Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition.

Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition and is a potent insulin secretagogue. Here, we show that insulin receptor (IR) signaling in osteoblasts controls osteoblast development and osteocalcin expression by suppressing the Runx2 inhibitor Twist2. Mice lacking IR in osteoblasts have low circulating undercarboxylated osteocalcin and reduced bone acquisition due to decreased bone formation and deficient numbers of osteoblasts. With age, these mice develop marked peripheral adiposity and hyperglycemia accompanied by severe glucose intolerance and insulin resistance. The metabolic abnormalities in these mice are improved by infusion of undercarboxylated osteocalcin. These results indicate the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast ensures osteoblast differentiation and stimulates osteocalcin production, which in turn regulates insulin sensitivity and pancreatic insulin secretion.

Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein.

Insulin resistance and elevated glucagon levels result in nonsuppressible hepatic glucose production and hyperglycemia in patients with type 2 diabetes. The CREB coactivator complex controls transcription of hepatic gluconeogenic enzyme genes. Here, we show that both the antidiabetic agent metformin and insulin phosphorylate the transcriptional coactivator CREB binding protein (CBP) at serine 436 via PKC iota/lambda. This event triggers the dissociation of the CREB-CBP-TORC2 transcription complex and reduces gluconeogenic enzyme gene expression. Mice carrying a germline mutation of this CBP phosphorylation site (S436A) demonstrate resistance to the hypoglycemic effect of both insulin and metformin. Obese, hyperglycemic mice display hepatic insulin resistance, but metformin is still effective in treating the hyperglycemia of these mice since it stimulates CBP phosphorylation by bypassing the block in insulin signaling. Our findings point to CBP phosphorylation at Ser436 by metformin as critical for its therapeutic effect, and as a potential target for pharmaceutical intervention.

Activation of the canonical ER stress IRE1-XBP1 pathway by insulin regulates glucose and lipid metabolism.

Knockout of the transcription factor X-box binding protein (XBP1) is known to decrease liver glucose production and lipogenesis. However, whether insulin can regulate gluconeogenesis and lipogenesis through XBP1 and how insulin activates the inositol-requiring enzyme-XBP1 ER stress pathway remains unexplored. Here, we report that in the fed state, insulin-activated kinase AKT directly phosphorylates inositol-requiring enzyme 1 at S724, which in turn mediates the splicing of XBP1u mRNA, thus favoring the generation of the spliced form, XBP1s, in the liver of mice. Subsequently, XBP1s stimulate the expression of lipogenic genes and upregulates liver lipogenesis as previously reported. Intriguingly, we find that fasting leads to an increase in XBP1u along with a drastic decrease in XBP1s in the liver of mice, and XBP1u, not XBP1s, significantly increases PKA-stimulated CRE reporter activity in cultured hepatocytes. Furthermore, we demonstrate that overexpression of XBP1u significantly increases cAMP-stimulated expression of rate-limiting gluconeogenic genes, G6pc and Pck1, and glucose production in primary hepatocytes. Reexpression of XBP1u in the liver of mice with XBP1 depletion significantly increases fasting blood glucose levels and gluconeogenic gene expression. These data support an important role of XBP1u in upregulating gluconeogenesis in the fasted state. Taken together, we reveal that insulin signaling via AKT controls the expression of XBP1 isoforms and that XBP1u and XBP1s function in different nutritional states to regulate liver gluconeogenesis and lipogenesis, respectively.

An Efficient Supervised Deep Hashing Method for Image Retrieval.

In recent years, searching and retrieving relevant images from large databases has become an emerging challenge for the researcher. Hashing methods that mapped raw data into a short binary code have attracted increasing attention from the researcher. Most existing hashing approaches map samples to a binary vector via a single linear projection, which restricts the flexibility of those methods and leads to optimization problems. We introduce a CNN-based hashing method that uses multiple nonlinear projections to produce additional short-bit binary code to tackle this issue. Further, an end-to-end hashing system is accomplished using a convolutional neural network. Also, we design a loss function that aims to maintain the similarity between images and minimize the quantization error by providing a uniform distribution of the hash bits to illustrate the proposed technique's effectiveness and significance. Extensive experiments conducted on various datasets demonstrate the superiority of the proposed method in comparison with state-of-the-art deep hashing methods.

Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes.

