Design and fabrication of new infrared (IR) nonlinear optical (NLO) materials with balanced properties are urgently needed since commercial chalcopyrite-like (CL) NLO crystals are suffering from their intrinsic drawbacks. Herein, the first defect-CL (DCL) alkali-earth metal (AEM) selenide IR NLO material, DCL-MgGa2 Se4 , has been rationally designed and fabricated by a structure prediction and experiment combined strategy. The introduction of AEM tetrahedral unit MgSe4 effectively widens the band gap of DCL compounds. The title compound exhibits a wide band gap of 2.96 eV, resulting in a high laser induced damage threshold (LIDT) of ≈3.0 × AgGaS2 (AGS). Furthermore, the compound shows a suitable second harmonic generation (SHG) response (≈0.9 × AGS) with a type-I phase-matching (PM) behavior and a wide IR transparent range. The results indicate that DCL-MgGa2 Se4 is a promising mid-to-far IR NLO material and give some insights into the design of new CL compound with outstanding IR NLO properties based on the AEM tetrahedra and the structure predication and experiment combined strategy.

Patients with heart failure with preserved ejection fraction (HFpEF) have large individual differences, unclear risk stratification, and imperfect treatment plans. Risk prediction models are helpful for the dynamic assessment of patients' prognostic risk and early intensive therapy of high-risk patients. The purpose of this study is to systematically summarize the existing risk prediction models and novel prognostic factors for HFpEF, to provide a reference for the construction of convenient and efficient HFpEF risk prediction models.

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease that causes multi-organ complications, seriously affecting patients' quality of life and survival. Understanding its pathogenesis remains challenging, with current clinical treatment regimens often proving ineffective.

Recent studies demonstrated cutaneous phosphorylated α synuclein (p-syn) deposition in idiopathic and some monogenetic Parkinson disease (PD) patients, suggesting synucleinopathy identical to that in the brain. Although the LRRK2 Gly2385Arg (G2385R) variant is a common PD risk factor in the Chinese population, the pathogenesis of PD with G2385R variant has not been reported. We investigated whether synucleinopathy and small fiber neuropathy (SFN) are associated with the G2385R variant.

Objectives: To evaluate the current evidence whether Chinese medicine compound (CMC) can reduce the serum levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP). Methods: We comprehensively searched PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), the Database for Chinese Technical Periodicals (VIP), and Wanfang data. We then performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) assessing the CMC therapy methods. This study is registered with PROSPERO, number CRD42020216284. Results: In total, 65 studies were eligible for inclusion, including 6099 patients. The result of the meta-analysis showed that compared with common Western medicine therapy, CMC monotherapy or combined with Western medicine was able to reduce serum RF (SMD= -0.85, 95%CI -1.04 to -0.67) and anti-CCP (SMD= -0.56, 95%CI -0.79 to -0.32) levels to some extent. In the efficacy meta-analysis, a greater number of CMC-treated patients achieved the efficacy criteria after a period of treatment, where the relative risk (RR) was 1.20 [1.08, 1.33] for achieving ACR20, 1.57 [1.38, 1.78] for ACR50, and 2.21 [1.72, 2.84] for ACR70. At the same time, there was a statistically significant difference in the effective rate of the patient's TCM symptoms (RR = 1.22, 95%CI 1.19-1.26). Conclusions: Through this meta-analysis and systematic review, we found that CMC for the treatment of RA is effective in reducing RF and anti-CCP levels and might have better clinical efficacy than Western medicine monotherapy. Some active components are responsible for this efficacy and worth further exploring.

Blood reperfusion of ischemic cerebral tissue may cause cerebral ischemia-reperfusion (CIR) injury. Necroptosis and inflammation have been demonstrated to be involved in the disease-related process of CIR injury. The E3 ubiquitin ligase carboxyl terminus of Hsp70-interacting protein (CHIP) can modulate multiple cellular signaling processes, including necroptosis and inflammation. Numerous studies have demonstrated the neuroprotective effects of CHIP on multiple central nervous system (CNS) diseases. However, the effects of CHIP on CIR injury have not been fully explored. We hypothesize that CHIP can exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury. In the present study, adult wild-type (WT) C57BL/6 mice and CHIP knock-in (KI) mice with a C57BL/6 background and CHIP overexpression in neural tissue underwent middle cerebral artery occlusion (MCAO) surgery to simulate CIR onset. Our data indicated that CHIP expression in the peri-infarct tissue was markedly increased after MCAO surgery. Compared with WT mice, CHIP KI mice significantly improved neurological deficit scores, decreased cerebral infarct volume, and attenuated brain edema and neuronal damage. Meanwhile, CHIP overexpression attenuated necroptosis and inflammation induced by MCAO surgery. These findings indicated that overexpression of CHIP might exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury, and increasing CHIP levels may be a potential strategy in cerebrovascular disease therapy.

