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This study systematically investigates the effects of high-power continuous wave laser (CWL) treatment on the mechanical behavior and failure mechanisms of SM400A steel, comparing these outcomes with those of untreated specimens. The findings reveal that while CWL treatment enhances surface hardness, it has minimal impact on the strength of thick structural steel components. However, excessive laser energy density leads to surface defects and softening of the microstructure, adversely affecting the material's toughness. This results in a reduction in elongation at fracture, transitioning the failure mode from ductile to brittle. The study concludes that to ensure the safe use of laser-treated structures, the laser energy density should be carefully controlled not to exceed 3000 J/cm2.

Abstract All-solid-state lithium batteries have attracted widespread attention for next-generation energy storage, potentially providing enhanced safety and cycling stability. The performance of such batteries relies on solid electrolyte materials; hence many structures/phases are being investigated with increasing compositional complexity. Among the various solid electrolytes, lithium halides show promising ionic conductivity and cathode compatibility, however, there are no effective guidelines when moving toward complex compositions that go beyond ab-initio modeling. Here, we show that ionic potential, the ratio of charge number and ion radius, can effectively capture the key interactions within halide materials, making it possible to guide the design of the representative crystal structures. This is demonstrated by the preparation of a family of complex layered halides that combine an enhanced conductivity with a favorable isometric morphology, induced by the high configurational entropy. This work provides insights into the characteristics of complex halide phases and presents a methodology for designing solid materials.

Summary: Pancreas development is tightly controlled by multilayer mechanisms. Despite years of effort, large gaps remain in understanding how histone modifications coordinate pancreas development. SETD2, a predominant histone methyltransferase of H3K36me3, plays a key role in embryonic stem cell differentiation, whose role in organogenesis remains elusive. Here, by combination of cleavage under targets and tagmentation (CUT&Tag), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and bulk RNA sequencing, we show a dramatic increase in the H3K36me3 level from the secondary transition phase and decipher the related transcriptional alteration. Using single-cell RNA sequencing, we define that pancreatic deletion of Setd2 results in abnormalities in both exocrine and endocrine lineages: hyperproliferative tip progenitor cells lead to abnormal differentiation; Ngn3+ endocrine progenitors decline due to the downregulation of Nkx2.2, leading to insufficient endocrine development. Thus, these data identify SETD2 as a crucial player in embryonic pancreas development, providing a clue to understanding the dysregulation of histone modifications in pancreatic disorders.

This study explored the feasibility of direct coating of steel surfaces treated with a continuous-wave laser (CWL). The adhesion and corrosion resistance of Heavy-Duty Paint coatings were evaluated on CWL-treated surfaces and compared with those of surfaces treated with molten alumina blasting. The results showed that the surface texture created by CWL provided greater adhesion of the Rc-I coating than its cohesive strength. However, the presence of oxides on the CWL-treated surfaces caused a high cathodic disbondment (CD), which reduced the corrosion resistance of the coated steel in corrosive environments. Decreasing the laser head sweep speed can improve the surface roughness and area but does not address the issues of CD and corrosion creep (CC). This study concludes that, given the limitations of current commercial CWL systems, it is recommended to blast CWL-treated surfaces before coating to improve durability and corrosion resistance in corrosive environments.

