥ 14-year-old patients with ALL that can provide accurate risk stratification and determine the clinical strategy.

Proper phosphorylation of septin 12 regulates septin 4 and soluble adenylyl cyclase expression to induce sperm capacitation.

Septin-based ring complexes maintain the sperm annulus. Defective annular structures are observed in the sperm of Sept12- and Sept4-null mice. In addition, sperm capacitation, a process required for proper fertilization, is inhibited in Sept4-null mice, implying that the sperm annulus might play a role in controlling sperm capacitation. Hence, we analyzed sperm capacitation of sperm obtained from SEPT12 Ser196 phosphomimetic (S196E), phosphorylation-deficient (S196A), and SEPT4-depleted mutant mice. Capacitation was reduced in the sperm of both the Sept12 S196E- and Sept12 S196A-knock-in mice. The protein levels of septins, namely, SEPT4 and SEPT12, were upregulated, and these proteins were concentrated in the sperm annulus during capacitation. Importantly, the expression of soluble adenylyl cyclase (sAC), a key enzyme that initiates capacitation, was upregulated, and sAC was recruited to the sperm annulus following capacitation stimulation. We further found that SEPT12, SEPT4, and sAC formed a complex and colocalized to the sperm annulus. Additionally, sAC expression was reduced and disappeared in the annulus of the SEPT12 S196E- and S196A-mutant mouse sperm. In the sperm of the SEPT4-knockout mice, sAC did not localize to the annulus. Thus, our data demonstrate that SEPT12 phosphorylation status and SEPT4 activity jointly regulate sAC protein levels and annular localization to induce sperm capacitation.

Cyclin-Dependent Kinase 9 Inhibition as a Potential Treatment for Hepatocellular Carcinoma.

PURPOSE: Composite cyclin-dependent kinase (CDK) inhibition has shown potential as a treatment for hepatocellular carcinoma (HCC) in preclinical studies. We tested whether the specific inhibition of CDK9 was effective against HCC. METHODS: The effects of two specific CDK9 inhibitors, BAY1143572 and AZD4573, in HCC cell lines were examined. We tested the in vivo efficacy of CDK9 inhibition in mouse xenograft models of HuH7 human HCC cells and in an orthotopic model of BNL mouse HCC cells. Overexpression and knockdown of CDK9 were performed to confirm the efficacy of CDK9 inhibition. RESULTS: CDK9 inhibitors exhibited potent antiproliferative activities in HCC cells regardless of the levels of c-myc expression while inhibiting the downstream signals of CDK9, such as the phosphorylation of RNA polymerase II. These 2 CDK9 inhibitors induced apoptosis in HCC cells and reduced the expression of antiapoptotic proteins such as myeloid cell leukemia-1 and survivin. In the xenograft studies, mice receiving either CDK9 inhibitor exhibited significantly slower tumor growth than did the mice receiving vehicles. In the orthotopic model, the HCC growth in mice receiving a CDK9 inhibitor also tended to be slower than that in the control group. Overexpression of CDK9 in HuH7 cells reduced the efficacy of both CDK9 inhibitors. Knockdown of CDK9 expression reduced the proliferative activities of HCC cells. CONCLUSION: We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC.

Novel mutation of MAP3K1 gene in 46,XY DSD with complete gonadal dysgenesis.

OBJECTIVE: Swyer syndrome, or 46, XY complete gonadal dysgenesis, is a disorder of human sexual development which present with female external genitalia, lack of female reproductive organs, and a 46, XY karyotype. Many genes that participate in human sexual development have been implicated in the pathogenesis of 46, XY gonadal dysgenesis. CASE REPORT: A 18-year-old phenotypically female was presented with primary amenorrhea. Surveillance revealed hypergonadotropic hypogonadism, a normal male 46, XY karyotype and absent of functional gonad, which was confirmed by pathological examination of the streak gonad. Whole exome sequencing showed germline mutations of a novel missense variant, c.570G > C, p.Lys190Asn, in exon 2 of MAP3K1 gene. CONCLUSION: Given evolutionary conservation of lysine residue at position 190, the amino acid substitution may interfere with interaction between MAP3K1 and RHOA, and contributes to complete gonadal dysgenesis in the context of 46,XY.