The invasion and metastasis of tumor cells are the hallmarks of malignant diseases and the greatest obstacle to overcome. Heparanase-mediated degradation of heparan sulfate (HS) is the critical process for tumor angiogenesis and metastasis, therefore, heparanase become an attractive target for cancer research. Herein, we reported a native fucosylated glycosaminoglycan (nHG) extracted from sea cucumber Holothuria fuscopunctata and a depolymerized nHG (dHG) and its contained oligosaccharides (hs17, hs14, hs11, hs8 and hs5), acting as heparanase inhibitors. nHG and its derivatives have the ability to bind with heparanase directly, leading to significant inhibition of heparanase activity. Moreover, their apparent binding affinity to heparanase was comparable to their inhibitory effect, which was elevated along with the increase of chain length, similar to the effect of heparins. In addition, oligosaccharides inhibited the migration and invasion of 4T1 mammary carcinoma cells and human umbilical vein endothelial cells (HUVECs) and also suppressed tube formation in Matrigel matrix and angiogenesis in the chick chorioallantoic membrane (CAM) assay. In the metastatic mouse model, oligosaccharides exhibited practical antimetastatic effects on 4T1 mammary carcinoma cells. According to the reported anticoagulant activity and the low bleeding tendency of dHG and its oligosaccharides, the use of the oligosaccharides may lead to better effects on tumor patients with thrombosis tendency.

Paroxysmal kinesigenic dyskinesia (PKD), the most common type of paroxysmal movement disorders, is caused by mutations in PRRT2 gene. We identified an unreported PRRT2 c. 535 C > T (p. Q 1 7 9 *) pathogenic mutation in a Chinese Han family with PKD and generated an induced pluripotent stem cell (iPSC) line from a patient in the family by reprogramming fibroblasts with sendai virus. The iPSC line was characterized for genetic uniqueness, genomic integrity, pluripotency, and differentiation ability. This iPSC line will be a powerful tool to to study the molecular mechanisms underlying PKD.

The p.Thr61Ile (p.T61I) mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) was deemed a causative factor in Parkinson's disease (PD). However, the pathomechanism of the CHCHD2 p.T61I mutation in PD remains unclear. Few existing mouse models of CHCHD2-related PD completely reproduce the features of PD, and no transgenic or knock-in (KI) mouse models of CHCHD2 mutations have been reported. In the present study, we generated a novel CHCHD2 p.T61I KI mouse model, which exhibited accelerated mortality, progressive motor deficits, and dopaminergic (DA) neurons loss with age, accompanied by the accumulation and aggregation of α-synuclein and p-α-synuclein in the brains of the mutant mice. The mitochondria of mouse brains and induced pluripotent stem cells (iPSCs)-derived DA neurons carrying the CHCHD2 p.T61I mutation exhibited aberrant morphology and impaired function. Mechanistically, proteomic and RNA sequencing analysis revealed that p.T61I mutation induced mitochondrial dysfunction in aged mice likely through repressed insulin-degrading enzyme (IDE) expression, resulting in the degeneration of the nervous system. Overall, this CHCHD2 p.T61I KI mouse model recapitulated the crucial clinical and neuropathological aspects of patients with PD and provided a novel tool for understanding the pathogenic mechanism and therapeutic interventions of CHCHD2-related PD.

To explore the relationship between serum levels of inflammatory markers and symptomatic severity of bipolar disorder (BD).

CRISPR/Cas9-mediated genome editing provides potential for therapeutic development. Efficacy and long-term safety represent major concerns that remain to be adequately addressed in preclinical studies. Here we show that CRISPR/Cas9-mediated genome editing in two distinct SOD1-amyotrophic lateral sclerosis (ALS) transgenic mouse models prevented the development of ALS-like disease and pathology. The disease-linked transgene was effectively edited, with rare off-target editing events. We observed frequent large DNA deletions, ranging from a few hundred to several thousand base pairs. We determined that these large deletions were mediated by proximate identical sequences in Alu elements. No evidence of other diseases was observed beyond 2 years of age in these genome edited mice. Our data provide preclinical evidence of the efficacy and long-term safety of the CRISPR/Cas9 therapeutic approach. Moreover, the molecular mechanism of proximate identical sequences-mediated recombination provides mechanistic information to optimize therapeutic targeting design, and to avoid or minimize unintended and potentially deleterious recombination events.

