STAMBP is Required for Long-Term Maintenance of Neural Progenitor Cells Derived from hESCs.

Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by global developmental delay, severe microcephaly, capillary malformations, etc. Previous biochemical investigations and loss-of-function studies in mice have provided insights into the mechanism of STAMBP, however, it remains controversial how STAMBP deficiency leads to malformation of those affected tissues in patients. In this study, we investigated the function and underlying mechanism of STAMBP during neural differentiation of human embryonic stem cells (hESCs). We found that STAMBP is dispensable for the pluripotency maintenance or neural differentiation of hESCs. However, neural progenitor cells (NPCs) derived from STAMBP-deficient hESCs fail to be long-term maintained/expanded in vitro. We identified the anti-apoptotic protein CFLAR is down-regulated in those affected NPCs and ectopic expression of CFLAR rescues NPC defects induced by STAMBP-deficiency. Our study not only provides novel insight into the mechanism of neural defects in STAMBP mutant patients, it also indicates that the death receptor mediated apoptosis is an obstacle for long-term maintenance/expansion of NPCs in vitro thus counteracting this cell death pathway could be beneficial to the generation of NPCs in vitro.

A highly conductive and robust micrometre-sized SiO anode enabled by an in situ grown CNT network with a safe petroleum ether carbon source.

SiO-based materials as lithium-ion anodes have attracted huge attention owing to their ultrahigh capacity. However, they usually undergo severe volume expansion over the repeated lithiation/delithiation processes and have low electronic conductivity, leading to an inferior cycling stability and poor rate capability. In this study, carbon nanotubes in situ grown on the surface of commercially available micro-sized SiO (D50 = 5 µm) were prepared. The conductive network composed of one-dimensional carbon nanotubes could enhance its conductivity and enhance the structural stability during the cycling. The synthesized 3D-SiO@C material demonstrates good long-term cycling stability, with a reversible capacity of up to 687.7 mA h g-1 after 1000 cycles, and it maintains a high reversible capacity of 736.8 mA h g-1, even at a high current density of 1 A g-1.

CENPA promotes glutamine metabolism and tumor progression by up-regulating SLC38A1 in endometrial cancer.

Glutamine addiction is a significant hallmark of metabolic reprogramming in tumors and is crucial to the progression of cancer. Nevertheless, the regulatory mechanisms of glutamine metabolism in endometrial cancer (EC) remains elusive. In this research, we found that elevated expression of CENPA and solute carrier family 38 member 1 (SLC38A1) were firmly associated with worse clinical stage and unfavorable outcomes in EC patients. In addition, ectopic overexpression or silencing of CENPA could either enhance or diminish glutamine metabolism and tumor progression in EC. Mechanistically, CENPA directly regulated the transcriptional activity of the target gene, SLC38A1, leading to enhanced glutamine uptake and metabolism, thereby promoting EC progression. Notably, a prognostic model utilizing the expression levels of CENPA and SLC38A1 genes independently emerged as a prognostic factor for EC. More importantly, CENPA and SLC38A1 were significantly elevated and positively correlated, as well as indicative of poor prognosis in multiple cancers. In brief, our study confirmed that CENPA is a critical transcription factor involved in glutamine metabolism and tumor progression through modulating SLC38A1. This revelation suggests that targeting CENPA could be an appealing therapeutic approach to address pan-cancer glutamine addiction.

BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.

Post-translational modifications (PTMs) on histones play essential roles in cell fate decisions during development. However, how these PTMs are recognized and coordinated remains to be fully illuminated. Here, we show that BRPF1, a multi-histone binding module protein, is essential for pluripotency in human embryonic stem cells (ESCs). BRPF1, H3K4me3, and H3K23ac substantially co-occupy the open chromatin and stemness genes in hESCs. BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well. Deletion of the N terminal or PHD-zinc knuckle-PHD (PZP) module in BRPF1 completely impairs its functions in hESCs while PWWP module deletion partially impacts the function. In sum, we reveal BRPF1, the multi-histone binding module protein that bridges the crosstalk between different histone modifications in hESCs to maintain pluripotency.