Abstract Background Type 2 diabetes (T2D) is characterized by a progressive deterioration of β‐cell function with a continuous decline in insulin secretion. Glucokinase (GCK) facilitates the rate‐limiting step of glycolysis in pancreatic β‐cells, to acquire the proper glucose‐stimulated insulin secretion. Multiple glucokinase activators (GKAs) have been developed and clinically tested. However, the dynamic change of human pancreatic GCK expression during T2D progression has not been investigated. Methods We evaluated GCK expression by measuring the average immunoreactivity of GCK in insulin+ or glucagon+ cells from pancreatic sections of 11 nondiabetic subjects (ND), 10 subjects with impaired fasting glucose (IFG), 9 with well‐controlled T2D (wT2D), and 5 individuals with poorly controlled T2D (uT2D). We also assessed the relationship between GCK expression and adaptive unfolded protein response (UPR) in human diabetic β‐cells. Results We did not detect changes of GCK expression in IFG islets. However, we found β‐cell GCK levels were significantly increased in T2D with adequate glucose control (wT2D) but not in T2D with poor glucose control (uT2D). Furthermore, there was a strong positive correlation between GCK expression and adaptive UPR (spliced X‐box binding protein 1 [XBP1s] and activating transcription factor 4 [ATF4]), as well as functional maturity marker (urocortin‐3 [UCN3]) in human diabetic β‐cells. Conclusions Our study demonstrates that inductions of GCK enhanced adaptive UPR and UCN3 in human β‐cells, which might be an adaptive mechanism during T2D progression. This finding provides a rationale for exploring novel molecules that activate β‐cell GCK and thereby improve pharmacological treatment of T2D.

Electrolytes, function as an ion conducting membrane between battery electrodes, are essential for rechargeable batteries. Here, the authors report high-entropy liquid electrolytes and reveal substantial impact of the increasing entropy on lithium-ion solvation structures for highly reversible lithium batteries.

Objective: The mechanistic target of rapamycin complex 1 (mTORC1) is a key molecule that links nutrients, hormones, and growth factors to cell growth/function. Our previous studies have shown that mTORC1 is required for β-cell functional maturation and identity maintenance; however, the underlying mechanism is not fully understood. This work aimed to understand the underlying epigenetic mechanisms of mTORC1 in regulating β-cell functional maturation. Methods: We performed Microarray, MeDIP-seq and ATAC-seq analysis to explore the abnormal epigenetic regulation in 8-week-old immature βRapKO islets. Moreover, DNMT3A was overexpressed in βRapKO islets by lentivirus, and the transcriptome changes and GSIS function were analyzed. Results: We identified two major epigenetic silencing mechanisms, DNMT3A-dependent DNA methylation and PRC2-dependent H3K27me3 modification, which are responsible for functional immaturity of Raptor-deficient β-cell. Overexpression of DNMT3A partially reversed the immature transcriptome pattern and restored the impaired GSIS in Raptor-deficient β-cells. Moreover, we found that Raptor directly regulated PRC2/EED and H3K27me3 expression levels, as well as a group of immature genes marked with H3K27me3. Combined with ATAC-seq, MeDIP-seq and ChIP-seq, we identified β-cell immature genes with either DNA methylation and/or H3K27me3 modification. Conclusion: The present study advances our understanding of the nutrient sensor mTORC1, by integrating environmental nutrient supply and epigenetic modification, i.e., DNMT3A-mediated DNA methylation and PRC2-mediated histone methylation in regulating β-cell identity and functional maturation, and therefore may impact the disease risk of type 2 diabetes.

Interface chemistry is essential for highly reversible lithium-metal batteries. Here the authors investigate amide-based electrolyte that lead to desirable interface species, resulting in dense Li-metal plating and top-down Li-metal stripping, responsible for the highly reversible cycling.

During the progression of type 2 diabetes, insulin-producing β-cells can lose their identity and become reprogrammed into other cell types. Here the authors show that murine diabetic β-cells require the protein Raptor for maintaining β-cell health and preventing them from turning into α-cells, independent of Raptor’s involvement in regulating blood sugar levels.