[Progress on measurement of tibial posterior slope and its biomechanical relationship with posterior cruciate ligament].

The most reliable and convenient measurement method of tibial posterior slope(TPS) and its biomechanical relationship with posterior cruciate ligament (PCL) are still controversial. For X-ray measurement, it is recommended to use full-length lateral X-ray of the lower extremity in quatrous section, which has advantage of highly repeatable and common in the daily diagnosis and treatment process, but it is only applicable to patients with tibial rotation within 15°. When the rotation exceeds 30°, it is difficult to identify the inner contour of platform and is no applicable. If it is only used for daily diagnosis and treatment evaluation, when tibial rotation angle is less than 15°, lateral knee X-ray also has a certain reference significance, but the accuracy could not meet requirements of higher clinical research. For CT measurement method, it could correct tibial rotation, but using the fitting point to measure tibial posterior slope on three-dimensional CT reconstruction is only applicable to knee joint without degeneration, more osteophyte affects the way of using fitting point to determine the plane of tibia with real tibia platform conformity degree, have some limitations. For measurement of MRI, it could not only correct tibial rotation, but also minimize the effect of osteophytes by using tibial anatomical axis as the reference axis, which is a good measurement method. For the biomechanical relationship between tibial posterior slope and tibial posterior slope, increased tibial posterior slope indirectly alleviates tension of PCL through tibial anterior displacement or directly reduces load on posterior cruciate ligament in tibial osteotomies, suggesting a protective mechanism for tibial posterior slope;in total knee arthroplasty with cruciate ligament preserved, the size of tibial posterior slope will affect roll back mechanism of femur. When affected knee with PCL injury, it should be avoid to release then aggravate injury, and the stress could be alleviated by increasing tibial posterior slope appropriately. There has been no unified conclusion on the range of tibial posterior slope that is most beneficial to PCL. The natural tibial posterior slope is between 7 ° and 10°, which is considered to be the most beneficial to protection of PCL, but further studies are needed according to the differences in patients' bone status, surgical methods and so on.

Unusual glomus tumor of the lower leg: A case report.

BACKGROUND: Glomus tumors are rare neoplasms, usually found on the fingers or toes. Glomus tumours that occur in the lower leg are even rarer and is likely to be misdiagnosed or underdiagnosed. This article will document the diagnosis, treatment, and follow-up of a rare glomus tumor of the lower leg, which had been misdiagnosed for up to 15 years. CASE SUMMARY: The patient was a A 36-year-old woman who had suffered from localized pain in her left lower leg for 15 years. After a complete physical examination, a glomus tumor on her lower leg was considered and removed surgically. The specimen was pathologically diagnosed as a glomus tumor. There was no relapse at a 4-year follow-up. CONCLUSION: Correct diagnosis and complete removal of the glomus tumor is important.

Effects of Septin-14 Gene Deletion on Adult Cognitive/Emotional Behavior.

While various septin GTPases have been reported for their physiological functions, their roles in orchestrating complex cognitive/emotional functions in adult mammals remained scarcely explored. A comprehensive behavioral test battery was administered to two sexes of 12-week-old Septin-14 (SEPT14) knockout (KO) and wild-type (WT) mice. The sexually dimorphic effects of brain SEPT14 KO on inhibitory avoidance (IA) and hippocampal mGluR5 expression were noticed with greater IA latency and elevated mGluR5 level exclusively in male KO mice. Moreover, SEPT14 KO appeared to be associated with stress-provoked anxiety increase in a stress-related navigation task regardless of animals' sexes. While male and female WT mice demonstrated comparable cell proliferation in the dorsal and ventral hippocampal dentate gyrus (DG), both sexes of SEPT14 KO mice had increased cell proliferation in the ventral DG. Finally, male and female SEPT14 KO mice displayed dampened observational fear conditioning magnitude and learning-provoked corticosterone secretion as compared to their same-sex WT mice. These results, taken together, prompt us to conclude that male, but not female, mice lacking the Septin-14 gene may exhibit increased aversive emotion-related learning and dorsal/ventral hippocampal mGluR5 expressions. Moreover, deletion of SEPT14 may be associated with elevated ventral hippocampal DG cell proliferation and stress-provoked anxiety-like behavior, while dampening vicarious fear conditioning magnitudes.