Comparison of clinical outcomes of using the nonirradiated and irradiated allograft for anterior cruciate ligament (ACL) reconstruction: A systematic review update and meta-analysis.

BACKGROUND: This study was a systematic review comparing the clinical outcomes of using the nonirradiated and irradiated allograft for anterior cruciate ligament (ACL) reconstruction. METHODS: A comprehensive literature search was conducted using multiple databases, including Medline, Embase, and Cochrane. All databases were searched from the earliest records through August 2019 using the following Boolean operators: irradiated AND nonirradiated AND ACL AND allograft. All prospective and retrospective controlled trials were retrieved that directly compared physical examination and knee function scores and patient-rated outcomes between the nonirradiated and irradiated allograft for ACL reconstruction. RESULTS: Three prospective and 2 retrospective articles were identified by the search, and the findings suggested that the nonirradiated allografts were superior to the irradiated allografts based on improved knee joint functional scores and decreased failure rate, even though there was no significantly difference with respect to overall IKDC, range of motion, vertical jump test, and one-leg hop test. CONCLUSIONS: Irradiated allograft should be limited to be used in ACL surgery and further research into new alternative sterilization techniques are needed to avoiding the disease transmission without interference with the biomechanical properties of the grafts.

MicroRNA-221 Upregulates the Expression of P-gp and Bcl-2 by Activating the Stat3 Pathway to Promote Doxorubicin Resistance in Osteosarcoma Cells.

MicroRNA-221 (miRNA-221) is upregulated in several malignant tumors and is associated with poor patient prognosis. Therefore, the present study aimed to investigate the role and underlying mechanism of miRNA-221 in doxorubicin (DOX) resistance in osteosarcoma cells. We constructed DOX-resistant Saos-2/DOX cells and treated them with DOX. Cell viability was determined by performing a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cells were transfected with either miRNA-221 mimic or miRNA-221 inhibitor; quantitative (q)RT-PCR was performed to detect the expression of miRNA-221. Flow cytometry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling (TUNEL) staining were used to detect cell apoptosis. The immunofluorescence method was also used to detect cell signal transduction and activator of transcription 3 (Stat3) protein expression distribution. In addition, Western blotting was used to detect changes in the expression of each protein. We found that miRNA-221 was upregulated in Saos-2/DOX cells. Moreover, the miRNA-221 mimic induced DOX resistance in Saos-2 cells, whereas the miRNA-221 inhibitor enhanced DOX sensitivity in Saos-2/DOX cells. The miRNA-221 mimic upregulated the expression of phosphorylated-Stat3, P-glycoprotein (P-gp), and B-cell lymphoma-2 (Bcl-2) proteins in Saos-2 cells and induced the entry of Stat3 into the nucleus, whereas the miRNA-221 inhibitor exerted the opposite effect. Pretreatment with the Stat3 chemical inhibitor, STAT3-IN-3, significantly inhibited the upregulation of P-gp and Bcl-2 protein expression induced by the miRNA-221 mimic in Saos-2 cells; it also caused the Saos-2 cells to overcome DOX resistance induced by the miRNA-221 mimic. Thus, miRNA-221 increased the expression of P-gp and Bcl-2 by activating the Stat3 pathway to promote DOX resistance in osteosarcoma cells, indicating a potential use of miRNA-221 in osteosarcoma treatment.

Effects of Lévy noise on the Fitzhugh-Nagumo model: A perspective on the maximal likely trajectories.

This paper considers about the escape paths of the FitzHugh-Nagumo neural system driven by symmetric α-stable Lévy noise (non-Gaussian noise). The existing research has shown that noise can make this system produce a spike pulse, which corresponds to a state transition. To analyze the effects of Lévy noise on the state transition, a novel statistical quantity called maximal likely trajectory, which is obtained by recording the maximizer of the probability density function at every moment, is used to characterize the escape paths of the equilibrium and revel the relationship between state transition and noise intensity or Lévy motion index. The numerical experiments show that for fixed Lévy motion index, the larger noise intensity can promote this neural system to an excitatory state. In addition, the influence of Lévy motion index on the state transition depends on the selection of noise intensity in this neural system. Meanwhile, as a comparison, the case driven by Brownian motion (Gaussian noise) is also taken into account, which shows that in some situations Lévy noise makes the FitzHugh-Nagumo system excited in shorter time. In addition, the maximal likely trajectory provides us with a new perspective to show the existence of a separatrix in the stochastic setting of the FitzHugh-Nagumo model and also depict the rough shape of the middle part of this separatrix.