Blade tip-timing is one of the most widely used non-contact measurement methods for rotating blade vibration. The classic blade tip-timing method is to identify the vibration parameters of the blade based on the time of blade tip arrival to the tip-timing sensor installed on the casing. Since the vibration measurement of blade tip-timing is a serious under-sampling method, the blade resonance frequency is usually higher than the sampling frequency of the BTT data acquisition system, resulting in a large identification error of blade vibration parameters. In view of the above shortcomings, a blade vibration parameters identification method is proposed based on the mapping matching between the static waveform of the sensor and the dynamic waveform of the blade tip-timing. The modulation effects of different vibration displacements, velocities and vibration amplitudes on the tip-timing waveform of the sensor are analyzed. The vibration displacements and velocities of the blade tip passing through the sensor are obtained by the waveform mapping method, and then the vibration parameters of the blade are identified. The influence of the number of blade tip-timing sensors on the identification accuracy of the blade vibration parameters identification algorithm is observed based on the waveform mapping theory. The identification accuracy of waveform mapping method is compared with other methods. The results show that compared with the under-sampled time of arrival (TOA) data of classic BTT applications, the modulation of the sensor waveform output by blade vibration can provide additional data, and the waveform mapping method can not only reduce the number of sensors but also improve the identification accuracy of blade vibration parameters. The waveform mapping method has higher identification accuracy of blade vibration parameters compared with the waveform method in the reference.

Graphene/silicon (Gr/Si) Schottky barrier solar cells (SBSCs) are attractive for harvesting solar energy and have been gaining grounds for its low-cost solution-processing. The interfacial barrier between graphene and silicon facilitates the reducing excessive carrier recombination while accelerating the separation processes of photo-generated carriers at the interface, which empowers the performance of Gr/Si SBSCs. However, the difficulty to control the interface thickness prevents its application. Here, we introduce the graphene oxide quantum dots (GOQDs) as a unique interfacial modulation species with tunable thickness by controlling the GOQDs particle size. The power conversion efficiency (PCE) of 13.67% for Gr/Si-based SBSC with outstanding stability in the air is obtained with the optimal barrier thickness (26 nm) and particle size (4.15 nm) of GOQDs. The GOQDs in Gr/Si-based SBSCs provide the extra band bending which further enhances the PCE for its photovoltaic applications.

Blade tip timing (BTT) technology is the most effective means for real-time monitoring of blade vibration. Accurately extracting the time of blade tip reaching the sensors is the key to ensure the accuracy of the BTT system. The tip clearance changes due to various complex forces during high-speed rotation. The traditional BTT signal extraction method does not consider the influence of tip clearance change on timing accuracy and introduces large timing errors. To solve this problem, a quadratic curve fitting timing method was proposed. In addition, based on the measurement principle of the eddy current sensors, the relationship among the output voltage of the eddy current sensor, tip clearance, and the blade cutting magnetic line angle was calibrated. A multisensor vibration parameter identification algorithm based on arbitrary angular distribution was introduced. Finally, the experiments were conducted to prove the effectiveness of the proposed method. The results show that in the range of 0.4 to 1.05 mm tip clearance change, the maximum absolute error of the timing values calculated by the proposed method is 26.0359 us, which is much lower than the calculated error of 203.7459 us when using the traditional timing method. When the tip clearance changed, the constant speed synchronous vibration parameters of No. 0 blade were identified. The average value of the vibration amplitude is 1.0881 mm. Compared with the identification results without changing tip clearance, the average value error of the vibration amplitude is 0.0017 mm. It is proved that within the blade tip clearance variation of 0.4 to 0.9 mm, the timing values obtained by the proposed timing method can accurately identify the vibration parameters of the blade.

Blade serial number identification is one of the key issues in blade tip-timing vibration measurement without once-per-revolution (OPR) sensor. In order to overcome the shortcomings of the existing blade serial number identification methods without OPR sensor, a new identification method of blade serial number based on blade tip clearance is proposed in this paper. The relationship between blade tip-timing data and blade serial number can be identified by the matching relationship between blade tip clearance under static state and dynamic state. According to the finite element simulation and experimental data, the accuracy of the blade serial number identification method based on blade tip clearance is verified by using the OPR sensor method. The results show that in the nonresonant rotation speed region, the method can identify the blade serial number, and the identification result is consistent with the result of the OPR sensor method. In the resonance rotation speed region, when the blade tip clearance change caused by the blade circumferential bending vibration is less than the dispersion of initial blade tip clearance, the method in this paper can accurately identify the blade serial number. Otherwise, the inference method can be used. It provides theoretical support and technical basis for the engineering application of blade tip-timing vibration measurement technology without OPR sensor.

mTORC1 regulates beta cell survival, function and adaptation to physiologic and pathological stimuli. Here Niet al. demonstrate that that deficiency of Raptor, a component of mTORC1 complex, impairs insulin secretion and glucose tolerance in mice by affecting maturation of beta cells during the postnatal period.