Src Activation Aggravates Podocyte Injury in Diabetic Nephropathy via Suppression of FUNDC1-Mediated Mitophagy.

Background and purpose: Mitophagy plays a significant role in the progression of diabetic nephropathy (DN), although the regulatory mechanisms remain unclear. Recently, accumulating evidence demonstrated that impaired mitochondrial function and mitophagy are involved in DN. Here, we are aimed to explore the role of c-Src (Src) and FUNDC1-related mitophagy in the development of DN. Methods: The db/db mice were used to establish a DN mice model. The mice accepted PP2 (Src inhibitor) treatment to study the role of Src in DN. Kidney function was measured via biochemical testing. Renal histopathology and morphometric analysis were conducted via hematoxylin-eosin (HE), periodic acid-Schiff (PAS), Masson's staining, and transmission electron microscopy (TEM). We measured degree of apoptosis in kidney by TUNEL assay. Indices of mitophagy (LC3 and p62) were evaluated by Western blotting and immunofluorescence. Complementary in vitro assays were conducted using human podocytes subjected to high glucose in combination with PP2 treatment or FUNDC1 small interfering RNAs (siRNAs). Flow cytometry was used to detect the apoptotic cells. Mitochondrial function was evaluated by JC-1 staining. Double immunofluorescence labeling of LC3 and TOMM20 used to assess the degree of mitophagy. Results: Increased Src activation was detected in the kidneys of db/db mice, and its expression was positively correlated with mitochondrial damage, podocyte apoptosis, and renal dysfunction. Inhibition of Src activation with PP2 protected against mitochondrial damage and podocyte apoptosis. In vitro experiments in podocytes established that high glucose increased Src activation, promoting FUNDC1 phosphorylation and inhibiting mitophagy. Consistent with the mouse model, inhibiting Src activity protected podocytes against mitochondrial damage. FUNDC1 silencing negated the actions of PP2, indicating that FUNDC1-mediated mitophagy is downstream pathway of Src. Conclusion: In summary, our data indicated that Src is a culprit factor in diabetic renal damage via suppression of FUNDC1-mediated mitophagy, promoting the development of DN.

Harnessing Natural Products by a Pharmacophore-Oriented Semisynthesis Approach for the Discovery of Potential Anti-SARS-CoV-2 Agents.

Natural products possessing unique scaffolds may have antiviral activity but their complex structures hinder facile synthesis. A pharmacophore-oriented semisynthesis approach was applied to (-)-maoelactone A (1) and oridonin (2) for the discovery of anti-SARS-CoV-2 agents. The Wolff rearrangement/lactonization cascade (WRLC) reaction was developed to construct the unprecedented maoelactone-type scaffold during semisynthesis of 1. Further mechanistic study suggested a concerted mechanism for Wolff rearrangement and a water-assisted stepwise process for lactonization. The WRLC reaction then enabled the creation of a novel family by assembly of the maoelactone-type scaffold and the pharmacophore of 2, whereby one derivative inhibited SARS-CoV-2 replication in HPA EpiC cells with a low EC50 value (19±1 nM) and a high TI value (>1000), both values better than those of remdesivir.

Phase II Study of Gemcitabine, Peg-Asparaginase, Dexamethasone and Methotrexate Regimen for Newly Diagnosed Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: Final Analysis With Long-Term Follow-Up and Rational Research for the Combination.

