Search

Multicenter international clinical trials demonstrated the clinical safety and efficacy by using stem cell educator therapy to treat type 1 diabetes (T1D) and other autoimmune diseases. Previous studies characterized the peripheral blood insulin-producing cells (PB-IPC) from healthy donors with high potential to give rise to insulin-producing cells. PB-IPC displayed the molecular marker glucose transporter 2 (GLUT2), contributing to the glucose transport and sensing. To improve the clinical efficacy of stem cell educator therapy in the restoration of islet β-cell function, we explored the GLUT2 expression on PB-IPC in recent onset and longstanding T1D patients. In the Food and Drug Administration (FDA)-approved phase 2 clinical studies, patients received one treatment with the stem cell educator therapy. Peripheral blood mononuclear cells (PBMC) were isolated for flow cytometry analysis of PB-IPC and other immune markers before and after the treatment with stem cell educator therapy. Flow cytometry revealed that both recent onset and longstanding T1D patients displayed very low levels of GLUT2 on PB-IPC. After the treatment with stem cell educator therapy, the percentages of GLUT2+CD45RO+ PB-IPC were markedly increased in these T1D subjects. Notably, we found that T1D patients shared common clinical features with patients with other autoimmune and inflammation-associated diseases, such as displaying low or no expression of GLUT2 on PB-IPC at baseline and exhibiting a high profile of the inflammatory cytokine interleukin (IL)-1β. Flow cytometry demonstrated that their GLUT2 expressions on PB-IPC were also markedly upregulated, and the levels of IL-1β-positive cells were significantly downregulated after the treatment with stem cell educator therapy. Stem cell educator therapy could upregulate the GLUT2 expression on PB-IPC and restore their function in T1D patients, leading to the improvement of clinical outcomes. The clinical data advances current understanding about the molecular mechanisms underlying the stem cell educator therapy, which can be expanded to treat patients with other autoimmune and inflammation-associated diseases. [ABSTRACT FROM AUTHOR]

As an important cornerstone of the fourth industrial revolution, the industrial Internet transforms isolated industrial systems into connected networks and is an important expansion direction for digital industrialization. Anomaly detection in the industrial Internet of things environment is of great significance for automated decision-making. To address the problem that most existing methods fail to effectively consider the complex unknown topological relationships between sensors and the multi-scale patterns inherent in the industrial IoT temporal data, an unsupervised anomaly detection method MSTSAD with multi-scale spatiotemporal feature fusion for industrial IoT temporal data is proposed, which firstly constructs a novel bi-directional spatiotemporal feature extraction module to sequentially captures the correlation and bidirec- tional dependency between multiple time series. Secondly, a multi- scale gated temporal convolutional neural network is designed to adaptively extract multi-scale temporal features of time series, and a dual affine projection is introduced to realize the cross- fusion of multi-scale temporal features and spatiotemporal features to enhance the feature extraction of the model on the original data. Finally, a variational self-encoder combined with adversarial training is proposed to amplify the reconstruction error of anomalies and enhance the anti-interference ability of the model to train data noise, which enhances the ability of model to discriminate anomalous data. Experiments are conducted on four publicly available datasets, GPW, ECG5000, Occupancy and SWaT, in comparison with five state-of-the-art methods, and the experimental results show that F1 scores of MSTSAD are enhanced by 0.015-0.047. [ABSTRACT FROM AUTHOR]

Thus far, glossing studies have remained at the level of individual words rather than including their lexical environment. To fill this gap, the present study explored if different glossing conditions would have a distinct impact on L2 reading comprehension and incidental lexical and collocational learning. Sixty-three first language (L1) Cantonese speakers read two English stories that contained 12 adjective-pseudonoun collocations. The participants were placed in one of the three conditions, i.e., unglossed, single-word glossed, and collocation glossed. Participants' reading comprehension was measured with twelve true-or-false statements for each story, and their lexical and collocational learning was assessed using unannounced recognition and recall tests. The results revealed that collocational glossing promoted reading comprehension significantly compared to the other two reading conditions. In addition, while both glossing conditions promoted lexical and collocational knowledge in the immediate posttest, collocational glossing demonstrated a more durable facilitative impact in the delayed posttest. [ABSTRACT FROM AUTHOR]

Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca(2+) leak) through ryanodine receptors. Beta-adrenergic (β-AR) tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII) and the subsequent phosphorylation of the ryanodine receptor. When β-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent evidence has indicated that CaMKII activation can be regulated by cellular oxidizing agents, such as reactive oxygen species. Here, we investigate how the cellular second messenger, nitric oxide, mediates CaMKII activity downstream of the adrenergic signaling cascade and promotes the generation of arrhythmogenic spontaneous Ca(2+) waves in intact cardiomyocytes. Both SCaWs and SR Ca(2+) leak were measured in intact rabbit and mouse ventricular myocytes loaded with the Ca-dependent fluorescent dye, fluo-4. CaMKII activity in vitro and immunoblotting for phosphorylated residues on CaMKII, nitric oxide synthase, and Akt were measured to confirm activity of these enzymes as part of the adrenergic cascade. We demonstrate that stimulation of the β-AR pathway by isoproterenol increased the CaMKII-dependent SR Ca(2+) leak. This increased leak was prevented by inhibition of nitric oxide synthase 1 but not nitric oxide synthase 3. In ventricular myocytes isolated from wild-type mice, isoproterenol stimulation also increased the CaMKII-dependent leak. Critically, in myocytes isolated from nitric oxide synthase 1 knock-out mice this effect is ablated. We show that isoproterenol stimulation leads to an increase in nitric oxide production, and nitric oxide alone is sufficient to activate CaMKII and increase SR Ca(2+) leak. Mechanistically, our data links Akt to nitric oxide synthase 1 activation downstream of β-AR stimulation. Collectively, this evidence supports the hypothesis that CaMKII is regulated by nitric oxide as part of the adrenergic cascade leading to arrhythmogenesis.

