Astronauts at are risk of losing 1.0 – 1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs designed to preserve the musculoskeletal system. This article reviews the basics of bone formation and resorption and details how exposure to microgravity or simulated microgravity affects the structure and function of osteoblasts, osteocytes, osteoclasts, and their mesenchymal and hematologic stem cell precursors. It details the critical roles that insulin-like growth facor-1 and its receptor IGFR1 play in maintaining bone homeostasis and how exposure of bone cells to microgravity affects the function of these growth factors. Lastly, it discusses the potential of tumor necrosis factor-related apoptosis-inducing ligand, syncytin-A, and sclerostin inhibitors and recombinant IGF-1 as a bone-saving treatment for astronauts in space and during their colonization of the Moon.

Molecular analysis is an easier means to identify and isolate a specific gene which has imperative function for growth, body composition , fat deposition, metabolic and skeletal traits as well as the molecular genetics selection on individual genes is a very efficient method to genetically improve economically important traits in chickens. Insulin- like growth factor 1 ( IGF-1)is a member of a heterogeneous group of peptides with important growth.Transforming growth factorβ ( TGF-β) belongs to a large family of growth and differentiation factors that play a pivotal role in a great variety of biological activities including morphogenesis, development and differentiation. DNA was extracted from 48 chickens sampled from three strains Lohman (17) , Sinai (24) and Gimmizah (7) IGF-1 gene and TGFβ2 gene were amplified using PCR protocol. Electrophoresis was carried out on the products of PCR , bands viewed on transilluminator. The size of IGF-1 gene was 675 bp while the size of TGFβ2 gene was 188bp. Sharp bands were purified and sequenced and used the dendrogram to show the relationships between other vertebrate species

The present study investigated the insulin-like growth factors (IGFs) and their receptors and binding proteins among different pig breeds during weaning. Sixty Duroc (DR), Taoyuan black (TB), and Xiangcun black (XB) piglets (20 piglets per breed) were selected at 21 and 24 days of age (three days of post-weaning) to analyze organ indices, plasma concentrations of IGF and IGF-binding proteins (IGFBPs) using ELISA kits, and gene expression of IGF system-related components in different tissues. The plasma IGFBP-3 level in TB piglets was higher (P > 0.05) than in the XB and DR piglets at 21 days of age. At 21 days of age, compared with the DR piglets, the IGF-1 expression was lower (P < 0.05) in the kidney but was higher (P < 0.05) in the spleen of XB and TB piglets. At 24 days of age, the IGF-1 expression was higher (P < 0.05) in the kidney of TB piglets than in the XB and DR piglets, while IGFBP-3 in the stomach and IGFBP-4 in the liver of XB and TB piglets were lower (P < 0.05) compared with the DR piglets. Weaning down-regulated (P < 0.05) the IGF-1 expression in the jejunum, spleen, and liver of piglets, while up-regulated (P < 0.05) IGFBP-3 expression in the stomach, IGFBP-4 in the liver, IGFBP-5 in the ileum, and IGFBP-6 in the jejunum of DR piglets. Spearman’s correlation analysis showed a negative correlation (P < 0.05) between plasma IGFBP-2 and IGFBP-5 and the organ index of piglets. Collectively, there were significant differences in IGF system components among different pig breeds. The IGF system components were altered during weaning, which might be involved in weaning stress to decrease the growth of piglets.

Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, of tissue differentiation and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. But even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF-GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced.

Insulin-like growth factor binding proteins (IGFBPs) are critical modulators of the metabolism. In adults, IGFBPs are associated with obesity and insulin resistance but the association of IGFBPs with metabolic homeostasis in children and adolescents is not fully characterized. In this study we investigated the association of plasma IGFBPs (IGFBP-1, 3 and 7) with weight status, central adiposity and cardiovascular disease markers Hs-CRP and Ox-LDL. A total of 420 adolescents (age 11-14 years) were randomly recruited from public middle schools in Kuwait. IGFBPs were measured using bead-based multiplexing while Hs-CRP and Ox-LDL were measured using ELISA. IGFBP-1 levels were significantly lower in obese and overweight participants compared to normal weight children. Only IGFBP-1 was negatively associated with waist circumference to height (WC/Ht) ratio. IGFBP-1 was negatively correlated with Hs-CRP while IGFBP-3 and IGFBP-7 were negatively correlated with Ox-LDL. These data demonstrate a robust negative association of IGFBP-1, but not IGFBP-3 or -7, with overweight and obesity, and the inflammation marker Hs-CRP. Central adiposity (WC/Ht ratio) was a stronger predictor of IGFBP-1 than BMI-for-age z-score. IGFBP-1 could thus be used as a sensitive predictive diagnostic tool for obesity and its subsequent effects in screening and monitoring of obesity-related metabolic complications in adolescents.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent world-wide. It progresses from simple steatosis to non-alcoholic steatohepatitis (NASH). Fibrosis is often present during NAFLD progression; however, factors determining which subjects develop NASH or fibrosis are unclear. Insulin-like growth factor binding proteins (IGFBP) is a family of secreted proteins involved in senescence and scarring mainly synthetized in the liver. Here we aimed to study the association of IGFBP and its induced senescence with the progression of NAFLD and liver fibrosis. Materials and Methods: 16 weeks old male C57BL/6 mice weighing 23 ± 3 g were fed either Methionine-Choline Deficient or control diet for 2, 8 or 12 weeks. Blood and liver samples were collected; histological assessment of NAFLD and fibrosis was performed. Fat contents were measured. Cellular senescence was evaluated in the liver. IGFBP levels were assessed in liver and serum. Data was expressed as Mean ± SD and analyzed by one-way ANOVA followed Tukey’s test. Lineal regression models were applied for NAFLD and fibrosis progression. p

Background: Since cytokine receptor like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. Methods: The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno associated virus (AAV) or AAV containing CRLF1 was determined by morpholog-ical, histological and microCT analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were deter-mined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes us-ing real time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. Results: Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondro-genic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and Cardiotrophin like Cytokine (CLC) stimulated catabolic events via STAT3 activation. Conclusion: A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells.

Histone post-translational modification is one of the main mechanisms of epigenetic regulation, which plays a crucial role in the control of gene expression and various biological processes. However, whether or not it affects fungal virulence is not clear in Sclerotinia sclerotiorum. In this study, we identified and cloned the histone methyltransferase Defective in methylation 5 (Dim5) in S. sclerotiorum, which encodes a protein containing a typical SET domain. SsDim5 was found to be dynamically expressed during infection. Knockout experiment demonstrated that deletion of SsDim5 reduced the virulence in Ssdim5-1/Ssdim5-2 mutant strains, accompanied by a significant decrease in H3K9 trimethylation levels. Transcriptomic analysis further revealed the downregulation of genes associated with mycotoxins biosynthesis in SsDim5 deletion mutants. Additionally, the absence of SsDim5 affected the fungus's response to oxidative and osmotic, as well as cellular integrity. Together, our results indicate that the H3K9 methyltransferase SsDim5 is essential for H3K9 trimethylation, which regulating fungal virulence to host plants through impacting on mycotoxins biosynthesis, and the response to environmental stresses in S. sclerotiorum.

This study examined the patterns of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) deposition in the small intestine and colon to evaluate the association between histopathological severity of EFEMP1 deposition and constipation and determine if amyloid transthyretin (ATTR) and EFEMP1 deposits can colocalize. In 40 older cases (≥80 years of age), EFEMP1 deposition in the small intestine initiated in the submucosal and subserous vessels, subserous interstitium, and serosa (early stage); progressing to the muscularis propria and peri-Auerbach plexus area (intermediate stage); and finally, spreading diffusely to areas, excluding the mucosa and muscularis mucosa (advanced stage). The colon had a similar pattern of progression. During the middle-to-advanced stages, amyloid formation was observed in some vascular and serous deposits. We identified a subgroup of cases in which EFEMP1 deposition was the only presumed cause of constipation. Additionally, we demonstrated the colocalization of ATTR and EFEMP1 deposition. Apple-green birefringence was detected under polarized light only in approximately one-half of the cases in the small intestine and one-third of the cases in the colon. These findings emphasize that EFEMP1 deposits may be associated with lower gastrointestinal pathological conditions. Given the challenges of histopathological diagnosis on Congo red-stained specimens, we recommend the combined use of elastic fiber staining and immunohistochemistry for EFEMP1 to prevent overlooking this deposition.

(1) Background: Angiotensin II, a major culprit in cardiovascular disease, activates mediators that are also involved in pathological cardiac remodelling. We aimed at investigating the effects of two of them: aldosterone (Ald) and transforming growth factor-beta-1 (TGF-β1 ), on cardiac remodelling in an in vivo model. (2) Methods: Six-week-old male wild-type (WT) and TGF-β1 -overexpressing transgenic (TGF-β1 -TG) mice were infused with subhypertensive doses of Ald for 2 weeks, and/or treated orally with eplerenone from postnatal day 21. Heart’s ventricles were examined: by morphometry, immunoblotting to assess intracellular signalling pathways, RT qPCR to determine hypertrophy and fibrosis marker genes. (3) Results: TGF-β1 -TG mice spontaneously developed cardiac hypertrophy and interstitial fibrosis, exhibited higher baseline phosphorylation of p44/42 and p38 kinases, fibronectin and ANP mRNA expression. Ald induced a comparable increase in ventricular heart weight-to-body-weight ratio and cardiomyocyte diameter in both strains, but less pronounced increase in interstitial fibrosis in transgenic compared to WT mice (23.6% vs 80.9%, p&lt;0.005). Ald increased phosphorylation of p44/42 and p38 in WT but not TGF-β1 -TG mice. While eplerenone-enriched chow partially prevented Ald-induced cardiac hypertrophy in both genotypes and interstitial fibrosis in WT controls, it completely protected from additional fibrosis in transgenic mice. (4) Conclusions: Ald appears to induce cardiac hypertrophy independently of TGF-β1 , while in case of fibrosis downstream signalling pathways of these two factors probably converge

Expression of Krüppel–like factor 15 (KLF15), a stress induced transcription factor, is induced during bovine herpesvirus 1 (BoHV-1) reactivation from latency, and KLF15 stimulates BoHV-1 replication. Transient transfection studies revealed KLF15 and glucocorticoid receptor (GR) cooperatively transactivate the BoHV-1 immediate early transcription unit 1 (IEtu1), herpes sim-plex virus type 1 (HSV-1) infected cell protein 0 (ICP0), and ICP4 promoter. The IEtu1 promoter drives expression of bICP0 and bICP4, two key BoHV-1 transcriptional regulatory proteins. Based on these studies, we hypothesized infection is a stressful stimulus that increases KLF15 ex-pression and enhances productive infection. New studies demonstrated that silencing KLF15 impaired HSV-1 productive infection and KLF15 steady state protein levels were increased at late stages of productive infection. KLF15 was primarily localized to the nucleus following in-fection of cultured cells with HSV-1, but not BoHV-1. When cells were transfected with a KLF15 promoter construct and then infected with HSV-1, promoter activity was significantly increased. The ICP0 gene and to a lesser extent bICP0 transactivated the KLF15 promoter in the absence of other viral proteins. In contrast, BoHV-1 or HSV-1 encoded VP16 had no effect on KLF15 pro-moter activity. Collectively, these studies revealed HSV-1 and BoHV-1 productive infection in-creased KLF15 steady state protein levels, which correlated with increased virus production.

Chronic inflammatory diseases are considered the most significant cause of death worldwide. Current treatments for inflammatory diseases are limited due to the lack of understanding of the biological factors involved in early-stage disease progression. Nerve growth factor (NGF) is a neurotrophic factor directly associated with inflammatory and autoimmune diseases like osteoarthritis, multiple sclerosis, and rheumatoid arthritis. It has been shown that NGF levels are significantly upregulated at the site of inflammation and play a crucial role in developing a robust inflammatory response. However, little is known about NGF's temporal expression profile during the initial progressive phase of inflammation. This study aimed to determine the temporal expression pattern of NGF in rat skin during Adjuvant-Induced Arthritis (AIA). Sprague Dawley rats were randomly divided into control and Complete Freund's Adjuvant (CFA) treated groups. Levels of NGF were evaluated following unilateral AIA at different time points and it was found that peripheral inflammation due to AIA significantly upregulated the expression of NGF mRNA and Protein in a biphasic pattern. These results suggest that NGF signaling is crucial for initiating and maintaining peripheral neurogenic inflammation in rats during AIA.