The impacts of thyroid hormones (TH) on lipid profile in euthyroid adults have gained much attention. It is currently unknown whether BMI influences such interaction. In the present study, we investigate the role of BMI in modulating the association between TH and lipid parameters in 1372 euthyroid healthy adults. Our results show that thyroid parameters are differentially associated with lipid profile. FT3 is positively correlated with total cholesterol (β=0.176±0.046, P

BackgroundRecent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in affecting obesity. However, the supporting evidence on the relationship between BAT and central obesity and metabolic profile in large population based studies is sparse.Methodology/principal findingsWe studied 4011 (2688 males and 1323 females) tumor-free Chinese adults aged 18-89 for BAT activities, visceral/subcutaneous fat areas (VFA/SFA), waist circumferences (WC) and metabolic parameters. We found that the prevalence of BAT was around 2.7% in our study participants, with a significant sexual difference (5.5% in the females vs. 1.3% in the males; pConclusions/significanceOur data suggest that decreased amount of active BAT might be associated with accumulation of visceral fat content and unfavorable metabolic outcomes.

BACKGROUND: To date, the available non-invasive remedies for primary aldosteronism are not satisfactory in clinical practice. The phosphoinositide 3-kinase (PI3Ks)/protein kinase B (PKB or AKT)/mammalian target of rapamycin (mTOR) signaling pathway is essential for tumorigenesis and metastasis in many types of human tumors, including renal cancer, adrenal carcinoma and pheochromocytoma. The possibility that this pathway is also necessary for the pathogenesis of primary aldosteronism has not yet been explored. To answer this question, we investigated the activity of the PI3K/AKT/mTOR signaling pathway in normal adrenal glands (NAGs), primary aldosteronism (PA) patients and NCI-H295R cells. METHODOLOGY/PRINCIPAL FINDINGS: Between January 2005 and December 2011, we retrospectively reviewed the records of 45 patients with PA. We compared clinical characteristics (age, gender and biochemical data) and the expression of phospho-AKT (p-AKT), phospho-mTOR (p-mTOR), phospho-S6 (p-S6) and vascular endothelial growth factor (VEGF) by immunohistochemical staining and western blotting, analyzing 30 aldosterone-producing adenomas (APAs), 15 idiopathic hyperaldosteronism (IHA) tissues and 12 NAGs following nephrectomy for renal tumors (control group). Compared with the control group, most of the PA patients presented with polydipsia, polyuria, resistant hypertension, profound hypokalemia, hyperaldosteronemia and decreased plasma renin activity. Compared with normal zona glomerulosa, the levels of p-AKT, p-mTOR, p-S6 and VEGF were significantly upregulated in APA and IHA. No significant differences were found between APA and IHA in the expression of these proteins. Additionally, positive correlations existed between the plasma aldosterone levels and the expression of p-AKT and p-mTOR. In vitro studies showed that mTOR inhibitor rapamycin could inhibit cell proliferation in NCI-H295R cells in a dose- and time-dependent manner. Furthermore, this inhibitor also decreased aldosterone secretion. CONCLUSIONS: Our data suggest that the PI3K/AKT/mTOR signaling pathway, which was overactivated in APA and IHA compared with normal zona glomerulosa, may mediate aldosterone hypersecretion and participate in the development of PA.