Apoptosis is a physiological process that occurs in all cell types of the human body, and it profoundly changes the fate of hair by affecting hair follicle cells. This review outlines the cellular changes, intrinsic biochemical characteristics, and mechanisms underlying apoptosis and summarizes the hair follicle life cycle, including development, cycle stages, and corresponding cellular changes. Finally, the relationship between apoptosis and the hair cycle is discussed and the significance of apoptosis in hair loss conditions and drug treatments is highlighted. Apoptosis induces cellular changes and exhibits distinctive properties through intricate signaling pathways. Hair follicles undergo cyclic periods of growth, regression, and dormancy. Apoptosis is closely correlated with the regression phase by triggering hair follicle cell death and shedding. Regulation of apoptosis in hair follicles plays an essential role in hair loss due to maladies and drug treatments. Mitigating apoptosis can enhance hair growth and minimize hair loss. A comprehensive understanding of the correlation between apoptosis and the hair cycle can facilitate the development of novel treatments to prevent hair loss and stimulate hair regeneration. [ABSTRACT FROM AUTHOR]

Studies have shown that neuronal nitric oxide synthase (nNOS, NOS1) knockout mice ([NOS1.sup.-/1]) have increased or decreased contractility, but consistently have found a slowed rate of intracellular [Ca.sup.2+] ([Ca.sup.2+].sub.i]) decline and relengthening. Contraction and [[Ca.sup.2+].sub.i] decline are determined by many factors, one of which is phospholamban (PLB). The purpose of this study is to determine the involvement of PLB in the NOS1-mediated effects. Force-frequency experiments were performed in trabeculae isolated from [NOS1.sup.-/-] and wild-type (WT) mice. We also simultaneously measured [Ca.sup.2+] transients (Fluo-4) and cell shortening (edge detection) in myocytes isolated from WT, [NOS1.sup.-/-], and [PLB.sup.-/-] mice. [NOS1.sup.-/-] trabeculae had a blunted force-frequency response and prolonged relaxation. We observed similar effects in myocytes with NOS1 knockout or specific NOS1 inhibition with S-methyl-L-thiocitrulline (SMLT) in WT myocytes (i.e., decreased [Ca.sup.2+] transient and cell shortening amplitudes and prolonged decline of [[Ca.sup.2+].sub.i]. Alternatively, NOS1 inhibition with SMLT in [PLB.sup.-/-] myocytes had no effect. Acute inhibition of NOS1 with SMLT in WT myocytes also decreased basal PLB serinel6 phosphorylation. Furthermore, there was a decreased SR [Ca.sup.2+] load with NOS1 knockout or inhibition, which is consistent with the negative contractile effects. Perfusion with FeTPPS (peroxynitrite decomposition catalyst) mimicked the effects of NOS1 knockout or inhibition. [beta]-Adrenergic stimulation restored the slowed [[Ca.sup.2+].sub.i] decline in [NOS1.sub.-1-] myocytes, but a blunted contraction remained, suggesting additional protein target(s). In summary, NOS1 inhibition or knockout leads to decreased contraction and slowed [[Ca.sup.2+].sub.i] decline, and this effect is absent in [PLB.sup.-/-] myocytes. Thus NOS1 signaling modulates PLB serine l6 phosphorylation, in part, via peroxynitrite. NOS1; peroxynitrite; force-frequency response

Signaling via endothelial nitric oxide synthase (NOS3) limits the heart's response to [beta]-adrenergic ([beta]-AR) stimulation, which may be protective against arrhythmias. However, mechanistic data are limited. Therefore, we performed simultaneous measurements of action potential (AP, using patch clamp), [Ca.sup.2+] transients (fluo 4), and myocyte shortening (edge detection). L-type [Ca.sup.2+] current ([I.sub.Ca]) was directly measured by the whole cell ruptured patch-clamp technique. Myocytes were isolated from wild-type (WT) and NOS3 knockout (NO[S3.sup.-/-]) mice. NO[S3.sup.-/-] myocytes exhibited a larger incidence of [beta]-AR (isoproterenol, 1 [micro]M)-induced early after-depolarizations (EADs) and spontaneous activity (defined as aftercontractions). We also examined [I.sub.Ca], a major trigger for EADs. NO[S3.sup.-/-] myocytes had a significantly larger [beta]-AR-stimulated increase in [I.sub.Ca] compared with WT myocytes. In addition, NO[S3.sup.-/-] myocytes had a larger response to [beta]-AR stimulation compared with WT myocytes in [Ca.sup.2+] transient amplitude, shortening amplitude, and AP duration (APD). We observed similar effects with specific NOS3 inhibition [L-[N.sup.5]-(1-iminoethyl)-ornithine (L-NIO), 10 [micro]M] in WT myocytes as with NOS3 knockout. Specifically, L-NIO further increased isoproterenol-stimulated EADs and aftercontractions. L-NIO also further increased the isoproterenol-stimulated/ca, [Ca.sup.2+] transient amplitude, shortening amplitude, and APD (all P < 0.05 vs isoproterenol alone). L-NIO had no effect in NO[S3.sup.-/-] myocytes. These results indicate that NOS3 signaling inhibits the [beta]-AR response by reducing {I.sub.Ca] and protects against arrhythmias. This mechanism may play an important role in heart failure, where arrhythmias are increased and NOS3 expression is decreased. endothelial nitric oxide synthase; cardiac myocytes; early afterdepolarizations; action potential