Vessel co-option correlates with resistance against anti-angiogenic agents and chemotherapy in colorectal cancer liver metastasis (CRCLM). We previously identified higher intensity of neutrophils in the tumour microenvironment of vessel co-opting CRCLM lesions compared to their angiogenic counterparts. Herein, we demonstrated that over 50% of the neutrophils in vessel co-opting lesions are expressing pro-apoptotic markers including cleaved caspase-3 and poly (ADP-ribose) polymerase-1 (PARP-1). Our previous publications suggested upregulation of transforming growth factor-beta (TGFβ1) in the microenvironment of vessel co-option CRCLM. Therefore, we examined the effect of TGFβ1 on the expression of cleaved caspase-3 and PARP-1 in neutrophils in vitro. Significantly, we noticed the upregulation of pro-apoptotic markers upon exposure to TGFβ1. This finding might pave the way to determine the role of neutrophils in developing vessel co-option in CRCLM in the future.

The 2-Acetyl-1-pyrroline (2-AP) is the most important volatile in determining the aroma of fragrant rice, however, the transcriptional regulation mechanism of 2-AP biosynthesis in fragrant rice is still unclear. In this study, the Osp5cs1 knockout mutant lines and OsP5CS1 over-expression lines were constructed by genetic transformation of indica rice cultivar i.e., ‘Zhonghua11’, which was knocked out OsBADH2 to produce fragrance in aromatic rice. The OsP5CS1 gene was also identified as a key gene in the 2-AP biosynthesis pathway of aromatic rice. The OsP5CS1 promoter was used as bait, and the transcription factor OsbZIP60-like was screened by yeast one-hybrid assays. The transcription factor OsbZIP60-like specifically bound to the OsP5CS1 gene. The dual luciferase reporting system found that OsbZIP60-like transcription factor promoted the transcriptional activation of OsP5CS1. Compared with the wild type, the OsP5CS1 gene expression was significantly down-regulated in Osbzip60-like mutant, and resulted in substantial reduction in 2-AP biosynthesis. Moreover, the OsP5CS1 gene expression was significantly up-regulated in OsbZIP60-like over-expressed plants, and the 2-AP concentrations were also increased whereas the Osbzip60-like mutants were found to be sensitive to Zn deficiency. Overall, the OsbZIP60-like transcription factor promoted the 2-AP accumulation. This study provides a theoretical basis for the transcriptional regulation mechanism of 2-AP biosynthesis and explores the function of OsbZIP transcription factor in fragrant rice.

Saturated fatty acids are implicated in the development of metabolic diseases, including obesity and type 2 diabetes. There is evidence, however, that polyunsaturated fatty acids can counteract the pathogenic effects of saturated fatty acids. To gain insight into the early molecular mechanisms by which fatty acids influence hypothalamic inflammation and insulin resistance, we performed time-course experiments in a hypothalamic cell line, using different durations of treatment with the saturated fatty acid palmitate, and the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). Western blot analysis revealed that palmitate elevated the protein levels of phospho(p)AKT in a time-dependent manner. This effect seems involved in the pathogenicity of palmitate, as temporary inhibition of the PI3K/AKT pathway by selective PI3K inhibitors prevented palmitate-induced insulin resistance. Similarly to palmitate, DHA also increased levels of pAKT, but to a weaker extent. Co-administration of DHA with palmitate decreased pAKT close to the basal level after 8 h, and prevented palmitate-induced insulin resistance after 12 h. Measurement of the inflammatory markers pJNK and pNFκB-p65 revealed tonic elevation of both markers in the presence of palmitate alone. DHA alone transiently induced elevation of pJNK, returning to basal levels by 12 h treatment. Co-administration of DHA with palmitate prevented palmitate-induced inflammation after 12 h, but not at earlier time points.

We have previously shown that the transmembrane protein ODZ1 promotes cytoskeletal remodelling of glioblastoma (GBM) cells and invasion of the surrounding parenchyma through activation of a RhoA-ROCK pathway. We also described that GBM cells can control the expression of ODZ1 through transcriptional mechanisms triggered by binding of IL-6 to its receptor and a hypoxic environment. Epidermal growth factor (EGF) plays a key role in the invasive capacity of GBM. However, the molecular mechanisms that enable tumor cells to acquire the morphological changes to migrate out from the tumor core have not been fully characterized. Here we show that EGF is able to induce the expression of ODZ1 in primary GBM cells. We analysed the levels of EGF receptor (EGFR) in 20 GBM primary cell lines and found expression in 19 of them by flow cytometry. We selected two cell lines that do or do not express EGFR and found that EGFR-expressing cells responded to EGF ligand by increasing ODZ1 at the mRNA and protein level. Moreover, blockade of EGF-EGFR binding by Cetuximab, inhibition of the p38 MAPK pathway or siRNA-mediated knockdown of MAPK11 (p38 MAPK) reduced the induction of ODZ1 in response to EGF. Overall, we show that EGF may activate an EGFR-mediated signalling pathway through p38 MAPK, to upregulate the invasion factor ODZ1, which may initiate morphological changes for tumor cells to invade the surrounding parenchyma. These data identify a new candidate of the EGF-EGFR pathway for novel therapeutic approaches.

Type 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight. The present standard-of-care for type 1 diabetes is exogenic insulin substitutional therapy. The most advanced stretegies in this area is the development of hybrid-closed loop system and the producing of long-acting insulins. Progresses in stem cell therapies have started to revolutionize the care of patients with type 1 diabetes; however, significant challenges remain including the limited islets availability, difficulties in maintaining the viability, the heterogeneity within a complex pathology and in patients’ responses to treatment. On the way, a considerable amount of efforts in maximizing the islet transplantation effectiveness by controlling the advantageous of different stem cell approaches. With the availability and the use of big data, the concept of precision medicine is gaining wide attention worldwide and could bring the dream of “presonlaized” therapies as a reality in the near future. Here we review the current range of treatments available as well as recent pre-clinical breakthroughs in the field of personlaized medicine for type 1 diabetes.

Dipeptidyl peptidase 9 (DPP9) is a multifunctional intracellular protease with roles in tumour growth, inflammation and mitochondrial function. We developed a hepatocyte-specific DPP9 knockout mouse (DPP9-KO) to explore DPP9 in a mouse model of hepatocellular carcinoma (HCC). DPP9-KO mice were generated by crossing Albumin-Cre mice (Wt/Wt Cre+/+) with DPP9 floxed mice (Fl/Fl Cre-/-). Mice were treated with Diethylnitrosamine and Thioacetamide then an atherogenic High Fat Diet until 28 weeks of age. DPP9-KO mice had reduced liver and subcuta-neous adipose tissue mass and lower fasting plasma glucose, fewer small macroscopic liver nod-ules compared to DPP9-WT mice. However, there were no differences in the total number of mac-roscopic liver nodules, tumour burden, inflammation score and steatosis score. Consistent with the known ability of DPP9 to suppress NLRP1 activation, activated caspase-1 protein was ele-vated in DPP9-KO mouse liver. Additionally, Nfkbib, Cxcl10 and Ccl5 mRNA and protein levels of autophagy marker beclin1 and tumour suppressor p53 were increased. In conclusion, DPP9 de-pletion in hepatocytes may reduce liver cancer initiation, via mechanisms that may include in-creased autophagy and innate tumour suppression in this experimental model. Finally, the data supports DPP9 having a role in glucose regulation by the liver.

Insulin resistance/hyperinsulinemia as an independent risk factor for the development and worsening of HFpEF. Serafino Fazio MD¹, Valentina Mercurio MD, PhD2, Valeria Fazio MD3, Antonio Ruvolo MD⁴, Flora Affuso MD, PhD⁵. Authors’ Affiliation: ¹ Department of Internal Medicine (retired Professor). Federico II University, Via Sergio Pansini 5. 80135 Naples, Italy. 2 Department of Translational Medical Sciences. Federico II University. Via Sergio Pasini 5. 80135 Naples, Italy. ³ UOC Medicina Interna, Azienda Ospedaliera di Caserta, 81100 Caserta, Italy, ⁴ UOC Cardiologia AORN dei colli PO CTO, Viale Colli Aminei 21, 80100 Naples, Italy. ⁵ Independent researcher, Viale Raffaello 74, 80129 Naples, Italy. Abstract Heart failure (HF) has become a subject of continuous interest since it has been declared new pandemic in 1997 because of the exponential increase in hospitalizations for HF in the latest years. HF is the final state to which all heart diseases of different etiologies lead if not adequately treated, therefore it is highly prevalent worldwide, with a progressive increase with age, reaching a prevalence of 10% in subjects over the age of 65 years. It should also be underlined that lately, while the prevalence of HF with left ventricular reduced ejection fraction (HFrEF) is slowly decreasing, the incidence of HF with left ventricular preserved ejection fraction (HFpEF) is progressively increasing. In deed, among patients consecutively hospitalized for HF between 1987 and 2001 in a study from the Mayo Clinic Hospitals in Olmsted County, Minnesota, prevalence of HFpEF increased from 38% to 54%. HFpEF is typically characterized by concentric remodeling of the left ventricle (LV) with impaired diastolic function and increased filling pressures. Over the years, also the prevalence of insulin resistance/hyperinsulinemia in the general adult population has progressively increased, primarily due to lifestyle changes, particularly in developed and developing countries, with a range that globally ranges between 15.5% and 46.5%. Notably, insulin resistance (IR)/hyperinsulinemia (Hyperins) is present in up to 60% of patients with HF and is significantly higher in subjects with HfpEF. In the scientific literature it has been well highlighted that the increased circulating levels of insulin are associated with conditions of insulin resistance are responsible for progressive cardiovascular alterations over the years. In the setting of HFpEF, insulin stimulates the concentric remodeling of the left ventricle with associated diastolic dysfunction, which, coincidentally. Unfortunately, IR/Hyperins, despite being a well-known cardiovascular risk factor, is still not screened in the general population and is not treated as promptly as it should be, and this could at least in part concur in the progressive increase in prevalence of HFpEF in the general adult population. The aim of this manuscript was to review scientific literature that support a pathophysiologic connection between IR/Hyperins and HFpEF to stimulate the scientific community towards the identification of hyperinsulinemia associated with insulin resistance as an independent cardiovascular risk factor in development and worsening of HF, believing that its adequate screening in the general population and appropriate treatment could reduce the prevalence of HFpEF and improve its progression.

This study aimed to investigate the appearance and frequencies of the booroola polymorphism of the bone morphogenetic protein receptor 1b (BMPR1B) gene (FecB) and the embrapa polymorphism of the growth differentiation factor 9 (GDF9) gene (FecGE) in sheep in Thailand. A total of 454 cross-bred sheep blood samples were collected from four provinces in Thailand during August 2022 to July 2023. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to identify the FecB and FecGE genotype. The history of ewe birth types was collected from the owners to analyze the association between Fecundity (Fec) genotypes and the history of birth types. The genotypic frequencies of FecB for homozygous genotype (B/B), heterozygous genotype (+/B) and wild-type (+/+) were 0.22%, 1.54%, and 98.24%, respectively. Meanwhile, the genotypic frequencies of FecGE for homozygous genotype (E/E), heterozygous genotype (+/E), and wildtype (+/+) were 0.00%, 2.42%, and 97.58%, respectively. Furthermore, three ewes exhibited both FecB and FecGE genotypes. Fisher’s exact test revealed that the possessor of FecB genotype was associated with multiple births (p&lt;0.01). Both FecB and FecGE mutations were identified in crossbred sheep in Thailand. Sheep containing FecB allele is a better candidate to be selected to improve the prolificacy of crossbred sheep in Thailand.

Matrices and their inverses allow accurate calculations to be produced quickly and compactly and can be used to control any process represented by a system of equations. Singular matrices require extensive workarounds (costing time and money) to solve these systems of equations because they have no inverse. Finding their inverse involves division by zero. Nevertheless, recently a new number set called semi-structured complex numbers was developed to enable division by zero in algebraic equations. The aim of this research was to demonstrate that the inverse of a singular matrix can be found using semi-structured complex numbers. This research reveals (1) Singular matrices and their inverses can be used to find a unique solution to a pair of simultaneous equations that appear to have infinitely many solutions or appear to have no solution; (2) Singular matrices map coordinates in projective space to coordinates in Euclidean space and their inverse maps coordinates in Euclidean space to coordinates in projective space; (3) the inverse of a singular matrix proves that parallel lines in Euclidean space do not intersect but in projective space intersect at a “point at infinity” and (4) collinear lines that intersect at infinitely many points in Euclidean space only intersect at one point in projective space.

Factors affecting the host-virus interaction must be understood for the effective application of bacteriophages to combat bacterial pathogens. Two novel E. coli phages, the T1-like siphophage LL5 and the rV5-like myophage LL12, were subjected to forward genetic screens against the Keio collection, a library of single non-essential gene deletions in E.coli str. BW25113. These genome-wide screens and subsequent experiments identified eight genes required for efficient propagation of phage LL5 and six genes required for propagation of LL12. The majority of the genes identified were involved in production of the phage receptors. E. coli mutants deficient in heptose II and the phosphoryl substituent of heptose I of the inner core lipopolysaccharide (LPS) were unable to propagate phage LL5, as were mutants deficient in the outer membrane protein TolC. Mutants lacking glucose I of the LPS outer core failed to propagate LL12. Two cytoplasmic chaperones, PpiB and SecB, were found to be required for efficient propagation of phage LL5 but not LL12. This approach may be useful for identifying phage receptors and required host factors in other phages, which would provide valuable information for their potential use as therapeutics and for phage engineering.