BACKGROUND: Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in controlling obesity. It is known that ß-adrenoceptor-UCP1 system regulates BAT in rodent, but its influence in adult humans remains to be shown. The present study is to determine whether BAT activity can be independently stimulated by elevated catecholamines levels in adult human, and whether it is associated with their adiposity. METHODOLOGY/PRINCIPAL FINDINGS: We studied 14 patients with pheochromocytoma and 14 normal subjects who had performed both ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) and plasma total metanephrine (TMN) measurements during 2007-2010. The BAT detection rate and the mean BAT activity were significantly higher in patients with elevated TMN levels (Group A: 6/8 and 6.7±2.1 SUVmean· g/ml) than patients with normal TMN concentrations (Group B: 0/6 and 0.4±0.04 SUVmean· g/ml) and normal subjects (Group C: 0/14 and 0.4±0.03 SUVmean·g/ml). BAT activities were positively correlated with TMN levels (R = 0.83, p

Context: Diabetes is an age-related disease; however, the mechanism underlying senescent beta cell failure is still unknown. Objective: The present study was designed to investigate whether and how the differentiated state was altered in senescent human beta cells by excluding the effects of impaired glucose tolerance. Methods: We calculated the percentage of hormone-negative/chromogranin A-positive endocrine cells and evaluated the expressions of forkhead box O1 (FoxO1) and Urocortin 3 (UCN3) in islets from 31 nondiabetic individuals, divided into young (<40 years), middle-aged (40-60 years) and elderly (>60 years) groups. We also assessed adaptive unfolded protein response markers glucose-regulated protein 94 (GRP94), and spliced X-box binding protein 1 (XBP1s) in senescent beta cells and their possible contributions to maintaining beta cell identity and differentiation state. Results: We found an almost 2-fold increase in the proportion of dedifferentiated cells in elderly and middle-aged groups compared with the young group (3.1± 1.0% and 3.0±0.9% vs 1.7±0.5%, P<.001). This was accompanied by inactivation of FoxO1 and loss of UCN3 expression in senescent human beta cells. In addition, we demonstrated that the expression levels of adaptive unfolded protein response (UPR) components GRP94 and XBP1s declined with age. In vitro data showed knockdown GRP94 in Min6-triggered cells to dedifferentiate and acquire progenitor features, while restored GRP94 levels in H2O2-induced senescent Min6 cells rescued beta cell identity. Conclusion: Our finding highlights that the failure to establish proper adaptive UPR in senescent human beta cells shifts their differentiated states, possibly representing a crucial step in the pathogenesis of age-related beta cell failure. [ABSTRACT FROM AUTHOR]

Statins are cholesterol-lowering agents that increase the incidence of diabetes and impair glucose tolerance via their detrimental effects on nonhepatic tissues, such as pancreatic islets, but the underlying mechanism has not been determined. In atorvastatin (ator)-treated high-fat diet-fed mice, we found reduced pancreatic β-cell size and β-cell mass, fewer mature insulin granules, and reduced insulin secretion and glucose tolerance. Transcriptome profiling of primary pancreatic islets showed that ator inhibited the expression of pancreatic transcription factor, mechanistic target of rapamycin (mTOR) signaling, and small G protein (sGP) genes. Supplementation of the mevalonate pathway intermediate geranylgeranyl pyrophosphate (GGPP), which is produced by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, significantly restored the attenuated mTOR activity, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) expression, and β-cell function after ator, lovastatin, rosuvastatin, and fluvastatin treatment; this effect was potentially mediated by sGP prenylation. Rab5a, the sGP in pancreatic islets most affected by ator treatment, was found to positively regulate mTOR signaling and β-cell function. Rab5a knockdown mimicked the effect of ator treatment on β-cells. Thus, ator impairs β-cell function by regulating sGPs, for example, Rab5a, which subsequently attenuates islet mTOR signaling and reduces functional β-cell mass. GGPP supplementation could constitute a new approach for preventing statin-induced hyperglycemia. [ABSTRACT FROM AUTHOR]