Sclerostin has traditionally been thought of as a local inhibitor of bone acquisition that antagonizes the profound osteoanabolic capacity of activated Wnt/ß-catenin signaling, but serum sclerostin levels in humans exhibit a correlation with impairments in several metabolic parameters. These data, together with the increased production of sclerostin in mouse models of type 2 diabetes, suggest an endocrine function. To determine whether sclerostin contributes to the coordination of whole-body metabolism, we examined body composition, glucose homeostasis, and fatty acid metabolism in Sost-/- mice as well as mice that overproduce sclerostin as a result of adeno-associated virus expression from the liver. Here, we show that in addition to dramatic increases in bone volume, Sost-/- mice exhibit a reduction in adipose tissue accumulation in association with increased insulin sensitivity. Sclerostin overproduction results in the opposite metabolic phenotype due to adipocyte hypertrophy. Additionally, Sost-/- mice and those administered a sclerostin-neutralizing antibody are resistant to obesogenic diet-induced disturbances in metabolism. This effect appears to be the result of sclerostin's effects on Wnt signaling and metabolism in white adipose tissue. Since adipocytes do not produce sclerostin, these findings suggest an unexplored endocrine function for sclerostin that facilitates communication between the skeleton and adipose tissue.

Inter-organ communication and regulation of beta cell function.

The physiologically predominant signal for pancreatic beta cells to secrete insulin is glucose. While circulating glucose levels and beta cell glucose metabolism regulate the amount of released insulin, additional signals emanating from other tissues and from neighbouring islet endocrine cells modulate beta cell function. To this end, each individual beta cell can be viewed as a sensor of a multitude of stimuli that are integrated to determine the extent of glucose-dependent insulin release. This review discusses recent advances in our understanding of inter-organ communications that regulate beta cell insulin release in response to elevated glucose levels.

System for exposing cultured cells to intermittent hypoxia utilizing gas permeable cultureware.

Tissue intermittent hypoxia (IH) occurs in obstructive sleep apnea, sickle cell anemia, physical exercise and other conditions. Poor gas solubility and slow diffusion through culture media hampers mimicking IH-induced transitions of O(2) in vitro. We aimed to develop a system enabling exposure of cultured cells to IH and to validate such exposure by real-time O(2) measurements and cellular responses. Standard 24-well culture plates and plates with bottoms made from a gas permeable film were placed in a heated cabinet. Desired cycling of O(2) levels was induced using programmable solenoids to purge mixtures of 95% N(2) + 5% CO(2) or 95% O(2) + 5% CO(2). Dissolved oxygen, gas pressure, temperature, and water evaporation were measured during cycling. IH-induced cellular effects were evaluated by hypoxia inducible factor (HIF) and NF-κB luciferase reporters in HEK296 cells and by insulin secretion in rat insulinoma cells. Oxygen cycling in the cabinet was translated into identical changes of O(2) at the well bottom in gas permeable, but not in standard cultureware. Twenty-four hours of IH exposure increased HIF (112%), NF-κB (111%) and insulin secretion (44%). Described system enables reproducible and prolonged IH exposure in cultured cells while controlling for important environmental factors.

Complete Genome Sequence Analysis of Bacillus subtilis MC4-2 Strain That against Tobacco Black Shank Disease.

The MC4-2 bacterium strain was isolated and purified from the Periplaneta americana intestine as a biocontrol agent with good antagonistic effect against the pathogens of a soil-borne disease called tobacco black shank. The MC4-2 strain was found to have good broad-spectrum inhibition by plate stand-off test. Based on 16S rRNA and gyrB genes, ANI analysis, and other comparative genomics methods, it was determined that the MC4-2 strain was Bacillus subtilis. The complete genome sequence showed that the genome size was 4,076,630 bp, the average GC content was 43.78%, and the total number of CDSs was 4,207. Genomic prediction analysis revealed that a total of 145 genes were annotated by the CAZy, containing mainly GH and CE enzymes that break down carbohydrates such as glucose, chitin, starch, and alginate, and a large number of enzymes involved in glycosylation were present. A total of ten secondary metabolite clusters were predicted, six clusters of which were annotated as surfactin, bacillaene, fengycin, bacillibactin, subtilosin A, and bacilysin. The present investigation found the biological control mechanism of B. subtilis MC4-2, which provides a strong theoretical basis for the best use of this strain in biological control methods and provides a reference for the subsequent development of agents of this bacterium.