Mosquitoes have distinct developmental and adult life history, and the vectorial capacity of females has been shown to be affected by the larval nutritional environment. However, little is known about the effect of developmental nutrition on insulin-signaling and nutrients storage. In this study, we used Aedes aegypti, the yellow fever mosquito, to determine whether larval nutrition affects insulin gene expression. We also determined the traits regulated by insulin signaling, such as stored-nutrients levels and fecundity. We raised mosquito larvae on two different diets, containing either high protein or high carbohydrates. Development on a high-carbohydrate diet resulted in several life-history phenotypes indicative of suboptimal conditions, including increased developmental time and decreased fecundity. Additionally, our data showed that insulin transcript levels are affected by a high-carbohydrate diet during development. Females, not males, reared on high-carbohydrate diets had much higher transcript levels of insulin-like peptide 3 (ILP3), a mosquito equivalent of human insulin, and these females more readily stored sugar from the meal into lipids. We also found that AaILP4, not AaILP3, transcript levels were much higher in the males after a sugar meal, suggesting sex-specific differences in insulin-signaling pathway. Our findings suggest a conserved mechanism of carbohydrate-mediated hyperinsulinemia in animals.

Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung, and high VCAM-1 expression correlated with poor survival of lung cancer patients. VCAM-1 knockdown reduced invasion in A549 human lung cancer cells, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1-mediated A549 cell invasion. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed invasion in A549 and NCI-H1299 lung cancer cell lines. Taken together, these results suggest that VCAM-1-D6 is a novel therapeutic target in VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion.

Tissue-like phantoms are widely used as a model for mimicking the optical properties of live tissue. This paper presents the results of a diffusion reflection method as well as fluorescence lifetime imaging microscopy measurements of fluorescein-conjugated gold nanorods in solution as well as inserted in solid tissue-imitating phantoms. A lack of consistency between the fluorescence lifetime results of the solutions and the phantoms raises a question about the ability of tissue-like phantoms to maintain the optical properties of inserted contrast agents.

Chitinase 3-like 1 （also known as CHI3L1 or YKL-40）is a mammalian chitinase that has no enzymatic activity, but has the ability to bind to chitin, the polymer of N-acetylglucosamine (GlcNAc). Chitin is a component of fungi, crustaceans, arthropods including insects and mites, and parasites, but is completely absent from mammals, including humans and mice. In general, chitin-containing organisms produce CHI3L1 to protect the body from exogenous pathogen as well as hostile environments, and it was thought that it has a similar effect in mammals. However, recent studies have revealed that CHI3L1 plays a pro-inflammatory role by inducing anti-apoptotic activity in epithelial cells and macrophages. Under chronic inflammatory conditions such as inflammatory bowel disease and chronic obstructive pulmonary disease, many groups already confirmed that the expression of CHI3L1 is significantly induced on the apical side of epithelial cells, and activates many downstream pathways involved in inflammation and carcinogenesis. In this review article, we will summarize the expression of CHI3L1 under the chronic inflammatory conditions in various disorders and would like to discuss the potential roles of CHI3L1 in those disorders on various cell types.

Background and Aim. Since virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, post-hepatitis C virus (HCV) infection would be a cause for liver cirrhosis that would progress to HCC. Cytotoxic T cells (Tc) are known to be involved in post-HCV complications and HCC pathogenesis. The inhibitory checkpoint Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is expressed on Tc. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression post-HCV and moreover, to evaluate LAIR-1 expression as a non-invasive biomarker for HCC progression in the context of liver cirrhosis post-HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. We studied LAIR-1 expression on Tc related to the progression of liver cirrhosis in a case-controlled study enrolled 64 patients with post-HCV G4-HCC and 37 patients with post-HCV G4-liver cirrhosis. Methods: LAIR-1 expression was analyzed by flow cytometry. Results: LAIR-1 expression on Tc and the percentage of Tc positive for LAIR-1 (LAIR-1+Tc %) were significantly higher in the post-HCV G4-HCC group compared to the post-HCV G4-liver cirrhosis

Focal cartilage defects are a prevalent knee problem affecting people of all ages. Due to its avascular nature, cartilage has limited self-repair capacity, and osteochondral defects can lead to pain and long-term complications such as osteoarthritis. Autologous chondrocyte implantation (ACI) has been a successful surgical approach for repairing osteochondral defects over the past two decades. However, a major drawback of ACI is the de-differentiation of chondrocytes during their in vitro expansion. In this study, we isolated ovine chondrocytes and cultured them in a two-dimensional environment as for ACI procedures. We hypothesised that the 3D scaffolds would support the cells re-differentiation without the need for growth factors and so we encapsulated them into soft collagen and alginate (col/alg) hydrogels. Chondrocytes embedded into hydrogels were viable and proliferated. After 7 days they acquired a rounded morphology and started to aggregate. Gene expression studies showed that the genes associated with chondrogenesis started to be up regulated as early as day one. At 21 days chondrocytes had extensively colonized the hydrogel, forming large cell clusters and started to deposit collagen II and aggrecan with limited collagen type I deposition. These findings highlight the potential of soft col/alg hydrogels to enhance ACI outcomes by creating a favourable microenvironment for chondrocyte reprogramming and re-differentiation, eliminating the dependency on growth factors.

Huntington's disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD.

LR004 is a novel chimeric (human/mouse) monoclonal antibody developed for the treatment of advanced colorectal carcinoma with detectable epidermal growth factor receptor (EGFR) expression. We aimed to investigate the preclinical pharmacokinetics (PK) and in vivo biodistribution of LR004. The PK profiles of LR004 were initially established in rhesus monkeys. Subsequently, 125I radionuclide-labeled LR004 was developed and its binding activity to the EGFR antigen were evaluated. Furthermore, the biodistribution, autoradiography, and NanoSPECT/CT of 125I-LR004 in xenograft mice bearing A431 tumors were examined. The PK data revealed a prolonged half-life and nonlinear PK characteristics of LR004 within the dose range of 6–54 mg/kg. The radiochemical purity of 125I-LR004 was approximately 98.54%, and iodination of LR004 did not affect its specific binding activity to the EGFR antigen. In a classical biodistribution study, 125I-LR004 exhibited higher uptake in highly perfused organs than in poorly perfused organs. Prolonged retention properties of 125I-LR004 in tumors were observed at 4 and 10 days. Autoradiography and NanoSPECT/CT confirmed the significant accumulation and sustained retention of 125I-LR004 at the tumor site in xenograft mice. These findings demonstrated the adequate tumor targeting capabilities of 125I-LR004 in EGFR-positive tumors, which may improve dosing strategies and future drug development.

Spermatogenesis is critical for insect reproduction and is regulated by many different genes. In this study, we found that Forkhead transcription factor Fd59a functions as a key factor in spermatogenesis of Drosophila melanogaster. Fd59a contains a conversed Forkhead domain, and it is clustered to the FoxD subfamily with other FoxD members from some insect and vertebrate species. Mutation in Fd59a caused swelling in the apical region of the testis. More importantly, only a few mature sperm were present in the seminal vesicle of Fd59a mutant flies compared to the control flies, and the fertility of Fd59a2/2 mutant males was significantly lower than that of the control flies. Immunofluorescence staining showed that the homeostasis of testis stem cell niche in Fd59a2/2 mutant and Fd59a RNAi flies was disrupted, and apoptosis of sperm bundles was increased. Furthermore, results from RNA-sequencing and qRT-PCR suggest that Fd59a can regulate expression of genes related to reproductive process and cell death. Taken together, our results indicated that Fd59a plays a key role in the spermatogenesis of Drosophila.

Alveolar Rhabdomyosarcoma (ARMS), an invasive subtype of Rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic fusion genes PAX3-FOXO1 or PAX7-FOXO1. ARMS patients exhibit an overexpression of the pleiotropic cytokine Transforming growth factor beta (TGF-β). This overexpression of TGF-β1 causes an increased expression of a downstream transcription factor called SNAIL, which promotes Epithelial to Mesenchymal Transition (EMT). Overexpression of TGF-β also inhibits myogenic differentiation, making ARMS patients highly resistant to chemotherapy. In this review, we first describe different types of RMS and then focus on ARMS and the impact of TGF-β in this tumor type. We next highlight current chemotherapy strategies including a combination of FDA approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC), Cabozantinib, Bortezomib, Vinorelbine, AZD 1775 and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS which include all trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-β1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future.

DNA damage repair lies at the core of all cells’ survival strategy, including cancerous. Therefore, targeting such repair mechanisms forms the major goal of cancer therapeutics. The mechanism of DNA repair has been tousled with the discovery of multiple kinases. Recent studies on Tousled like Kinases have brought significant clarity on the effectors of these kinases which stands to regulate DSB repair. In addition to their well-established role in the DDR and cell cycle checkpoint mediation after DNA damage or inhibitors of replication, their suspected involvement in the actual DSB repair process has more recently been strengthened by the important finding that TLK1 phosphorylates RAD54 and regulates some of its activities and localization in the cell. Earlier findings of its regulation of RAD9 during checkpoint deactivation as well as defined steps during NHEJ ends processing were earlier hints of its important involvement broadly in DSB repair. All this has opened up new avenues to target cancer cells in combination therapy with genotoxins and TLK inhibitors.

Type-2 diabetes mellitus (T2DM) have been strongly associated with single nucleotide polymorphisms (SNPs) in the TCF7L2 gene. This study investigated the association between rs12255372, rs7903146 and T2DM in a Ghanaian population. A case-control study design was used for this study. A total of 106 T2DM patients and 110 control participants were selected. Basic data collected included body mass index, blood pressure and socio-demographics. Fasting blood samples were collected and used for serum lipid analysis, HbA1c, plasma glucose estimation and DNA extraction. Common and allele-specific primers were designed for genotyping using the Modified Tetra-Primer Amplification assay. Associations were evaluated using logistic regression models. The rs7903146 risk variant was significantly associated with 2.16 vs 4.06 increased odds for T2DM in patients <60 years vs ≥60 years. Both rs7903146 and rs12255372 are significantly associated with increased odds of T2DM in women, overweight/obese; T2DM negative family history (T2DM-NFH) and low-HDL-C. In a multivariate model, rs7903146 but not rs12255372 was significantly associated with 2.18, 5.01 and 2.25 increased odds of T2DM, under the codominant, recessive and additive model, respectively (p<0.05). The association between rs7903146 and rs12255372 with T2DM is more highly associated in a subgroup- women and those with T2DM-NFH, yet have cardiometabolic risk.

Recent studies have elucidated the diversity of genes encoding venom in sea anemones. However, most of those genes are yet to be explored in an evolutionary context. Insulin is a common peptide across metazoans and has been coopted into a predatory venom in many venomous lineages. In this study, we focus on the diversity of insulin-derived venoms in sea anemones and on elucidating their evolutionary history. We sourced data for 34 species of sea anemones and found sequences belonging to two venom families that have Insulin PFAM annotations (Cono-Insulin, VP302). Our findings show that both families have undergone duplication events. Members of each of the independently evolving clades have consistent predicted protein structures and distinct dN/dS values. Our work also shows that VP302 is part of a multidomain venom contig and has experienced a secondary gain into the venom system of cuticulate sea anemones.

“De-[Constructing] Growth” is offered as a deeper and more useful conceptualization that avoids the negative connotations of, and resistance to, “degrowth” by decoupling profit from unsustainable consumption, production, and inequality.

Many protein expression systems are primary utilised to produce a single, specific recombinant protein. In contrast, most biological processes such as virus assembly rely upon a complex of several interacting proteins rather than the activity of a sole protein. The high complexity of the baculovirus genome, coupled with a multiphase replication cycle incorporating distinct transcriptional steps, made it the ideal system to manipulate for high-level expression of a single or co-expression of multiple foreign proteins within a single cell. We have developed and utilised a series of recombinant baculovirus systems to unravel the sequential assembly process of a complex non-enveloped model virus, Bluetongue virus (BTV). The high protein yields expressed by the baculovirus system not only facilitated structure-function analysis of each viral proteins but were also advantageous to crystallography studies and supported the first atomic level resolution of a recombinant viral protein, the major BTV capsid protein. Further, the formation of recombinant double-shelled virus-like particles (VLPs) provided insights into the structure-function relationships among the four major structural proteins of the BTV whilst also representing a potential candidate for a viral vaccine. The baculovirus multi-gene expression system facilitated the study of structurally complex viruses (both non-enveloped and enveloped viruses) and heralded in a new generation of viral vaccines.