Gastric cancer stem cells (GCSCs) have been used as a therapeutic target. This study aims to estimate the role of miR-98-5p (termed miR-98) in the development of GCSCs.

Previously we identified the p.Thr61Ile mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) in a Chinese family with autosomal dominant Parkinson's disease. But the mechanism is still unclear. In this study, we explored the effects of CHCHD2 p.Thr61Ile mutation in cells and its association with coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10). We found that overexpression of Parkinson's disease-associated T61I mutant CHCHD2 did not produce mitochondrial dysfunction. Rather, its protective effect from stress was abrogated. And, the level of the CHCHD2 protein and mRNA in patient fibroblasts was not significantly different from control. In addition, CHCHD2 T61I mutation caused increased interaction with CHCHD10 and reduced CHCHD10 level. The mitochondrial ultrastructural alterations in CHCHD2 T61I mutant patient fibroblasts are similar to that of CHCHD10 mutations. We therefore propose that CHCHD10 is involved in the development of Parkinson's disease caused by CHCHD2 loss-of-function mutation p.T61I.

Ras-related protein 39B (RAB39B) mutation has been reported as a potential cause of X-linked Parkinson's disease (PD), a rare form of familial PD. Recently, a novel RAB39B mutation was identified in an X-linked juvenile parkinsonism family and the dermal fibroblasts of the patient were obtained and successfully induced to induced pluripotent stem cells (iPSCs) by the human OSKM transcription factors using the Sendai-virus delivery system. Our model may offer a good platform for further research of the pathomechanism, drug testing, and gene therapy of this disease.

Our study retrospectively investigated the expression of forkhead/winged helix transcription factor (Foxp3) in renal tissue and clinical features of patients with hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN). A total of 58 patients with HBV-GN were assigned to group A; 45 serum and renal tissue HBsAg-negative patients with nephritis were group B; 24 serum HBsAg-positive and renal tissue HBsAg-negative patients with slightly increased serum creatinine without nephritis were group C. Clinical manifestations, laboratory indices and renal biopsies were recorded. Expression of Foxp3, CD4 and CD25 in renal tissue was detected by immunohistochemistry. In group A, 74.1% were serum HBeAg-negative, with serum complement C3 level of 0.99±0.27 g/l, and deposition rates of renal complement C3 and C1q in renal tissue of 34.9 and 16.3% respectively; 25.9% were serum HBeAg-positive, with serum complement C3 level of 0.19±0.17 g/l, and deposition rates of renal complement C3 and C1q in renal tissue of 80 and 46.7%, respectively. A significant difference was found in C3 and C1q between HBeAg-negative and HBeAg-positive group (P<0.05). Increased urinary protein and decreased serum albumin were found in patients in group A with moderate levels of HBV DNA compared with patients with low levels of HBV DNA in the same group over 24 h (P<0.05). The numbers of Foxp3+ lymphocytes, CD4+ T cells and CD25+ T cells in the tubulointerstitium of patients in groups A and B were 3.41±1.16 vs. 3.52±1.27, 2.78±0.15 vs. 3.12±0.17 and 2.90±0.20 vs. 3.09±0.18, respectively. The clinical manifestation of HBV-GN is nephrotic syndrome, and HBV DNA is correlated with urinary protein and serum albumin levels. Activation of C3 and C1q may be related to the pathogenesis of HBV-GN in serum HBeAg-positive patients. Downregulation of Foxp3 expression in regulatory T cells is related to the development and progression of HBV-GN.

Diabetic encephalopathy may lead to cognitive deficits in diabetic patients and diminish quality of life. It has been shown that protracted hyperglycaemia is directly associated with neuronal apoptosis, which is involved in diabetic encephalopathy. The anaphase-promoting complex (APC) is essential for the survival of post-mitotic neurons. In our previous study, we found that the mitotic arrest deficient protein MAD2B, one of APC inhibitors, was expressed in neurons in central nervous system. However, whether MAD2B is involved in hyperglycaemia-induced apoptosis and thus takes part in diabetic encephalopathy is still unknown. To address this issue, we first explored the expression of MAD2B and cyclin B1 detected by immunofluorescence and Western blot. It was found that hyperglycaemia remarkably increased the expression of MAD2B and accumulation of cyclin B1 in cortices of diabetes mellitus rat model and in cultured primary neurons. To further explore the role of MAD2B in hyperglycaemia-induced neuronal injury, we depleted MAD2B expression by a specifically targeted shRNA against MAD2B. We observed that MAD2B deficiency alleviated cyclin B1 expression and apoptotic neuronal death. These results demonstrate that MAD2B expression is the main culprit for accumulation of cyclin B1 and apoptosis in neurons under high glucose. Moreover, inhibition of the expression of MAD2B prevented neurons from entering an aberrant S phase that led differentiated neurons into apoptotic cell death. These results suggest that hyperglycaemia induced neuronal apoptosis through inducing expression of MAD2B, which represents a novel mechanism of diabetic encephalopathy.