Patients with extranodal natural killer/T-cell lymphoma (ENKTL), nasal type are benefit from peg-asparaginase, gemcitabine, and methotrexate. Therefore, we conducted a prospective phase II trial using a combination of these drugs as GAD-M regimen in naïve ENKTL patients, simultaneously, explored the combinational mechanism. The GAD-M regimen was administered for 6 cycles sandwiched by radiotherapy for stage I/II and 6 cycles for stage III/IV patients. After 6 cycles, the overall response rate of 36 patients was 91.6%, and the complete remission rate increased to 83.3%. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 74.8% and 77.8%, respectively. The 5-year PFS and OS were 68.3% and 77.8%. No patient suffered from the central nervous system (CNS) relapse. Most patients experienced recoverable liver dysfunction and anemia in this study. The plasma MTX concentration ratio at 12 to 24 hr during the first cycle could be an early predictor of outcomes in ENKTL (PFS, P=0.005; OS, P=0.002). Additionally, we found that high dose MTX (HD-MTX) and gemcitabine had the synergistic effect of ENKTL cell in vitro. Mechanistically, we demonstrated that the combination could lead to obviously apoptosis in ENKTL cell with extremely release of reactive oxygen spices (ROS), which mediated by endoplasmic reticulum stress. In conclusion, the GAD-M regimen could be a new choice to newly diagnosed ENKTL, especially for stage I/II patients. Furthermore, our results showed the synergy effect of HD-MTX with gemcitabine in ENKTL. CLINICAL TRIAL REGISTRATION: This trial was registered at www.clinicaltrials.gov as #NCT01991158.

The association between BMI, smoking, drinking and thyroid disease: a cross-sectional study in Wuhan, China.

BACKGROUND: There is no clear conclusion on the relationship between thyroid disease and obesity and lifestyle factors such as smoking and drinking. In this study, we analysed the association of body mass index (BMI), smoking and drinking with subclinical hypothyroidism (SHO) and thyroid nodules (TNs) with the results of a cross-sectional survey of urban residents in central China and discussed the potential mechanism linking these predictive factors and the two diseases. METHODS: This study included 1279 participants who were recruited from a Chinese community in 2011 and 2012. A questionnaire, laboratory examination and ultrasound diagnosis were conducted on these participants. Binary logistic regression analysis was used to analyse these factors. RESULTS: Overweight (BMI ≥ 25 kg/m2) was closely related to SHO and TNs in univariate and multivariate logistic regression analyses. Smoking had a protective effect on SHO and TNs, while drinking had a protective effect on TNs in univariate logistic regression and multivariate logistic regression with some covariates, but there was no significant difference between smoking and drinking and the two kinds of thyroid diseases in multivariate logistic regression analysis with all the covariates. In subgroup analysis, BMI ≥ 25 kg/m2 was significantly associated with SHO in people with positive thyroid antibodies (odds ratio (OR) = 2.221, 95 % confidence interval (CI): 1.168-4.184, P = 0.015) and smokers (OR = 2.179, 95 % CI: 1.041-4.561, P = 0.039). BMI ≥ 25 kg/m2 was significantly associated with TNs in people over 60 years old (OR = 2.069, 95 % CI: 1.149-3.724, P = 0.015) and drinkers (OR = 3.065, 95 % CI: 1.413-6.648, P = 0.005). Drinking alcohol had a protective effect on TNs in smokers (OR = 0.456, 95 % CI: 0.240-0.865, P = 0.016) and people with BMI ≥ 25 kg/m2 (OR = 0.467, 95 % CI: 0.236-0.925, P = 0.029). No significant association was found between smoking and the two thyroid diseases in different subgroups. CONCLUSIONS: Obesity is a risk factor for both TNs and SHO, especially in elderly individuals and people with positive thyroid autoantibodies. Obesity and metabolic syndrome may be more associated with TNs than SHO. Smoking may have a protective effect on thyroid disease, while drinking may have a protective effect only on TNs.

Protein Kinase A-Mediated Septin7 Phosphorylation Disrupts Septin Filaments and Ciliogenesis.

Septins are GTP-binding proteins that form heteromeric filaments for proper cell growth and migration. Among the septins, septin7 (SEPT7) is an important component of all septin filaments. Here we show that protein kinase A (PKA) phosphorylates SEPT7 at Thr197, thus disrupting septin filament dynamics and ciliogenesis. The Thr197 residue of SEPT7, a PKA phosphorylating site, was conserved among different species. Treatment with cAMP or overexpression of PKA catalytic subunit (PKACA2) induced SEPT7 phosphorylation, followed by disruption of septin filament formation. Constitutive phosphorylation of SEPT7 at Thr197 reduced SEPT7‒SEPT7 interaction, but did not affect SEPT7‒SEPT6‒SEPT2 or SEPT4 interaction. Moreover, we noted that SEPT7 interacted with PKACA2 via its GTP-binding domain. Furthermore, PKA-mediated SEPT7 phosphorylation disrupted primary cilia formation. Thus, our data uncover the novel biological function of SEPT7 phosphorylation in septin filament polymerization and primary cilia formation.