Breast cancer (BC) is the most frequent form of malignancy and the second only to lung cancer as common cause of cancer-causing deaths in women. Notwithstanding many progresses in the field, metastatic BC has a very poor prognosis. As therapies are becoming more personalized to meet patients‘ needs, a better knowledge of the molecular biology leading to the disease unfolds the possibility to project more precise compounds or antibodies targeting definite alteration at the molecular level expressed in cancer cells of patients or as antigens on the surface of cell membranes. Fibroblast growth factor receptor (FGFR) is a druggable target -which is activated by its own ligands -namely the Fibroblast Growth Factors (FGFs). This pathway provides a vast range of interesting molecular targets pursued at different levels of clinical investigation. Herein we provide an update on the knowledge on genetic alterations of the receptors in breast cancer, their role in tumorigenesis and the most recent drugs against this particular receptor to treat the disease.

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, the metastatic breast cancer leaves a poor prognosis. In an era of personalized medicine, there is an urgent need for a better knowledge of the biology leading to the disease, which can lead to the design of always more accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the Fibroblast Growth Factor Receptor (FGFR) pathway, triggered by specific ligands. The FGFRs/FGFs axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of the FGFRs mutations leading to tumour formation and summarizes the state-of-the-art of therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

Most empirical work on sources of economic growth for different countries lack country-specific empirical evidence to guide policy choices in individual developing countries and previous studies of factor productivity tend to focus on the entire economy or a single sector. In this study, we use the recently developed growth accounting tools to explicitly determine the sources of economic growth at both national and sectoral levels in Zambia between 1970 and 2013. We use data from World Development Indicators and Zambia’s Central Statistical Office. On average, total factor productivity (TFP) contributes about 5.7% to economic growth. Sectoral analysis shows that agriculture contributes the least to GDP and that within each sector; factors that contribute to growth differ. Structural transformation has been slow and contributed to the observed inefficiency. We outline the implications of the observed growth and provide recommendations.

Background : ATPase inhibitor factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). Methods and results Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evidenced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extra-mitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP-synthase (E55A mutation), indication that these effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca2+ handling, which resulted in sarcoplasmic reticulum Ca2+ overloading. The effects of IF1 on Ca2+ handling were associated with the cytosolic activation of CaMKII and inhibition of CaMKII or co-expression of catalytically dead CaMKIIδC was sufficient to prevent IF-1 induced pathological hypertrophy. Conclusions IF1 represents a novel member of the fetal-like gene program that contributes to mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase independent, role for IF1 in mitochondrial Ca2+ handling and mitochondrial- to nuclear crosstalk involving CaMKII.

(1) Background: Many malignancies are driven by mutations which affect the gene for fibroblast growth factor receptor (FGFR) 1. Previously we have documented that signal transduction from FOP2–FGFR1 fusion protein in KG1 cells downregulated the expression of vitamin D receptor (VDR) gene. In this paper we investigated if also other FGFRs were responsible for the regulation of the VDR expression. (2) Methods: We used human myeloid leukemia cells U937, and bone cancer cell line U2OS, and cell transfection methods in order to address the above questions. (3) Results: In myeloid leukemia cells overexpression of FGFR 1-4 caused shift to granulocytic differentiation, upregulated expression of VDR, and sensitized these cells to 1,25-dihydroxyvitamin D (1,25D)-induced monocytic differentiation, while in bone cells, signal transduction activated by FGF1 was not responsible for regulation of VDR expression and activity. (4) Conclusions: Since the overexpression of FGFRs occurs in many neoplasms, it may be reasonable to use 1,25D analogs in these cancers, in which overexpression of FGFRs leads to VDR upregulation.

Global economy, financial markets and technology are on the verge of moving to a new stage of development – information society. Three major world countries the US, Russia and China will play a leading role in this process. However, the specific development path will depend on many factors, including the stability of legal systems, security of computer and financial technologies, the effectiveness of legislation. The focus of this article is to assess the current condition of the economy the major countries, to identify trends and methods of stabilization of legal systems on the basis of balance of rights and obligations of the business, suggest some methods of objective evaluation of the impact factors of the total taxes, fixed costs and the legal system dynamics on financial indicators.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that involve in regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result downstream activation of tyrosine kinases leading to tumor development. Targeting those FGFR alterations has shown to be effective in cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms and there are currently four FGFR inhibitors approved by the Food and Drug Administration (FDA). There have been developments of multiple agents targeting FGFR pathway including selective FGFR inhibitors, ligand traps, monoclonal antibodies, and antibody drug conjugates. However, most of these agents have variable and low responses with some intolerable toxicities and acquired resistances. This review will summarize previous clinical experiences and current developments of agents targeting FGFR pathway and discuss future directions of FGFR targeting agents.

Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., pro-NGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the “ideal” candidate in mediating Aβ-induced neuropathology. Besides pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.

The human degenerative cartilage has low regenerative potential. Chondrocyte transplantation offers a promising strategy for cartilage treatment and regeneration. Currently chondrogenesis using human pluripotent stem cells are accomplished using human recombinant growth factors. Here, we differentiated human induced pluripotent stem cells (hiPSCs) into chondrocytes and cartilage pellet using minicircle vectors. Minicircles are used as a non-viral gene delivery system for gene therapy in various diseases. Non-viral gene delivery can produce growth factors without integrating into the host genome. Minicircle vectors containing bone morphogenetic protein 2 (BMP2) and transforming growth factor, beta 3 (TGFβ3) were successfully generated and delivered to hiPSC-derived outgrowth (OG) cells. Cell pellets generated using minicircle-transfected OG cells successfully differentiated into chondrogenic lineage. Chondrogenic pellets transfected with growth factor-encoding minicircles effectively recovered osteochondral defect in rat models. Taken together, this work shows the potential application of minicircles in cartilage regeneration using hiPSCs.

The interaction between nanoparticles and cells has been studied extensively, but most research has focused on the effect of various nanoparticle characteristics, such as size, morphology, and surface charge, on the cellular uptake of nanoparticles. In contrast, there have been very few studies to assess the influence of cellular factors, such as growth factor responses, on the cellular uptake efficiency of nanoparticles. The aim of this study was to clarify the effects of epidermal growth factor (EGF) on the uptake efficiency of polystyrene nanoparticles (PS NPs) by A431 cells, a human carcinoma epithelial cell line. The results showed that EGF enhanced the uptake efficiency of A431 cells for PS NPs. In addition, inhibition and localization studies of PS NPs and EGF receptors (EGFRs) indicated that cellular uptake of PS NPs is related to the binding of EGF-EGFR complex and PS NPs. Different pathways are used to enter the cells depending on the presence or absence of EGF. In the presence of EGF, cellular uptake of PS NPs is via clathrin-mediated endocytosis, whereas in the absence of EGF, uptake of PS NPs does not involve clathrin-mediated endocytosis. Our findings indicate that EGF enhances cellular uptake of PS NPs by clathrin-mediated endocytosis. This result could be important for developing safe nanoparticles and their safe use in medical applications.

Semantic image segmentation has recently witnessed considerable progress by training deep convolutional neural networks (CNNs). The core issue of this technique is the limited capacity of CNNs to depict visual objects. Existing approaches tend to utilize approximate inference in a discrete domain or additional aides and do not have a global optimum guarantee. We propose the use of the multi-label manifold ranking (MR) method in solving the linear objective energy function in a continuous domain to delineate visual objects and solve these problems. We present a novel embedded single stream optimization method based on the manifold ranking (MR) model to avoid approximations without sacrificing expressive power. In addition, we propose a novel network, which we refer to as dual multi-scale manifold ranking (\textbf{DMSMR}) network, that combines the dilated, multi-scale strategies with the single stream MR optimization method in the deep learning architecture to further improve the performance. Experiments on high resolution images, including close-range and remote sensing datasets, demonstrate that the proposed approach can achieve competitive accuracy without additional aides in an end-to-end manner.

Background: Visceral leishmaniasis affects approximately 12 million people worldwide. Current existing drugs cause several side effects and resistance, the identification of new therapeutic targets for the development of new drugs is necessary. The vesicular trafficking in the parasite flagellar pocket is essential for parasite survival and proliferation, but little is known about the proteins involved in the endocytic/secretory pathways. In this work, we are describing the characterization of a transporter cargo protein SFT-2/Got-1 like in Leishmania infantum. Material and Methods: Using bioinformatics tools, the putative Got-1 protein A4HSK3 was characterized structurally and phylogenetically. Molecular biology was used to clone and express the protein and confocal fluorescence to determine its subcellular localization. Results: The Got-1 like protein presents four alpha helix TM conserved domains (aa38-aa147) characteristics of the Got-1/SFT-2 family proteins and an important Pen-2 conserved motif LGDYXXF located in the extracellular loop. Confocal microscopy suggests that Got-1/SFT-2 like is localized in the flagellar pocket, and is partially co-localized with the L. infantum presenilin-like protein. Phylogenetically, the Leishmania sp Got-1 like is contained in a subgroup of proteins clearly detached from the other Trypanosomatidae, such as T. cruzi and T. brucei. Conclusions: Our data show the presence of an important transported proteins, and its colocalization with the presenilin aspartyl protease in the flagellar pocket of the L. infantum open new perspectives to identify novel targets, which can be an alternative therapeutic strategy against leishmaniasis.

Promoting green development has become an important way to optimize the ecological and economic structure and promote sustainable development. The Yangtze River Economic Belt is an important economic corridor in China, and it remains to be examined whether the implementation of environmental regulations has enhanced the green total factor productivity (GTFP) of cities. This paper calculates the green total factor productivity of 107 cities within the Yangtze River Economic Belt by using the super-efficient SBM model and the GML index with Chinese city panel data from 2007-2019 and measures the intensity of environmental regulations through textual analysis. The bidirectional fixed-effects model constructed in this paper suggests an inverted U-shaped relationship between environmental regulation and GTFP, which is confirmed by a series of robustness tests. Green technology innovation and advanced industrial structure play a mechanism role in this. In regions with lower levels of green technology and industrial structure, the inverted U-shaped relationship between environmental regulation and green total factor productivity is more significant. In addition, the phenomenon of GTFP rising and then falling because of environmental regulation is more obvious in cities in the middle and upper reaches of the Yangtze River and outside the urban agglomerations. Therefore, when formulating environmental regulation policies, it is necessary to balance the relationship between economic development and environmental protection and harmonize the environment and economic development of the entire Yangtze River Basin.

The Sry-related HMG-box (Sox) family is a group of transcriptional regulators that play a critical role in many important developmental processes in both vertebrates and invertebrates. In aquatic animals, the function of Sox genes on sexual development has been gained particular attentions. The present study reported the molecular characterization of a Sox member (PtSoxE) in the swimming crab, Portunus trituberculatus, and tissue distribution analysis showed it was male-specific. Since the most highly expression of PtSoxE was found in the androgenic gland (AG), its relation to the insulin-like androgenic gland hormone (IAG) was further investigated. The PtSoxE siRNA caused a significant decrease in IAG expression in both AG and testis, whereas PtSoxE expression could be induced by treating with AG homogenate and rIAG. The result suggested a transcriptional interaction between PtSoxE and IAG. In addition, PtSoxE expression showed a closely positive correlation with several reported spermatogenesis-related genes, suggesting its involvement in testicular development of P. trituberculatus.

Insulin therapy is a cornerstone in the management of diabetes, yet the pursuit of optimizing its pharmacokinetic profile remains a focal point in diabetes research. For instance, insulin icodec of Novo Nordisk is a novel long-acting insulin analogue that exhibits an extended duration of action, providing a promising once-weekly treatment option for diabetic patients. However, designing insulin analogues with lower receptor affinity than that of insulin icodec could still produce a further extended duration of action than that of insulin icodec through the suppression of receptor-mediated internalization of insulin analogues. In this study, therefore, I present the design of a novel series of insulin analogues engineered towards lower binding affinity to the insulin receptor compared to that of insulin icodec. Through computational structural biophysics-based rational design strategies, this article aims to further extend the duration of action while maintaining therapeutic efficacy of insulin analogues. Utilizing homology molecular modeling and structural biophysics-based binding affinity calculations, this article puts forward a set of insulin analogues with lower binding affinity to insulin receptor than that of insulin icodec from a structural and biophysical point of view. Overall, this article calls for subsequent in vitro and in vivo evaluations of the efficacy and prolonged action of the engineered insulin analogues to pharmacokinetically test whether these analogues acutally surpass that of insulin icodec as hopeful candidates for next-generation insulin analogue therapies with improved duration of action and enhanced control of blood glucose levels for diabetic patients in future.