Emerging technologies for COVID (ET-CoV) detection and diagnosis: Recent advancements, applications, challenges, and future perspectives.

In light of the constantly changing terrain of the COVID outbreak, medical specialists have implemented proactive schemes for vaccine production. Despite the remarkable COVID-19 vaccine development, the virus has mutated into new variants, including delta and omicron. Currently, the situation is critical in many parts of the world, and precautions are being taken to stop the virus from spreading and mutating. Early identification and diagnosis of COVID-19 are the main challenges faced by emerging technologies during the outbreak. In these circumstances, emerging technologies to tackle Coronavirus have proven magnificent. Artificial intelligence (AI), big data, the internet of medical things (IoMT), robotics, blockchain technology, telemedicine, smart applications, and additive manufacturing are suspicious for detecting, classifying, monitoring, and locating COVID-19. Henceforth, this research aims to glance at these COVID-19 defeating technologies by focusing on their strengths and limitations. A CiteSpace-based bibliometric analysis of the emerging technology was established. The most impactful keywords and the ongoing research frontiers were compiled. Emerging technologies were unstable due to data inconsistency, redundant and noisy datasets, and the inability to aggregate the data due to disparate data formats. Moreover, the privacy and confidentiality of patient medical records are not guaranteed. Hence, Significant data analysis is required to develop an intelligent computational model for effective and quick clinical diagnosis of COVID-19. Remarkably, this article outlines how emerging technology has been used to counteract the virus disaster and offers ongoing research frontiers, directing readers to concentrate on the real challenges and thus facilitating additional explorations to amplify emerging technologies.

Brevibacillus brevis HNCS-1: a biocontrol bacterium against tea plant diseases.

As a biocontrol bacteria, Brevibacillus has been the subject of extensive research for agricultural applications. Antibacterial peptides (AMPs) are the main antibacterial products of Brevibacillus. This study isolated a strain of Br. brevis HNCS-1 from tea garden soil, and the strain has an antagonistic effect against five types of pathogens of tea diseases, namely Gloeosporium theae-sinensis, Elsinoe leucospira, Phyllosticta theaefolia, Fusarium sp., and Cercospora theae. To determine the genetic characteristics implicated in the biocontrol mechanism, the genome sequence of the HNCS-1 strain was obtained and analyzed further, and the data are deposited in the GenBank repository (No. CP128411). Comparative genomics analyses revealed that the HNCS-1 strain and 17 public Br. brevis share a core genome composed of 3,742 genes. Interestingly, only one non-ribosomal peptide synthetase (NRPS) gene cluster annotated as edeine is present in the core genome. And UHPLC-MS/MS detection results showd that edeine B and edeine A were the principal antibacterial peptides in the HNCS-1 strain. This study proves that edeine is the main antibacterial peptide of Br. brevis, and provides a new strategy for the identification of antibacterial products from other biocontrol bacteria.

Bio-accumulation effects of heavy metals Pb, Zn and Cd on Procecidochares utilis parasitism to Eupatorium adenophorum at Suzu metal mines, Yunnan.

Procecidochares utilis is an obligatory parasitic insect to Eupatorium adenophorum. Both organisms have been spread to some metal mines areas. The objective of this study is to comprehend the trend of heavy metals transfer and the process of their bio-accumulation in the soil-E. adenophorum-P. utilis system and particularly their impact on the parasitic effect of P. utilis to E. adenophorum to reflect the impact of heavy metals on obligate parasitic insect and its host. Therefore, a detailed investigation was carried out at the Suzu Lead-Zinc Mine in Yunnan Province using the concentric circle's method. The results showed that the parasitic rate of P. utilis to a single plant and branch is positively correlated with distance. The metals content of the soil in E. adenophorum and P. utilis, decreased dramatically with an increase in distance away from the center of the mining area. From which is cleared that these metals could enter to E. adenophorum and P. utilis through the soil-E. adenophorum-P. utilis system which likely to affect its parasitic activities. In addition, the parasitic rate is impacted by per Zn content greatly, and the parasitic rate per plant is affected by Cd content enormously. This work could provide important basis of data for further understanding and clarifying the effects of bioaccumulation and heavy metals pollution on various aspects of the food chain. Simultaneously, it could clarify and simplify whether heavy metal contamination affects the parasitic behaviour of some obligatory parasitic insects.