Immature pancreatic β-cells are highly proliferative, and the expansion of β-cells during the early neonatal period largely determines functional β-cell mass; however, the mechanisms are poorly characterized. We generated Ngn3RapKO mice (ablation of Raptor, an essential component of mechanistic target of rapamycin [mTORC1] in Ngn3+ endocrine progenitor cells) and found that mTORC1 was dispensable for endocrine cell lineage formation but specifically regulated both proliferation and identity maintenance of neonatal β-cells. Ablation of Raptor in neonatal β-cells led to autonomous loss of cell identity, decelerated cell cycle progression, compromised proliferation, and caused neonatal diabetes as a result of inadequate establishment of functional β-cell mass at postnatal day 14. Completely different from mature β-cells, Raptor regulated G1/S and G2/M phase cell cycle transition, thus permitting a high proliferation rate in neonatal β-cells. Moreover, Ezh2 was identified as a critical downstream target of mTORC1 in neonatal β-cells, which was responsible for G2/M phase transition and proliferation. Our discovery of the dual effect of mTORC1 in immature β-cells has revealed a potential target for replenishing functional β-cell pools by promoting both expansion and functional maturation of newly formed immature β-cells. [ABSTRACT FROM AUTHOR]

Genetic variation in specific transcription factors during heart formation may lead to congenital heart disease (CHD) or even miscarriage. The aim of the present study was to identify CHD-associated genes using next generation sequencing (NGS). The whole exome DNA sequence was obtained from a stillborn fetus diagnosed with tricuspid atresia and complete transposition of the great arteries using high-throughput sequencing methods. Subsequently, genetic variants of CHD-associated genes were selected and verified in 215 non-syndromic CHD patients and 249 healthy control subjects using polymerase chain reaction combined with Sanger sequencing. Genetic variants of previously reported CHD-inducing genes, such as cysteine rich with EGF like domains 1 and cbp/p300-interacting transactivator with Glu/Asp rich carboxy-terminal domain 2, were discovered through the NGS analysis. In addition, a novel non-synonymous mutation of the iroquois homeobox 1 (IRX1) gene (p.Gln240Glu) was identified. A total of three non-synonymous mutations (p.Gln240Glu, p.Ser298Asn and p.Ala381Glu) of the IRX1 gene were verified in 215 non-syndromic CHD patients, but not in 249 healthy volunteers. The results demonstrated that NGS is a powerful tool to study the etiology of CHD. In addition, the results suggest that genetic variants of the IRX1 gene may contribute to the pathogenesis of CHD. [ABSTRACT FROM AUTHOR]

The cellular and molecular mechanisms of glucose-stimulated β-cell proliferation are poorly understood. Recently, secreted frizzled-related protein 5 (encoded by Sfrp5; a Wnt signaling inhibitor) has been demonstrated to be involved in β-cell proliferation in obesity. A previous study demonstrated that glucose enhanced Wnt signaling to promote cell proliferation. We hypothesized that inhibition of SFRP5 contributes to glucose-stimulated β-cell proliferation. In this study, we found that the Sfrp5 level was significantly reduced in high glucose-treated INS-1 cells, primary rat β-cells, and islets isolated from glucose-infused rats. Overexpression of SFRP5 diminished glucose-stimulated proliferation in both INS-1 cells and primary β-cells, with a concomitant inhibition of the Wnt signaling pathway and decreased cyclin D2 expression. In addition, we showed that glucose-induced Sfrp5 suppression was modulated by the PI3K/AKT pathway. Therefore, we conclude that glucose inhibits Sfrp5 expression via the PI3K/AKT pathway and hence promotes rat pancreatic β-cell proliferation. [ABSTRACT FROM AUTHOR]