This study evaluated the effect of newly introduced calcium silicate-based temporary intracanal medicament Bio-C Temp and calcium hydroxide-based material UltraCal XS on the release of transforming growth factor β1 (TGF-β1) from root canal dentin. Twenty-two intact and fully developed human premolars from patients aged 15 – 18 were shaped and irrigated according to the current clinical recommendations. The teeth were then gently split in half, and the root canal dentin of paired samples was covered with Bio-C Temp or UltraCal XS. After 3 weeks of incubation, the specimens were conditioned with 17% EDTA and the collected solution was subjected to quantification of released TGF-β1 by performing ELISA. One-way analysis of variance (ANOVA), followed by Tukey’s test, was selected to determine the statistically significant differences between the groups at the 0.95 confidence level. The highest mean value of released TGF-β1 (1993.1 pg/ml) was detected in the control group, where root canal dentin was conditioned with 17% EDTA alone. Regarding experimental groups, Bio-C Temp released a statistically significant higher amount of TGF-β1 (282.14 pg/ml) compared to UltraCal XS (114.28 pg/ml; p = 0.0158). Bio-C Temp affected the release of growth factors from root canal dentin less than UltraCal XS and may therefore serve as an intracanal medicament for regenerative endodontic procedures.

Background: A large percentage of deaths in an epidemic or pandemic can be due to overshoot of population (herd) immunity, either from the initial peak or from planned or unplanned exit from lockdown or social distancing conditions. Objectives: We study partial unlock or reopening interaction with seasonal effects in a managed epidemic to quantify overshoot effects on small and large unlock steps and discover robust strategies for reducing overshoot. Methods: We simulate partial unlock of social distancing for epidemics over a range of replication factor, immunity duration and seasonality factor for strategies targeting immunity thresholds using overshoot optimization. Results: Seasonality change must be taken into account as one of the steps in an easing sequence, and a two step unlock, including seasonal effects, minimizes overshoot and deaths. It may cause undershoot, which causes rebounds and assists survival of the pathogen. Conclusions: Partial easing levels, even low levels for economic relief while waiting on a vaccine, have population immunity thresholds based on the reduced replication rates and may experience overshoot as well. We further find a two step strategy remains highly sensitive to variations in case ratio, replication factor, seasonality and timing. We demonstrate a three or more step strategy is more robust, and conclude that the best possible approach minimizes deaths under a range of likely actual conditions which include public response.

Proteins play a pivotal role in supporting athletes by promoting muscle hypertrophy and minimizing protein catabolism during exercise. They stimulate muscle protein synthesis, aiding in the repair of exercise-induced muscle damage and serving as an energy source, particularly for post-exercise glycogen replenishment. In individuals with phenylketonuria (PKU), for whom protein intake is limited to essential phenylalanine (Phe), supplementation with Phe-free amino acids or glycomacropeptides is necessary. Tailored for macronutrient and micronutrient content, these protein substitutes fulfill most protein requirements, but lack Phe, unlike dietary sources of protein. Protein requirements for athletes with PKU exceed general recommendations due to limited availability in supplements and potential catabolism mitigation. Various factors influence tolerated dietary Phe in PKU, including protein substitute quantity, distribution, pharmacological treatment, age, growth rate, pregnancy, catabolic states, and physical activity. While general protein requirements for PKU surpass those of the general population, adherence to supplement regimens is crucial for athletes and patients with PKU. Strategically timed protein substitutes enhance muscle protein synthesis, body composition, and sports performance within safety limits. Individualized intake is essential for optimal outcomes, as proteins have a multifaceted role in optimizing athletic performance and addressing challenges in PKU.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to the epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancers types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer, however, there have been strong advancements made in the incorporation of anti HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since, its ground breaking discovery there has been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of.

Incretin effect helps in regulating glucose homeostasis and maintaining glycaemic control within the human body. This effect is achieved by the two naturally occurring incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Such hormones released by specialized entero-endocrine cells of the gastrointestinal tract cause insulin augmentation after food consumption. However, incretin effects are impaired in type 2 diabetic, primarily attributed to the deterioration of GLP-1 function along with decreased GLP-1 receptor expression. Targeting this hormone has, therefore, become an important therapeutic approach to treat this diabetic condition. Native GLP-1’s brief half-life and rapid proteolytic degradation have generated significant enthusiasm in uncovering the long-acting GLP-1 receptor (GLP-1R) agonists to manage type 2 diabetes. These synthetic peptides mimic the natural GLP-1 to activate GLP-1R and effectively exert various physiological benefits in terms of weight management, blood pressure, lipid profile, obesity and major adverse cardiovascular event. This review paper provides insights into the structure, function and expression of GLP-1 and its receptor. It also summarizes existing literature regarding different types of GLP-1 receptor agonists, their effects on blood pressure and how they exert their actions. While animal models have contributed significantly to this area of study, the scarcity of human studies is noted, indicating a need for more investigation in this domain. Expanding research in humans will help in comprehending the impact of GLP-1 receptor agonists on blood pressure regulation and their underlying mechanisms.

Background: Amyloid beta peptides (Aβ) have been identified as the main pathogenic agents in Alzheimer’s disease (AD). Soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, show membrane-binding capacity to red blood cells (RBCs) and trigger several morphological and functional alterations in RBCs that can result in impaired oxygen transport and delivery. Since bioactive lipids have been recently proposed as potent protective agents against Aβ toxicity, we investigated the role of sphingosine-1-phosphate (S1P) in signaling pathways involved in the mechanism underlying ATP release in Aβ-treated RBCs. Methods: In RBCs following different treatments, ATP, 2,3 DPG, cAMP levels, and caspase 3 activity were determined by spectrophotometric and immunoassay. Results: S1P rescued the inhibition of ATP release from RBCs triggered by Aβ through a mechanism involving caspase-3 and restoring 2,3 DPG and cAMP levels within the cell. Conclusions: These findings reveal the molecular basis of S1P protection against Aβ in RBCs and suggest new therapeutic avenues in AD.

Breast cancer represents the most frequent cancer and the leading cause of cancer death among women. Thus, the prevention and early diagnosis of breast cancer appears to be of primary urgency as well as the development of new treatments able to improve its prognosis. Nerve Growth Factor (NGF) is a neurotrophic factor that plays a key role in the regulation of neuronal functions thought the binding to the Tropomyosin receptor kinase A (TrkA) and the Nerve Growth Factor receptor or Pan-Neurotrophin Receptor 75 (NGFR/p75NTR). Also, its precursor (pro-NGF) can extert biological activity by forming a trimeric complex with NGFR/p75NTR and sortilin or by binding to TrkA receptors with low affinity. Both in vitro and in vivo studies showed that NGF is synthesized and released by breast cancer cells and has mitogen, antiapoptotic and angiogenic effects on these cells through the activation of different signaling cascades that involve TrkA and NGFR/p75NTR receptors. Conversely, pro-NGF signaling has been related to breast cancer invasion and metastasis. Other studies suggested that NGF and its receptors could represent a good diagnostic and prognostic tool, as well as promising therapeutic targets for breast cancer. Here, we comprehensively summarize and systematically review the current experimental evidence on this topic.

Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked with defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of altered mitochondrial dynamics in pancreatic β cells using ge-netic/pharmacologic approaches, and how these affect insulin secretion.

Background: Myocardial infarction is increasing at a young age. New tools are needed to evaluate the risk population of young patients. GDF-15 has been implicated in several key mechanisms of atherogenesis and also is associated with increased mortality and cardiovascular events in patients with coronary artery disease. Arterial stiffness parameters, including pulse wave velocity, can also be measured using peripheral arterial tonometry and can indicate the presence or progression of atherosclerotic changes. The aim of this study is to evaluate the GDF-15 level and arterial stiffness parameters in patients with premature myocardial infarction Method: Thirty patients who recovered from a myocardial infarction were consecutively included. Fifteen age-sex-matched subjects were included as controls. The patients’ serum GDF-15 concentration levels were measured using relevant kits. Measurements of arterial stiffness [pulse-wave velocity (PWV) and augmentation index (AIx)] were performed using a Mobil-O-Graph arteriography system. Results: GDF-15 concentration levels were significantly higher in the patients with premature myocardial infarction when compared to controls. PWV and AIx were similar between the groups. GDF-15 level was negatively correlated with high-density cholesterol (HDL) and positively correlated with uric acid levels in all study populations. Conclusions: GDF-15 levels may be a risk factor for patients with premature myocardial infarction. This pilot study may trigger further studies to elucidate the central role of GDF-15 in the pathophysiology of early atherosclerosis in the young population.

Growth-regulating factor (GRF) is a plant-specific transcription factor family, which is involved in nearly all of the central developmental processes in plants. However, little is known about GRF family genes in cultivated sunflower. In this study, 17 GRF genes were identified and characterized from sunflower genome. Their gene structures, conserved motifs, chromosomal distributions and phylogenetic relationships were analyzed. The expression patterns of these genes were detected in various tissues of sunflower inbred line SK02R, which revealed that the 10 seed-specific GRF genes may play important roles during seed development in sunflower. Additionally, transcripts changes of the GRFs under two major abiotic stresses and phytohormones showed that most of the detected GRFs were reduced significantly by GA3 treatment, and other treatments(ABA, NaCl and PEG6000) differently regulated various sunflower growth-regulating factors at different time points. MiR396 target analysis indicated that there may exist a complicated homeostasis between miR396 and its targets GRF and WRKY transcription factor genes in cultivated sunflower. The phylogenetic and expression analyses of the GRF gene family in sunflower would be useful for further cloning and function exploration of the HaGRF genes.

Correlations among estrus cycle, pyometra, and canine diabetes mellitus (CDM) have been described since the late 1950s, and substantial progress in understanding mechanisms beyond was achieved nowadays. Progesterone-related diabetes mellitus (PRDM) in dogs is known for its particular potential for diabetes remission. Thus, a deep understanding of the physiopathological aspects involved is crucial to postulate treatment guidelines to improve the PRDM remission rate, as well as to inform preventive measures. This narrative review aims to provide relevant detailed information on 1) canine estrus cycle and its impact on CDM etiology and management, 2) the role of pyometra as a further cause of insulin resistance, and 3) useful individual therapeutic and preventive strategies. Pharmacological annulment of progesterone effects, as well as inflammatory and progesterone-related conditions resolution in association with adequate exogenous insulin therapy, and residual beta cell function, are key aspects to achieve remission, or at least to improve diabetic clinical control. In this way, spaying should be considered mandatory in most PRDM cases. Preventive measures against CDM can include spaying recommendations; however, individual-based recommendations should be considered since castration may be associated with some long-term health issues.

Cholesterol, a crucial component of cell membranes, influences various biological processes, including membrane trafficking, signal transduction, and host-pathogen interactions. Disruptions in cholesterol homeostasis have been linked to congenital and acquired conditions, including neurodegenerative disorders such as Alzheimer’s disease (AD). Previous research from our group has demonstrated that herpes simplex virus type I (HSV-1) induces an AD-like phenotype in several cell models of infection. This study explores the interplay between cholesterol and HSV-1-induced neurodegeneration. The impact of cholesterol was determined by modulating its levels with methyl-beta-cyclodextrin (MβCD) using the neuroblastoma cell lines SK-N-MC and N2a. We have found that HSV-1 infection triggers the intracellular accumulation of cholesterol in structures resembling endolysosomal/autophagic compartments, a process reversible upon MβCD treatment. Moreover, MβCD exhibits inhibitory effects at various stages of HSV-1 infec-tion, underscoring the importance of cellular cholesterol levels not only in the viral entry pro-cess but also in subsequent post-entry stages. MβCD also alleviated several features of AD-like neurodegeneration induced by viral infection, including lysosomal impairment and intracellu-lar accumulation of amyloid-beta peptide (Aβ) and phosphorylated tau. In conclusion, these findings highlight the connection between cholesterol, neurodegeneration, and HSV-1 infection, providing valuable insights into the underlying mechanisms of AD.

Low efficiency of in vivo transfection of a few fibers revealed a novel tissue network which temporally amplified growth stimulation in the entire regenerating rat soleus muscle. This acupuncture-like effect was demonstrated when the fibers began to grow after complete fiber degradation, synchronous inflammation, myoblast and myotube formation. The first detection of neonatal sarcoplasmic/endoplasmic reticulum ATPase (SERCA1b) has been made in this system. The neonatal, fast and slow SERCA isoforms displayed consequent change with innervation and differentiation, recapitulating events in muscle development. In vivo transfection of myotubes with plasmids expressing dominant negative Ras or a calcineurin inhibitor peptide (Cain/cabin) proved that the expression of the slow myosin heavy chain and the slow muscle type SERCA2a are dif-ferently regulated. In vivo transfection of a few nuclei of myotubes with dnRas or SER-CA1b shRNA stimulated fiber size growth in the whole regenerating muscle but only until the full size had been reached. Growth stimulation by Ras and SERCA1b antisense was abolished in co-transfection with Cain or in case of perimuscular injection with IL4 antibody. This revealed a novel signalling network resembling to scale-free networks which, starting from transfected fiber myonuclei as “hubs”, can amplify growth stimula-tion uniformly in the entire regenerating muscle.