Economic Friendly ZnO-Based UV Sensors Using Hydrothermal Growth: A Review.

Ultraviolet (UV) sensors offer significant advantages in human health protection and environmental pollution monitoring. Amongst various materials for UV sensors, the zinc oxide (ZnO) nanostructure is considered as one of the most promising candidates due to its incredible electrical, optical, biomedical, energetic and preparing properties. Compared to other fabricating techniques, hydrothermal synthesis has been proven to show special advantages such as economic cost, low-temperature process and excellent and high-yield production. Here, we summarize the latest progress in research about the hydrothermal synthesis of ZnO nanostructures for UV sensing. We particularly focus on the selective hydrothermal processes and reveal the effect of key factors/parameters on ZnO architectures, such as the laser power source, temperature, growth time, precursor, seeding solution and bases. Furthermore, ZnO hydrothermal nanostructures for UV applications as well as their mechanisms are also summarized. This review will therefore enlighten future ideas of low-temperature and low-cost ZnO-based UV sensors.

Gross morphology and ultrastructure of the salivary glands of the stink bug predator Eocanthecona furcellata (Wolff).

Eocanthecona furcellata Wolff (Hemiptera: Pentatomidae) is a native generalist predator which attacks and kills its prey by first inserting its stylet into the prey's body and then injecting saliva into it. Here, we describe the histology and ultrastructure of its salivary glands. The study showed that the salivary glands were made up of pairs of principal and tubular accessory salivary glands. The principal salivary glands were bilobed and consisted of a smaller anterior lobe and a larger elongated posterior lobe. The ducts of the principal and accessory salivary glands were located in a narrow region between the anterior and posterior lobe known as the hilum. The principal salivary gland was lined with a single-layered epithelium. The cells cytoplasm was enriched with rough endoplasmic reticulum and secretory, and the nucleus showed a higher level of uncondensed chromatin. The basal region of the cell had plasma membrane infoldings. The cytoplasm of the accessory gland was rich in rough endoplasmic reticulum and many large cavities. The ducts of the principal salivary gland were made up of a single layer of flattened cells which had a thin cuticle lining the apical portion. Variation in the lumen content of the different lobes, which made up the principal gland suggested that their chemical products also varied. These results indicate that these two salivary glands produce the proteins found in the saliva.

Increased pancreatic beta-cell proliferation mediated by CREB binding protein gene activation.

The cyclic AMP (cAMP) signaling pathway is central in beta-cell gene expression and function. In the nucleus, protein kinase A (PKA) phosphorylates CREB, resulting in recruitment of the transcriptional coactivators p300 and CREB binding protein (CBP). CBP, but not p300, is phosphorylated at serine 436 in response to insulin action. CBP phosphorylation disrupts CREB-CBP interaction and thus reduces nuclear cAMP action. To elucidate the importance of the cAMP-PKA-CREB-CBP pathway in pancreatic beta cells specifically at the nuclear level, we have examined mutant mice lacking the insulin-dependent phosphorylation site of CBP. In these mice, the CREB-CBP interaction is enhanced in both the absence and presence of cAMP stimulation. We found that islet and beta-cell masses were increased twofold, while pancreas weights were not different from the weights of wild-type littermates. beta-Cell proliferation was increased both in vivo and in vitro in isolated islet cultures. Surprisingly, glucose-stimulated insulin secretion from perfused, isolated mutant islets was reduced. However, beta-cell depolarization with KCl induced similar levels of insulin release from mutant and wild-type islets, indicating normal insulin synthesis and storage. In addition, transcripts of pgc1a, which disrupts glucose-stimulated insulin secretion, were also markedly elevated. In conclusion, sustained activation of CBP-responsive genes results in increased beta-cell proliferation. In these beta cells, however, glucose-stimulated insulin secretion was diminished, resulting from concomitant CREB-CBP-mediated pgc1a gene activation.

Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK.

Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin's anti-tumor effects.

The Emerging Role(s) for Kisspeptin in Metabolism in Mammals.