Myotonic dystrophy type 1 (DM1) is a dominantly inherited neurodegenerative disease caused by a CTG repeat expansion close to the DMPK gene. The fibroblasts from a patient with DM1 were successfully converted to induced pluripotent stem cells (iPSCs), designated ZZUi006-A, by employing episomal plasmids expressing OCT3/4, SOX2, KLF4, LIN28, L-MYC. The ZZUi006-A cell line may provide a robust platform for further study of DM1 pathogenesis as well as drug testing and gene therapy research.

AChR is concentrated at the postjunctional membrane at the neuromuscular junction. However, the underlying mechanism is unclear. We show that α-actinin, a protein known to cross-link F-actin, interacts with rapsyn, a scaffold protein essential for neuromuscular junction formation. α-Actinin, rapsyn, and surface AChR form a ternary complex. Moreover, the rapsyn-α-actinin interaction is increased by agrin, a factor known to stimulate AChR clustering. Downregulation of α-actinin expression inhibits agrin-mediated AChR clustering. Furthermore, the rapsyn-α-actinin interaction can be disrupted by inhibiting Abl and by cholinergic stimulation. Together these results indicate a role for α-actinin in AChR clustering.

The development of liver cancer would undergo a sequential progression from chronic inflammatory liver disease, cirrhosis to neoplasia. During these pathophysiological changes, abnormal liver microenvironment might induce the hepatocytes to die, abnormally proliferate and initiate cancer stem cells. Metallocarboxypeptidases (MCPs) involved in multiple biological functions including inflammation, fibrosis and stem cell niche formation. This study aimed to evaluate the expression of carboxypeptidase 4 (CPA4) in hepatitis, liver cirrhosis and liver cancer tissues, and revealed its clinical significance in liver cancer progression. We firstly found that the CPA4 levels in tissues were significantly higher in liver cancer patients than those in other three groups. Then, elevated levels of CPA4 was observed in 57/100 (57%) liver cancer samples, and significantly correlated with Grade and Stage. We also identified a significant positive correlation between aberrant elevation of CPA4 and overexpression of stem cell markers including CD90, AFP and CD34 with follow-up data (n=100). Further Kaplan-Meier analysis confirmed that high levels of CPA4 and CD90 were significant predictors of poor overall survival. Multivariate Cox regression model showed that CPA4 was an independent prognostic factor for patients with liver cancer. This study demonstrated for the first time that high CPA4 expression was closely correlated with hepatocarcinogenesis, and might be used as an independent poor prognostic factor in liver cancer.

Extracellular matrix metalloproteinase inducer (EMMPRIN) reportedly has a key regulatory role in matrix metalloproteinase (MMP) activities and the progression of atherosclerosis. Statins, which are anti-atherosclerotic pharmacological agents, are widely applied in clinical settings. The aim of the present study was to investigate the pharmaceutical effect of atorvastatin on EMMPRIN expression in atherosclerotic plaques. An atherosclerotic mouse model was established using apoliprotein E-deficient (ApoE-/-) mice raised on a high-fat diet. Additionally, a low (5 mg/kg/day) or high dosage (10 mg/kg/day) of atorvastatin suspension was administered orally for eight weeks, beginning on week 7 or 11 respectively. The effects of atorvastatin on atherosclerotic plaque formation and EMMPRIN expression were subsequently determined. The THP-1 cell line was used to investigate the effect of atorvastatin on EMMPRIN expression in vitro. The results demonstrated that the high-fat diet led to vulnerable plaques (VPs) and increased EMMPRIN expression in VPs in ApoE-/- mice. Atorvastatin treatment decreased EMMPRIN expression in the aortas and plaques of ApoE-/- mice. In vitro, oxidized low-density lipoprotein (ox-LDL) induced the expression of cyclooxygenase-2 (COX-2) and EMMPRIN in THP-1 macrophages, and atorvastatin inhibited ox-LDL-induced expression of PGE2, EMMPRIN and COX-2 in THP-1 macrophages. Therefore, the present data indicated that atorvastatin treatment reduces the vulnerability of atherosclerotic plaques and expression of EMMPRIN, and that the inhibitory effect of atorvastatin on EMMPRIN may occur via the COX-2/PGE2 signaling pathway in macrophages.