This study explored the effects of cryogenic treatment on the microstructure, hardness, and wear-resistance of diamond-like carbon (DLC) by cryogenically treating NAK 80 mold steel coated with DLC. Raman spectroscopy analyzed the structure of the DLC film. Nanoindenter analyzed the hardness and Young’s modulus of the film, and their relationship determined the wear resistance. Wear test assessed the wear rate and friction coefficient of the DLC film. The results showed that cryogenic treatment increased the rate of carbide precipitation and refined the grain structure. Raman spectroscopy indicated that the Raman intensity rate (I_D/I_G) of treated DLC films was smaller than those without cryogenic treatment. When the sp3 bond increased, the hardness and wear-resistance of the DLC film also increased.

The incidence of Type 1 Diabetes (T1D) in the Arab world, particularly, oil and gas rich Gulf Cooperative Council (GCC) countries has more than doubled in the last twenty years. Therefore, there is a dire need for careful systematic familial cohort studies, especially in high-risk populations. Several immunogenetic factors affect the pathogenesis of the disease. Genes in the human leukocyte antigen (HLA) account for the major genetic susceptibility to the disease. The triggering agents initiate disease onset by destruction of pancreatic β-cells. The autoantibodies against glutamic acid decarboxylase (GADA), insulinoma antigen-2 (IA-2A), insulin (IAA), and zinc transporter-8 (ZnT-8A) comprise the most reliable biomarkers for T1D in both children and adults. Although three of the GCC countries, namely Kuwait, Saudi Arabia and Qatar are among the top 10 countries with high incidence rate of T1D, no proper diagnostic and prediction tools were applied in the region. Understanding the disease sequelae in a homogenous gene pool with high consanguinity in the GCC could help solve the challenges in understanding pathogenesis, as well as hasten the prevention of T1D. Arab states must incorporate T1D predictive and intervention policies on a war-footing basis to minimize the burden of this serious disease.

Purpose: The study aimed to investigate if there were any links between liver function biomarkers and immunoglobulins levels in serum, and Toll-like receptors (TLRs) and neuropilin-1 (NRP1) in COVID-19 patients. The study also aimed to assess the accuracy—sensitivity, specificity, and area under the curve (AUC) by the receiver operator curve (ROC) analysis for immunoglobulins levels and TLRs expressions. Patients and Methods: This study included 150 patients (100 patients with confirmed COVID-19 and 50 healthy volunteers as a control group). Patients with COVID-19 were subdivided into two groups according to the severity of symptoms (moderate and severe, with 50 patients each). Serum C-reactive protein (CRP), alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), albumin, lactate dehydrogenase (LDH), immunoglobulin (Ig) G, and IgM levels were estimated. TLRs (TLR2 and TLR4) and NRP1 gene expression in blood samples were investigated using quantitative real-time polymerase chain reaction (qRT-PCR). ROC analysis was also applied to determine the accuracy of various detected parameters in predicting the possibility of COVID-19 infection. Results: In COVID-19 patients, serum parameters related to liver function, except serum albumin, CRP, IgG, IgM, and TLR2, TLR4, and NRP1 mRNA expression levels, significantly elevated compared to controls. Severe COVID-19 patients exhibited significantly higher liver enzymes (ALT, AST and LDH), CRP, and TLR2 mRNA expression levels and lower albumin levels than the moderate group. In the moderate and severe groups, ALT, CRP, TLR2, and TLR4 had a significant positive correlation with IgM levels. ALT, AST, LDH, CRP, TLR2, and TLR4 showed a significant positive correlation with IgG levels in both groups. In both the moderate and severe groups, NRP1 expression was found to be significantly correlated with CRP, IgG, IgM, TLR2, and TLR4. In contrast, serum albumin levels exhibited a significant negative correlation with IgG and IgM levels only in the severe group, but they showed a significant negative correlation with TLR2, TLR4, and NRP1 expression in both moderate and severe groups. Serum ALT and AST activities were positively correlated with NRP1 expression in the moderate group but not in the severe group and as well as TLR2 and TLR4 expression in both the moderate and severe groups. ROC analysis indicated that AUC was higher than 0.800 for serum IgM level and TLR4 gene expression in moderate COVID-19 group. Conclusions: The increased liver function biomarkers in serum and NRP1 expression are closely correlated with sustained activations in humoral and innate immune responses during COVID-19 infection. As a result, TLR2, TLR4, and NRP1 could be targets for limiting COVID-19 infection and impairment effects on liver function. Moreover, detection of IgM level in serum and TLR4 expression in blood have a good accuracy in predicting the possibility of infection with COVID-19 in moderate cases.

Background: Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells lose their adhesive properties and gain invasive, metastatic, and mesenchymal properties. Maintaining the balance between epithelial and mesenchymal stage is essential for tissue homeo-stasis. Many of the genes promoting mesenchymal transformation has been identified; however, our understanding of the genes responsible for maintaining the epithelial phenotype is limited. Our objective was to identify genes responsible for maintaining the epithelial phenotype and in-hibiting EMT. Methods: RNA seq was performed using an vitro model of EMT. CTGF expres-sion was determined by qPCR and Western blot analysis. Knockout of CTGF was done using the CTGF sgRNA CRISPR/CAS9. Tumorigenic potential was determined using NCG mice. Results: Knocked-out of CTGF in epithelial ovarian cancer cells leads to the acquisition of functional characteristics associated with the mesenchymal phenotype such as Anoikis resistance, cytoskel-eton remodeling, increased cell stiffness, and acquisition of invasion and tumorigenic capacity. Conclusions: We identified CTGF is an important regulator of the epithelial phenotype, and its loss is associated with early cellular modifications required for EMT. We describe a novel role for CTGF, regulating cytoskeleton and the extracellular matrix interactions necessary for conserva-tion of epithelial structure and function. These findings provide a new window to understand the early stages on mesenchymal transformation

A new biosensor based on Surface Plasmon Resonance Imaging detection technique for quantitative determination of Fibroblast Growth Factor-23 has been developed. The FGF-23 is mainly produced in the bone tissues as a phosphaturic hormone that upon secretion creates a trimeric complex with FGF receptor 1 and αKlotho. FGF-23 acts on the kidneys: it stimulates phosphate excretion and suppresses formation of active vitamin D. It has been proven that FGF-23 plays a role in bones’ carcinogenesis and its metastasis. The newly developed method based on the SPRi biosensor has been validated – the precision and accuracy as well as selectivity were acceptable and gave less than ±10% of recovery. The linear response of the biosensor ranges 1– 75 pg/ml. The limit of detection was 0.033 pg/ml and limit of quantification was 0.107 pg/ml. The biosensor was used to determine FGF-23 concentration in the plasma of healthy individuals as well as in the plasma of the patients with the clear cell carcinoma of the kidneys. The obtained results were compared with the results of the ELISA measurements. The determined Pearson correlation coefficients were close to 1 what showed that the newly developed biosensor can be used as the competitive method to the ELISA.

The Epidermal Growth Factor Receptor (EGFR) overexpression or its mutation mediates the sustaining proliferative signaling in cancers. Human EGFR-targeting monoclonal antibody (mAb) therapy such as cetuximab has been approved for clinical use in patients with colorectal cancers and head and neck squamous cell carcinomas. A reliable preclinical mouse model is essential to further develop the mAb therapy against EGFR. However, a mAb against mouse EGFR (mEGFR) for flow cytometry has not been established. In this study, we developed a specific and sensitive mAb for mEGFR using the Cell-Based Immunization and Screening (CBIS) method. The established anti-mEGFR mAb, EMab-300 (rat IgG1, kappa) reacted with mEGFR-overexpressed Chinese hamster ovary-K1 (CHO/mEGFR) and endogenously mEGFR-expressed cell lines, including NMuMG (a mouse mammary gland epithelial cell) and Lewis lung carcinoma cells by flow cytometry. The kinetic analysis using flow cytometry indicated that the dissociation constant (KD) of EMab-300 for CHO/mEGFR and NMuMG was 4.3 × 10−8 M and 1.9 × 10−8 M, respectively. These results indicated that EMab-300 applies to the detection of mEGFR by flow cytometry, and is expected in the use of preclinical study.

Bone morphogenetic protein (BMP) and platelet-derived growth factor (PDGF) are known to regulate and stimulate osteogenesis, both proteins playing an important role in bone homeostasis, constituting good candidates for osteoporosis´ treatment. Herein we aim to evaluate the effects of recombinant human BMP-7 (rhBMP7) and PDGF-BB (rhPDGF-BB) in oophorectomy-induced osteoporosis in rats. To this end, 40 Sprague-Dawley rats were submitted to oophorectomy surgery and treatments were started at the 100th day after the surgery, when all animals showed signs of osteoporosis. These peptide growth factors were applied intravenously once or twice a week and animals were followed for a total of five weeks. Two weeks after the end of the treatments, the animals were euthanized, the tissues were collected and Alkaline Phosphatase, X-ray, micro-CT and histology were assessed. The results indicate that the most promising treatments are: 20 µg/kg PDGF-BB + 30 µg/kg BMP-7 2x/week and 30 µg/kg BMP-7 2x/week, presenting an increase of 15% (p&lt;0.05) and 13% (p&lt;0.05) in bone volume fraction and 21% (p&lt;0.05) and 23% (p&lt;0.05) in trabecular number, respectively. In conclusion, rhPDGF-BB and rhBMP-7 are capable of inducing an increase in bone volume and density in this osteoporotic animal model, constituting interesting candidates for osteoporosis treatment.

Elevated circulating triglyceride levels have been linked to an increased risk of diabetes, although the precise mechanisms remain unclear. This study aimed to investigate whether low-density lipoprotein (LDL) cholesterol, homeostatic model assessment (HOMA) for insulin resistance, and C-reactive protein served as mediators in this association across a sample of 18,435 US adults. Mediation analysis was conducted using the PROCESS Version 4.3 Macro for SPSS. Simple medi-ation analysis revealed that all three potential mediators played a role in mediating the associa-tion. However, in the parallel mediation analysis, where all three mediators were simultaneously included, HOMA for insulin resistance remained a significant mediator (indirect effect coefficient, 0.47; 95% confidence interval [CI], 0.43—0.52; p < 0.05) after adjusting for all tested confounding factors. Conversely, LDL cholesterol (indirect effect coefficient, -0.13; 95% CI, -0.31—0.05; p > 0.05) and C-reactive protein (indirect effect coefficient, 0.01; 95% CI, -0.003—0.02; p > 0.05) ceased to be significant mediators. HOMA for insulin resistance accounted for 49% of the association between triglycerides and diabetes. In conclusion, HOMA for insulin resistance was the dominant mediator underlying the association between triglycerides and diabetes. Therefore, reducing triglyceride levels may hold promise for improving insulin sensitivity in diabetic patients.

Background: Study to assess glucose levels of people with type 1 diabetes (T1D) overnight based on insulin type and timing. Methods: Real-world, retrospective study in T1D using multiple daily insulin injections. Contin-uous glucose monitoring and insulin injections data were collected for ten hours after dinner us-ing the Insulclock® connected cap. Meal events were identified using ROC detection methodology. The timing of rapid insulin, second injections, and the type of insulin analogs used were evaluat-ed. Results: Nocturnal profiles (n=775, 49 subjects) were analyzed. Higher glucose AUC over 180mg/dL was observed in delayed injections (number; %; mg/dL x h): -45-15min (n=136; 17.5%, 175.9 ±271.0); -15-0min (n= 231; 29.8%, 164.0 ±237.1); 0+45min (n= 408; 52.6%, 203.6 ±260.9), (p 0.049). The use of ultrarapid (FiAsp®) (URI) vs rapid insulin analogs (RI) was associated with less hypoglycemia events (7.1 vs 13.6%; p 0.005) and TBR70 (1.7 +6.9 vs 4.6 +13.9%; p 0.003). Us-ers of glargine U300 vs degludec had higher TIR (70.7 vs 58.5 %) (Adjusted R-squared: 0.22, p < 0.001). The use of a correction injection (n= 144, 18.6%) was associated with higher hypoglycemia events (18.1 vs 9.5%; p 0.003), TBR70 (5.5 +14.2 vs 3.0 +11.1%; p 0.003), glucose AUC over 180 mg/dL (226.1 +257.8 vs 178.0 +255.3 mg/dL x h; p 0.001), and lower TIR (56.0 +27.4 vs 62.7 +29.6 mg/dL x h; p 0.004). Conclusions: Dinner rapid insulin timing, insulin types and correction injections affect nocturnal glucose profile in T1D.