Ventricular septal defect (VSD) is the most common type of congenital heart disease (CHD). The single gene mutations or absences that contribute to VSD development are well established; however, the aim of the present study was to measure gene expression variation between VSDs and normal fetal myocardial tissue. TWIST1, an important tumor biomarker, is a basic helix-loop-helix transcription factor that regulates cell proliferation, migration and differentiation in embryonic development and transformed tumor cells. Although growing evidence demonstrates that TWIST1 participates in a variety of human neoplastic diseases, the role of TWIST1 in VSD has remained elusive. Twenty-six VSD fetal myocardial tissue samples and 12 normal samples at matched gestational weeks (22-28 weeks) were included in the present study. Using reverse transcription quantitative polymerase chain reaction (PCR) and real-time PCR, it was demonstrated that TWIST1 mRNA was reduced by almost two-fold in the VSD samples compared with the normal samples. Western blot analysis also revealed that TWIST1 expression was decreased by ~three-fold (P=0.001) in the VSD samples compared with that in the normal samples. Of note, five complete ventricular (also called functionally univentricular or single ventricular) septal ageneses were identified among the specimens. For the five complete ventricular septal agenesis samples, similar results to those for other VSD fetal myocardial tissues were obtained. In conclusion, the results of the present study showed that TWIST1 mRNA and protein levels were reduced in VSDs. The present study was the first, to the best of our knowledge, to report that TWIST1 is not only a tumor biomarker, but may also be involved in the pathogenesis of VSD. [ABSTRACT FROM AUTHOR]

Use of sulfonylureas in diabetes treatment is based on their insulin-releasing effect on pancreatic β-cells. Prolonged action is known to degranulate β-cells, but functional consequences have not been examined at the cellular level. This study investigates influences of in vivo (48-h) and in vitro (24-h) glibenclamide treatment on the functional state of the β-cell population. Both conditions decreased cellular insulin content by >50% and caused an elevated basal insulin biosynthetic activity that was maintained for at least 24 h after drug removal. Glibenclamide stimulation of basal insulin synthesis was not achieved after a 2-h exposure; it required a calcium-dependent translational activity and involved an increase in the percent activated β-cells (50% after glibenclamide pretreatment vs. 8% in control cells). The glibenclamide-activated β-cell subpopulation corresponded to the degranulated β-cell subpopulation that was isolated by fluorescence-activated cell sorter on the basis of lower cellular sideward scatter. Glibenclamide pretreatment did not alter cellular rates of glucose oxidation but sensitized β-cells to glucose-induced changes in metabolic redox and insulin synthesis and release. In conclusion, chronic exposure to glibenclamide results in degranulation of a subpopulation of β-cells, which maintain an elevated protein and insulin synthetic activity irrespective of the presence of the drug and of glucose. Our study demonstrates that the in situ β-cell population also exhibits a functional heterogeneity that can vary with drug treatment. Glibenclamide induces degranulated β-cells with a sustained elevated basal activity that might increase the risk for hypoglycemic episodes. [ABSTRACT FROM AUTHOR]

Rechargeable batteries, especially lithium-ion batteries, are now widely used as power sources for portable electronics and electric vehicles, but material innovations are still needed to satisfy the increasing demand for larger energy density. Recently, lithium- and sodium-rich electrode materials, including the A2MO3-family layered compounds (A  =  Li, Na; M  =  Mn4+, Ru4+, etc), have been extensively studied as potential high-capacity electrode materials for a cumulative cationic and anionic redox activity. Negatively charged oxide ions can potentially donate electrons to compensate for the absence of oxidable transition metals as a redox center to further increase the reversible capacity. Understanding and controlling the state-of-the-art anionic redox processes is pivotal for the design of advanced energy materials, highlighted in rechargeable batteries. Hence, experimental and theoretical approaches have been developed to consecutively study the diverting processes, states, and structures involved. In this review, we attempt to present a literature overview and provide insight into the reaction mechanism with respect to the anionic redox processes, proposing some opinions as target oriented. It is hoped that, through this discussion, the search for anionic redox electrode materials with high-capacity rechargeable batteries can be advanced, and practical applications realized as soon as possible. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is associated with defective insulin secretion and reduced β cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of β cell failure is a key translational question. Here, we reverse engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic inflexibility and endocrine progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca2+ flux analyses of top candidate master regulatory (MR) proteins in islet cells validated transcription factor BACH2 and associated epigenetic effectors as key drivers of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a nondiabetic phenotype. BACH2-immunoreactive islet cells increased approximately 4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing β cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition. [ABSTRACT FROM AUTHOR]