Kisspeptin was initially identified as a metastasis suppressor. Shortly after the initial discovery, a key physiologic role for kisspeptin emerged in the regulation of fertility, with kisspeptin acting as a neurotransmitter via the kisspeptin receptor, its cognate receptor, to regulate hypothalamic GnRH neurons, thereby affecting pituitary-gonadal function. Recent work has demonstrated a more expansive role for kisspeptin signaling in a variety of organ systems. Kisspeptin has been revealed as a significant player in regulating glucose homeostasis, feeding behavior, body composition as well as cardiac function. The direct impact of kisspeptin on peripheral metabolic tissues has only recently been recognized. Here, we review the emerging endocrine role of kisspeptin in regulating metabolic function. Controversies and current limitations in the field as well as areas of future studies toward kisspeptin's diverse array of functions will be highlighted.

In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion.

Bone marrow harbors cells that have the capacity to differentiate into cells of nonhematopoietic tissues of neuronal, endothelial, epithelial, and muscular phenotype. Here we demonstrate that bone marrow-derived cells populate pancreatic islets of Langerhans. Bone marrow cells from male mice that express, using a CRE-LoxP system, an enhanced green fluorescent protein (EGFP) if the insulin gene is actively transcribed were transplanted into lethally irradiated recipient female mice. Four to six weeks after transplantation, recipient mice revealed Y chromosome and EGFP double-positive cells in their pancreatic islets. Neither bone marrow cells nor circulating peripheral blood nucleated cells of donor or recipient mice had any detectable EGFP. EGFP-positive cells purified from islets express insulin, glucose transporter 2 (GLUT2), and transcription factors typically found in pancreatic beta cells. Furthermore, in vitro these bone marrow-derived cells exhibit - as do pancreatic beta cells - glucose-dependent and incretin-enhanced insulin secretion. These results indicate that bone marrow harbors cells that have the capacity to differentiate into functionally competent pancreatic endocrine beta cells and that represent a source for cell-based treatment of diabetes mellitus. The results generated with the CRE-LoxP system also suggest that in vivo cell fusion is an unlikely explanation for the "transdifferentiation" of bone marrow-derived cells into differentiated cell phenotypes.

Hepatic estrogen receptor α is critical for regulation of gluconeogenesis and lipid metabolism in males.

Impaired estrogens action is associated with features of the metabolic syndrome in animal models and humans. We sought to determine whether disruption of hepatic estrogens action in adult male mice could recapitulate aspects of the metabolic syndrome to understand the mechanistic basis for the phenotype. We found 17ß-estradiol (E2) inhibited hepatic gluconeogenic genes such as phosphoenolpyruvate carboxykinase 1 (Pck-1) and glucose 6-phosphatase (G6Pase) and this effect was absent in mice lacking liver estrogen receptor α (Esr1) (LERKO mice). Male LERKO mice displayed elevated hepatic gluconeogenic activity and fasting hyperglycemia. We also observed increased liver lipid deposits and triglyceride levels in male LERKO mice, resulting from increased hepatic lipogenesis as reflected by increased mRNA levels of fatty acid synthase (Fas) and acetyl-CoA carboxylase (Acc1). ChIP assay demonstrated estradiol (E2) induced ESR1 binding to Pck-1, G6Pase, Fas and Acc1 promoters. Metabolic phenotyping demonstrated both basal metabolic rate and feeding were lower for the LERKO mice as compared to Controls. Furthermore, the respiratory exchange rate was significantly lower in LERKO mice than in Controls, suggesting an increase in lipid oxidation. Our data indicate that hepatic E2/ESR1 signaling plays a key role in the maintenance of gluconeogenesis and lipid metabolism in males.

The undoing and redoing of the diabetic ß-cell.

A hallmark of type 2 diabetes (T2DM) is the reduction in functional ß-cell mass, which is considered at least in part to result from an imbalance of ß-cell renewal and apoptosis, with the latter being accelerated during metabolic stress. More recent studies, however, suggest that the loss of functional ß-cell mass is not as much due to ß-cell death but rather to de-differentiation of ß-cells when these cells are exposed to metabolic stressors, opening the possibility to re-differentiate and restore functional ß-cell mass by therapeutic intervention. In parallel, clinical observations suggest that temporary intensive insulin therapy in early diagnosed humans with T2DM, so as to "rest" endogenous ß-cells, allows these patients to regain adequate insulin secretion and to maintain euglycemia for prolonged periods free of continued pharmacotherapy. Whether observations made in (mostly rodent) models of diabetes mellitus and in clinical trials are revealing identical mechanisms and therapeutic opportunities remains a tantalizing possibility. Our intention is for this review to serve as an overview of the field and commentary of this particularly exciting field of research.