The objectives of the study were to determine the spatial rate of CO₂ flux (Net Ecosystem Exchange) and soil moisture in a wetland ecosystem applying Sentinel-1 IW (Interferometric Wide) data of VH (Vertical Transmit/Horizontal Receive—cross polarization) and VV (Vertical Transmit/Vertical Receive—like polarization) polarization. In-situ measurements of carbon flux, soil moisture, and LAI (Leaf Area Index) were carried out over the Biebrza Wetland in north-eastern Poland. The impact of soil moisture and LAI on backscattering coefficient (σ°) calculated from Sentinel-1 data showed that LAI dominates the influence on σ° when soil moisture is low. The models for soil moisture have been derived for wetland vegetation habitat types applying VH polarization (R² = 0.70 to 0.76). The vegetation habitats: reeds, sedge-moss, sedges, grass-herbs, and grass were classified using combined one Landsat 8 OLI (Operational Land Imager) and three TerraSAR-X (TSX) ScanSAR VV data. The model for the assessment of Net Ecosystem Exchange (NEE) has been developed based on the assumption that soil moisture and biomass represented by LAI have an influence on it. The σ° VH and σ° VV describe soil moisture and LAI, and have been the input to the NEE model. The model, created for classified habitats, is as follows: NEE = f (σ° Sentinel-1 VH, σ° Sentinel-1 VV). Reasonably good predictions of NEE have been achieved for classified habitats (R² = 0.51 to 0.58). The developed model has been used for mapping spatial and temporal distribution of NEE over Biebrza wetland habitat types. Eventually, emissions of CO₂ to the atmosphere (NEE positive) has been noted when soil moisture (SM) and biomass were low. This study demonstrates the importance of the capability of Sentinel-1 microwave data to calculate soil moisture and estimate NEE with all-weather acquisition conditions, offering an important advantage for frequent wetlands monitoring.

The aim of this work is to compare two softwares (MAUD and TOPAS) based on the Rietveld algorithm and to test the concept of tolerance factor using the dissolution at high temperature of yttrium into BaTiO₃. In general, both softwares give up different values of the crystalline parameters however the trends are similar in most cases but the analysis of the strain and crystallite size in the BaTiO₃ crystals suggests that, in this particular case, MAUD offered results more consistent with the expected behavior. Using the crystalline parameters calculated by Rietveld, the tolerance factor values were obtained and these data suggest even better stability in the crystalline structure than that expected using theoretical parameters. Tolerance factor concept also indicates that Ti⁴⁺ should be preferred.

PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute depletion in cell lines and mice decreased PSD-95 expression. Furthermore, HSF1(+/-) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.

The accumulation of brown algae from the genus Sargassum has been increasing over the years in coastal regions of the Caribbean, Africa, Brazil, and Mexico. This causes harmful effects to the ecosystem, health, economy, and climate due to gas emissions from its decomposition process. There is the possibility of this biomass being reused in civil construction, and few studies have been carried out on its application to common Portland cement mortar. As such, the objective of this study is to evaluate the potential of sargassum ash as a mineral addition to partial replacement of fine aggregates in Portland cement mortar. Characterizations of the raw materials were carried out through X-ray fluorescence spectroscopy, loss on ignition, particle size distribution, Brunauer–Emmett–Teller (BET), real density, X-ray diffraction, scanning electron microscopy, and dispersion spectroscopy of electrons. The mortars were prepared by partially replacing the fine aggregate (sand) with sargassum ash, at 0%, 5%, 10% and 20%. Mortar performance was evaluated through water absorption, apparent porosity, apparent specific mass, compressive strength after 7, 28, and 63 days after curing. Lastly, a life cycle assessment in accordance with ISO standards 14040:2006 and 14044:2006. The results showed that replacing sand with sargassum ash increases water absorption, apparent porosity, and decreases the apparent specific mass and compressive strength as replacement increases. Nevertheless, the compressive strength results after 63 days, for 5 and 10% replacement did not differ statistically from reference values. The life cycle assessment indicates that mortars with partial replacement of sand by sargassum ash showed positive environmental impacts when compared to reference values for most categories regardless of the scenario analyzed, especially for mortar with 10% replacement. As such, the use of sargassum ash at 10% does not alter compressive strength values after 63 days while reducing its environmental impact. The application of this biomass in civil construction materials provides a destination for this algae that has been causing several social, environmental, and economic problems.

Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is an important target of monoclonal antibody (mAb) therapy such as trastuzumab. Due to the development of trastuzumab-deruxtecan, an antibody-drug conjugate, the targetable HER2-positive breast cancer patients have been expanded. To evaluate developing modalities using anti-HER2 mAbs, reliable preclinical mouse models are required. Therefore, sensitive mAbs against mouse HER2 (mHER2) should be established. This study developed mHER2 mAbs using the Cell-Based Immunization and Screening (CBIS) method. The established anti-mHER2 mAbs, H2Mab-300 (rat IgG2b, kappa) and H2Mab-304 (rat IgG1, kappa), reacted with mHER2-overexpressed Chinese hamster ovary-K1 (CHO/mHER2) and endogenously mHER2-expressed cell line, NMuMG (a mouse mammary gland epithelial cell) by flow cytometry. Furthermore, these mAbs never recognized mHER2-knockout NMuMG cells. The kinetic analysis using flow cytometry indicated that the dissociation constant (KD) of H2Mab-300 and H2Mab-304 for CHO/mHER2 was 1.2 × 10−9 M and 1.7 × 10−9 M, respectively. The KD of H2Mab-300 and H2Mab-304 for NMuMG was 4.9 × 10−10 M and 9.0 × 10−10 M, respectively. These results indicated that H2Mab-300 and H2Mab-304 could apply to the detection of mHER2 using flow cytometry and may be useful to obtain the proof of concept in preclinical studies.

The combination of freeze-dried aronia, red ginseng, ultraviolet-irradiated shiitake mushroom and natokinase (AGM; 3.4: 4.1: 2.4: 0.1) was examined to evaluate its effects on insulin resistance, insulin secretion and gut microbiome in a non-obese type 2 diabetic animal model. Pancreatectomized (Px) rats were provided high fat diets supplemented with either of 1) 0.5 g AGM (AGM-L), 2) 1 g AGM (AGM-H), 3) 1 g dextrin (control), or 4) 1g dextrin with 120 mg metformin (positive-control) per kg body weight for 12 weeks. AGM (1 g) contained 6.22 mg cyanidin-3-galactose, 2.5 mg ginsenoside Rg3 and 0.6 mg β-glucan. Px rats had decreased bone mineral density in the lumbar spine and femur and lean body mass in the hip and leg compared to the normal-control and AGM-L and AGM-H prevented the decrease. Visceral fat mass was lower in the control group than the normal-control group and its decrease was smaller by AGM-L and AGM-H. HOMA-IR was lower in descending order of the control, positive-control, AGM-L, AGM-H and normal-control groups. Glucose tolerance was deteriorated in the control group and it was improved by AGM-L and AGM-H more than in the positive-control group. Glucose tolerance is associated with insulin resistance and insulin secretion. Insulin tolerance indicated insulin resistance was highly impaired in diabetic rats, but it was improved in the ascending order of the positive-control, AGM-L and AGM-H. Insulin secretion capacity, measured by hyperglycemic clamp, was much lower in the control group than the normal-control group and it was improved in the ascending order of the positive-control, AGM-L and AGM-H. Diabetes modulated the composition of gut microbiome and AMG prevented the modulation of gut microbiome. In conclusion, AGM improved glucose metabolism by potentiating insulin secretion and reducing insulin resistance in insulin deficient type 2 diabetic rats. The improvement of diabetic status alleviated body composition changes and prevented changes of gut microbiome composition.

Ral-interacting protein 76 (RLIP76) is a potential factor with vascular endothelial growth factor (VEGF) in the corpus luteum and tumor angiogenesis. RLIP76, VEGF, and hypoxia-inducible factor-1 (HIF-1) are proteins that activate angiogenic functions in tumor and endothelial cells. RLIP76 is a main factor in tumor growth, and VEGF is a major endothelial cell protein for angiogenesis. Also, RLIP76 regulates a small GTPase (R-Ras, oncogene) in cell survival, spreading, and migration. HIF-1 is important in the corpus luteum, tumor angiogenesis, and tumor growth. VEGF and HIF-1 regulate the angiogenic function of RLIP76, and RLIP76 controls vascular growth in endothelial and tumor cells. RLIP76, R-Ras, VEGF, and HIF-1 may be useful in the research of corpus luteum and cancer therapy and the study of mechanisms of tumor angiogenesis. This review will help to elucidate the roles of RLIP76/R-Ras and VEGF via HIF-1 in corpus luteum and tumor angiogenesis, tumorigenesis, and the specific regulation of RLIP76 in luteal, tumor, and endothelial cells. Thus, we reviewed the angiogenesis of the corpus luteum and tumor in the ovarian and tumor microenvironment.

The Myb family of transcription factors (TFs) is a large and functionally diverse group found in all eukaryotes, but its role in fungi remains poorly understood. Here, we characterized a Myb family TF called MoMyb13 in the rice blast fungus, Magnaporthe oryzae. MoMyb13 has two Myb domains and has orthologues only in ascomycete fungi. Localization experiments confirmed that MoMyb13 is located in the nuclei, as expected for a TF. Phenotypic analysis showed that MoMyb13 mutants exhibited reduced growth, whitened colony appearance and no conidia formation. Importantly, these mutants completely lost pathogenicity, despite being able to form appressoria at their hyphae ends, suggesting that these appressoria were non-functional for causing infection. Furthermore, the mutant colonies lost hydrophobicity and had significantly reduced expression of the hydrophobin MPG1. However, overexpression of MPG1 in the mutants restored their hydrophobicity, but not pathogenicity. Stress assay showed that the mutants were more sensitive to SDS, CR and H2O2, but more tolerant to NaCl and SOR. In summary, our study revealed the essential role of the MoMyb13 in the growth, conidiation, hydrophobicity, stress response and pathogenicity of M. oryzae, and provides valuable insights into the working mechanism of Myb TFs in fungi.

This paper presents a system for identification of wind features, such as gusts and wind shear. These are of particular interest in the context of energy-efficient navigation of Small Unmanned Aerial Systems (UAS). The proposed system generates real-time wind vector estimates and a novel algorithm to generate wind field predictions. Estimations are based on the integration of an off-the-shelf navigation system and airspeed readings in a so-called direct approach. Wind predictions use atmospheric models to characterize the wind field with different statistical analyses. During the prediction stage, the system is able to incorporate, in a big-data approach, wind measurements from previous flights in order to enhance the approximations. Wind estimates are classified and fitted into a Weibull probability density function. A Genetic Algorithm (GA) is utilized to determine the shaping and scale parameters of the distribution, which are employed to determine the most probable wind speed at a certain position. The system uses this information to characterize a wind shear or a discrete gust and also utilizes a Gaussian Process regression to characterize continuous gusts. The knowledge of the wind features is crucial for computing energy-efficient trajectories with low cost and payload. Therefore, the system provides a solution that does not require any additional sensors. The system architecture presents a modular decentralized approach, in which the main parts of the system are separated in modules and the exchange of information is managed by a communication handler to enhance upgradeability and maintainability. Validation is done providing preliminary results of both simulations and Software-In-The-Loop testing. Telemetry data collected from real flights, performed in the Seville Metropolitan Area in Andalusia (Spain), was used for testing. Results show that wind estimation and predictions can be calculated at 1 Hz and a wind map can be updated at 0.4 Hz. Predictions show a convergence time with a 95% confidence interval of approximately 30 s.

A large diversity of epigenetic factors, such as microRNAs and histones modifications, are known to be capable of regulating gene expression without altering DNA sequence itself. In particular, miR-1 is considered the first essential microRNA in cardiac development. In this study, miR-1 potential role in early cardiac chamber differentiation is analyzed through specific signaling pathways. For this, we performed in chick embryos functional experiments by means of miR-1 microinjections into the posterior cardiac precursors -of both primitive endocardial tubes- committed to sinoatrial region fates. Subsequently, embryos were subjected to whole mount in situ hybridization, immunohistochemistry and RT-qPCR analysis. As a relevant nov-elty, our results revealed that miR-1 increases Tbx5, Gata4 and AMHC1, while this microRNA diminishes Mef2c expression, during early differentiation of cardiac sinoatrial region. Further-more, we observed in this developmental context that miR-1 upregulates CRABPII and RARß, and downregulates CRABPI, which are three crucial factors in retinoic acid signaling pathway. Interestingly, we also noticed that miR-1 directly interacts with HDAC4 and Calmodulin, as well as with Erk2/MAPK1, which are three key factors actively involved in Mef2c regulation. Our study shows, for the first time, a key role of miR-1 as an epigenetic regulator in early differenti-ation of cardiac sinoatrial region through orchestrating opposite actions between retinoic acid and Mef2c, fundamental to properly assign cardiac cells to their respective heart chambers. A better understanding of those molecular mechanisms modulated by miR-1 will definitely help in fields applied to therapy and cardiac regeneration and repair.