Detecting Genetic Ancestry and Adaptation in the Taiwanese Han People.

The Taiwanese people are composed of diverse indigenous populations and the Taiwanese Han. About 95% of the Taiwanese identify themselves as Taiwanese Han, but this may not be a homogeneous population because they migrated to the island from various regions of continental East Asia over a period of 400 years. Little is known about the underlying patterns of genetic ancestry, population admixture, and evolutionary adaptation in the Taiwanese Han people. Here, we analyzed the whole-genome single-nucleotide polymorphism genotyping data from 14,401 individuals of Taiwanese Han collected by the Taiwan Biobank and the whole-genome sequencing data for a subset of 772 people. We detected four major genetic ancestries with distinct geographic distributions (i.e., Northern, Southeastern, Japonic, and Island Southeast Asian ancestries) and signatures of population mixture contributing to the genomes of Taiwanese Han. We further scanned for signatures of positive natural selection that caused unusually long-range haplotypes and elevations of hitchhiked variants. As a result, we identified 16 candidate loci in which selection signals can be unambiguously localized at five single genes: CTNNA2, LRP1B, CSNK1G3, ASTN2, and NEO1. Statistical associations were examined in 16 metabolic-related traits to further elucidate the functional effects of each candidate gene. All five genes appear to have pleiotropic connections to various types of disease susceptibility and significant associations with at least one metabolic-related trait. Together, our results provide critical insights for understanding the evolutionary history and adaption of the Taiwanese Han population.

Clinical characteristics and outcomes of COVID-19 patients with gastrointestinal symptoms admitted to Jianghan Fangcang Shelter Hospital in Wuhan, China.

Coronavirus disease 2019 (COVID-19) is a health emergency worldwide, and gastrointestinal (GI) symptoms are increasingly reported in COVID-19 patients. However, sample size was small and the incidence of GI symptoms in patients was variable across studies, and the correlation between these symptoms and clinical outcomes remains incompletely understood. The objective of this study is to compare clinical characteristics and outcomes between patients with and without GI symptoms admitted to Jianghan Fangcang Shelter Hospital in Wuhan. This retrospective study recruited 1320 COVID-19 patients admitted to hospital from 5 February 2020 to 9 March 2020. On the basis of the presence of GI symptoms, the sample was divided into a GI group (n = 192) and a non-GI group (n = 1128). The three most common GI symptoms were diarrhea (8.1%), anorexia (4.7%), and nausea and vomiting (4.3%). The rate of clinical deterioration was significantly higher in the GI group than in the non-GI group (15.6% vs. 10.1%, P = .032). GI symptoms (P = .045), male gender P < .001), and increased C-reactive protein (P = .008) were independent risk factors for clinical worsening. This study demonstrated that the rate of clinical deterioration was significantly higher in the GI group. Furthermore, potential risk factors for developing GI symptoms, male gender, and increased C-reactive protein can help clinicians predict clinical outcomes in COVID-19 patients.

The SEPT12 complex is required for the establishment of a functional sperm head-tail junction.

The connecting pieces of the sperm neck link the flagellum and the sperm head, and they are important for initiating flagellar beating. The connecting pieces are important building blocks for the sperm neck; however, the mechanism of connecting piece assembly is poorly understood. In the present study, we explored the role of septins in sperm motility and found that Sept12D197N knock-in (KI) mice produce acephalic and immotile spermatozoa. Electron microscopy analysis showed defective connecting pieces in sperm from KI mice, indicating that SEPT12 is required for the establishment of connecting pieces. We also found that SEPT12 formed a complex with SEPT1, SEPT2, SEPT10 and SEPT11 at the sperm neck and that the D197N mutation disrupted the complex, suggesting that the SEPT12 complex is involved in the assembly of connecting pieces. Additionally, we found that SEPT12 interacted and colocalized with γ-tubulin in elongating spermatids, implying that SEPT12 and pericentriolar materials jointly contribute to the formation of connecting pieces. Collectively, our findings suggest that SEPT12 is required for the formation of striated columns, and the capitulum and for maintaining the stability of the sperm head-tail junction.