Protein kinase A determines platelet life span and survival by regulating apoptosis.

Apoptosis delimits platelet life span in the circulation and leads to storage lesion, which severely limits the shelf life of stored platelets. Moreover, accumulating evidence indicates that platelet apoptosis provoked by various pathological stimuli results in thrombocytopenia in many common diseases. However, little is known about how platelet apoptosis is initiated or regulated. Here, we show that PKA activity is markedly reduced in platelets aged in vitro, stored platelets, and platelets from patients with immune thrombocytopenia (ITP), diabetes, and bacterial infections. Inhibition or genetic ablation of PKA provoked intrinsic programmed platelet apoptosis in vitro and rapid platelet clearance in vivo. PKA inhibition resulted in dephosphorylation of the proapoptotic protein BAD at Ser155, resulting in sequestration of prosurvival protein BCL-XL in mitochondria and subsequent apoptosis. Notably, PKA activation protected platelets from apoptosis induced by storage or pathological stimuli and elevated peripheral platelet levels in normal mice and in a murine model of ITP. Therefore, these findings identify PKA as a homeostatic regulator of platelet apoptosis that determines platelet life span and survival. Furthermore, these results suggest that regulation of PKA activity represents a promising strategy for extending platelet shelf life and has profound implications for the treatment of platelet number-related diseases and disorders.

Safflower extract inhibiting apoptosis by inducing autophagy in myocardium derived H9C2 cell.

The Heart failure (HF) is considered as the end-stage of various heart disease and associated with high mortality globally. Progressive loss of cardiac myocytes via apoptosis is considered as the most important factor for HF pathology. In this study, we demonstrated that Safflower extract was able to inhibitthe apoptosis inducted by Angiotensin II (AngII) in a ratmyocardium derived cell line H9C2. Further examination of LC-3II conversion and autophagosome formation suggested Safflower extract induced autophagy in treated cell. Inhibition of Safflower extract induced autophagy by 3-methyladenine (3MA) abolished anti-apoptotic function of Safflower extract, while application of autophagy stimulator Rapamycin in H9C2 inhibited apoptosis as well. Moreover, treatment of H9C2 cell with Safflower extract also inhibited expression of pro-apoptotic genes BAD and Bax. In conclusion, our data indicated that Safflower extract inhibit apoptosis via inducing autophagy in myocardium cell and demonstrated the potential as novel therapeutic drug for Heart failure.

Major inducing factors of hypertensive complications and the interventions required to reduce their prevalence: an epidemiological study of hypertension in a rural population in China.

BACKGROUND: The complications of hypertension cause severe health problems in rural areas in China. We (i) screened the major factors inducing hypertensive complications and provided intervention measures; and (ii) verified the efficacy of the New Rural Cooperative Medical Scheme (NRCMS; a medical insurance scheme for rural residents) for hypertension management. METHODS: A survey was conducted in the villages of Yunnan (an underdeveloped province in southwest China). The NRCMS was initiated there in 2005. Data were collected through questionnaires, physical examination, electrocardiography, as well as blood and urine tests. To detect factors inducing hypertension complications, a generalized estimating equations model was developed. Multivariable logistic regression was used to analyze influencing factors for hypertension control. RESULTS: Poor management of hypertension was observed in women. Being female, old, poorly educated, a smoker, ignorant of the dangerousness of hypertension, and having uncontrolled hypertension made patients more prone to hypertension complications. Combination therapy with ≥ 2 drugs helped control hypertension, but most rural patients disliked multidrug therapy because they considered it to be expensive and inconvenient. The NRCMS contributed little to reduce the prevalence of complications and improve control of hypertension. CONCLUSIONS: The present study suggested that the NRCMS needs to be reformed to concentrate on early intervention in hypertension and to concentrate on women. To increase hypertension control in rural areas in China, compound products containing effective and inexpensive drugs (and not multidrug therapy) are needed.