β-Ga2O3 is a well-known semiconductor material for power devices and other applications. Recently, β-Ga2O3 has also been reported as a scintillator material with a light yield of approximately 8400 ph./MeV, scintillation decay time of &lt;1 μs, and density of 6.44 g/cm3. In this study, 2-inch diameter β-Ga2O3 single crystals were prepared by oxide crystal growth using the cold crucible (OCCC) method under various oxygen partial pressures. In the OCCC method, as in the cold crucible method, a high frequency is applied directly to the oxide materials, which are heated and melted, and the melt is held by the outermost solid material itself that is cooled by water using a copper hearth. In the OCCC method, crystal growth is performed while rotating the seed crystal, as in the Czochralski method, to increase the crystal diameter. The optical properties and radiation responses of the crystals grown under various oxygen partial pressures were evaluated.

The present studies were undertaken to address the role of fetuin-A in the growth and invasion potential in a triple negative breast cancer (TNBC) cell line, MDA-MB-468. Basal like TNBC that express high levels of ectopic fetuin-A have poorer prognosis for the patients compared to those that express low levels of the protein. We overexpressed fetuin-A in MDA-MB-468 and then determined the invasive potential of fetuin-A overexpressing cells vs controls transfected with empty vector. We also determined the adhesion and growth potential of the cells in the presence of only fetuin-A in serum free medium and also in complete medium. Our data suggest that fetuin-A overexpression significantly enhances the invasive potential of the cells and also the expression of Toll like receptor 4 (TLR4) on these cells. More importantly, the cells rely on fetuin-A-TLR4 signaling network for growth and invasion because the specific TLR4 inhibitor CLI-095 (resatorvid) abrogates fetuin-A mediated growth and invasion. Taken together, the data suggest that fetuin-A-TLR4 signaling network plays a significant role in the growth and invasion potential of TNBC.

Glutamate functions as the major excitatory neurotransmitter for primary sensory neurons and has a crucial role in sensitizing peripheral nociceptor terminals producing sensitization. Glutaminase (GLS) is the synthetic enzyme that converts glutamine to glutamate. GLS-immunoreactivity (-ir) and enzyme activity are elevated in dorsal root ganglion (DRG) neuronal cell bodies during chronic peripheral inflammation, but the mechanism for this GLS elevation is yet to be fully characterized. It has been well established that, after nerve growth factor (NGF) binds to its high-affinity receptor tropomyosin receptor kinase A (TrkA), a retrograde signaling endosome is formed. This endosome contains the late endosomal marker Rab7GTPase and is retrogradely transported via axons to the cell soma located in DRG. This complex is responsible for regulating the transcription of several critical nociceptive genes. Here, we show that this retrograde NGF signaling mediates the expression of GLS in DRG neurons during the process of peripheral inflammation. We disrupted the normal NGF/TrkA signaling in adjuvant-induced arthritic (AIA) Sprague Dawley rats by pharmacological inhibition of TrkA or blockade of Rab7GTPase, which significantly attenuated the expression of GLS in DRG cell bodies. These results indicate that NGF/TrkA signaling is crucial for the production of glutamate and has a vital role in the development of neurogenic inflammation. In addition, our pain behavioural data suggest that Rab7GTPase can be a potential target for attenuating peripheral inflammatory pain.

Apart from their established role in embryonic development Nerve Growth Factors (NGFs) have diverse functions in the nervous system. Their role in integration of physiological functioning of the nervous system is now attracting attention. In the present analysis, we propose a novel paradigm about a novel role of NGFs: NGFs play imperative role in maintaining psychological integrity of an individual as a biological system. This function may be mediated through HPA-axis- operated homeostatic mechanisms; stress induced disruption of which may lead to psychiatric disorders. Current literature suggests existence of constitutive homeostatic regulatory mechanisms for NGFs disruption which may lead to pertinent and imperative behavioural effects. NGFs are known to play crucial role in endocrine regulation. This is especially true with the prototype ‘NGF’ and Brain Derived Neurotrophic Factor (BDNF). These moieties have been observed to play important function in maintaining neuro-endocrine homeostasis thereby having a profound impact on the psychological health of an individual. Role of NGFs and HPA-axis activation (in separate studies) in developing psychiatric disorders - especially those born of stress - have been reported. Literature suggests their unique interplay for producing a common effect which might be implicated in stress induced genesis of psychiatric disorders. This aspect, therefore, needs to be elucidated further as a disease etiogenesis model. This model may yield important insights into the biology of psychiatric disorders and may open ways for new therapeutic approaches.

Iron is the most abundant micronutrient in plant mitochondria and it has a crucial role in biochemical reactions involving electron transfer. It has been described in Oryza sativa that Mitochondrial Iron Transporter (MIT) is an essential gene and that knockdown mutant rice plants have a decreased amount of iron in mitochondria, strongly suggesting that OsMIT is involved in mitochondrial iron uptake. In Arabidopsis thaliana, two genes encode MIT homologues. In this study, we analyzed different AtMIT1 and AtMIT2 mutant alleles, confirming that individually AtMIT1 nor AtMIT2 genes are essential. When we generated crosses between Atmit1 and Atmit2 alleles we were able to isolate homozygous double mutant plants. Interestingly, homozygous double mutant plants were obtained only when mutant alleles of Atmit2 with the T-DNA insertion in the intron region were used for crossings, and in these cases a correctly spliced AtMIT2 mRNA was generated, although at a low level. Atmit1 Atmit2 double homozygous mutant plants, which were knockout for AtMIT1 and knockdown for AtMIT2, were grown and chacterised in iron sufficient conditions. Pleiotropic developmental defects were observed including abnormal seeds, increased number of cotyledons, slow growth rate, pinoid stems, defects in flower structures and reduced seed set. We observed a possible phenomenon of T-DNA suppression in the next generation of Atmit1 Atmit2 double homozygous mutant plants, correlating with an increased splicing of the AtMIT2 intron containing the T-DNA. Molecular analysis of gene expression markers for mitochondrial and oxidative stress showed that Atmit1 Atmit2 double homozygous mutant plants express a degree of mitochondrial perturbation. A RNA-Seq study was performed and we could identify more than 760 genes differentially expressed in Atmit1 Atmit2, including genes involved in iron transport, coumarin metabolism, and hormones metabolism, transport and signaling. Our data suggest that some of the phenotypes observed in Atmit1 Atmit2 double homozygous mutant plants are mediated by defects in auxin homeostasis.

Arboviruses are infections caused by arboviruses that may be either symptomatic or asymptomatic, according to individuals' resistance and immune response, which dietary patterns can influence. Thus, this study aimed to investigate the possible association between the occurrence of clinical manifestations of arboviruses and the dietary pattern of the population studied. The study was conducted in a rural population in the metropolitan area of Belém, Pará State, Brazil. The sampling consisted of 95 individuals during a febrile outbreak. Two investigations were conducted: clinical-epidemiological-dietary and laboratory investigation based on blood samples taken for arbovirus analysis. Out of the 95 individuals studied, more than half (57.89%) showed clinical manifestations. Following the laboratory serology (HI and IgM ELISA) analyses, viral isolation in C6/36 cells, and viral genome detection (RT-qPCR), the final diagnosis of the cases was 47.37% Oropouche Fever, 2.11% Oropouche Fever and Chikungunya Fever, and 1.05% Mayaro Fever. Regarding dietary pattern, as for the comparison analyses, statistical significance was observed between dietary pattern and classification regarding the presence of symptoms (p<0.05); after the correspondence analysis, symptomatic cases were more associated with a bad dietary pattern, while asymptomatic cases were more associated with a good dietary pattern.

Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia. AZ683 has high affinity for CSF1R (K_i = 8 nM; IC₅₀ = 6 nM) and >250-fold selectivity over 95 other kinases and, in this paper, we report the radiosynthesis of [¹¹C]AZ683 and initial evaluation of its use in CSF1R PET. [¹¹C]AZ683 was synthesized by ¹¹C-methylation of the desmethyl precursor with [¹¹C]MeOTf in 3.0% non-corrected activity yield (based upon [¹¹C]MeOTf), >99% radiochemical purity and high specific activity. Preliminary PET imaging with [¹¹C]AZ683 revealed no brain uptake in rodents and nonhuman primates suggesting that [¹¹C]AZ683 is a poor candidate for imaging neuroinflammation, but that it could still be useful for peripheral imaging of inflammation.

The paper examines the impact of inward remittances flows on per capita GDP growth in Bangladesh during 1976-2012. We find that the growth effect of remittances is negative at first but becomes positive at a later stage, an evidence of a non-linear. Unproductive use of remittances was rampant in the beginning when they were received by migrant families but better social and economic investments led to more productive utilisation of remittances receipts at later periods. This was the possible mechanism behind the U-shaped relationship. Unlike what is suggested in the literature that the effect of remittances is more pronounced in a less financially developed economy, our evidence do not show that the effect of remittances on per capita GDP growth in Bangladesh is conditional on the level of financial development.

A novel scaffold design has been created to enhance tissue engineering and regenerative medicine by optimizing the controlled, prolonged release of hepatocyte growth factor (HGF), a powerful chemoattractant for endogenous mesenchymal stem cells. We present a new stacked scaffold that is made up of three different fibrin gel layers, each of which has HGF integrated into the matrix. The design attempts to preserve HGF's regenerative properties for long periods of time, which is necessary for complex tissue regeneration. These multi-layered fibrin gels have been mechanically evaluated using rheometry, and their degradation behavior has been studied using D-Dimer ELISA. Understanding the kinetics of HGF release from this novel scaffold configuration is essential for understanding HGF's long-term sustained bioactivity. A range of cell-based tests were carried out to verify the functionality of HGF following extended incorporation. These tests included 2-photon microscopy using phalloidin staining to examine cellular morphology, SEM analysis for scaffold-cell interactions, and scratch and scatter assays to assess migration and motility. The analyses show that the novel stacking scaffold promotes vital cellular processes for tissue regeneration in addition to supporting HGF's bioactivity. This scaffold design was developed for in situ tissue engineering. Using the body as a bioreactor, the scaffold should recruit mesenchymal stem cells from their niche thus combining the regenerative abilities of HGF and MSCs to promote tissue remodeling and wound repair.

Aim: Aging is companied by deteriorations of insulin resistance (IR) and insulin secretion. However, little is known about the roles of aging on different phases of insulin secretion (ISEC); i.e., the first- and second-phase of insulin secretion (FPIS, SPIS) and glucose effectiveness (GE). Methods: Totally 169 individuals (43 men and 126 women) with the similar fasting plasma glucose (FPG: 90 mg/dL) and BMI (men: 23 kg/m2, women 22 kg/m2) were enrolled. IR, FPIS, SPIS, and GE were estimated using our previously developed equations shown below. Pearson correlation analysis was conducted to assess the correlations between age and four diabetes factors (DFs: IR, FPIS, SPIS and GE). The equations that are used to calculate the DF in the present study were built and published by our group. Results: The age of the participants ranged from 18- to 78-year-old. Men had higher FPIS but lower HDL-C levels than women (2.067±0.159, 1.950±0.186 μU/min and 1.130±0.306, 1.348±0.357 mmol/dl, accordingly). The results of Pearson correlation revealed that age was negatively related to IR and GE in both genders (IR: r = -0.39, p < 0.001 for men, r = -0.24, p < 0.003 for women; GE: r = 0.66, p < 0.001 for men, r = 0.78, p < 0.001 for women). In the meanwhile, FPIS was also only found to be negatively correlated with age in female (r = -0.238, p = 0.003). But there was no different with SPIS and age in both of genders. Conclusions: We have found that in Chinese with normal FPG level (90 mg/dl) and body mass index (men: 23 kg/m2, women: 22: kg/m2), age is negatively related to IR and GE in both genders. At the same time, only FPIS was found to be negatively related to age in women. The tightness of their relationships, from the highest to the lowest are, GE, FPIS and IR accordingly. The importance of GE should be re-evaluated. These results should be interpreted with caution because of the small sample size.

PURPOSE: Breast cancer tumors frequently have intratumor heterogeneity. Tumors with high intratumor heterogeneity have caused therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to poor prognosis for HER2-targeted adjuvant therapies resistance in primary breast cancers. METHODS: This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with HER2 gene copy number within a tumor sample. Those heterogeneity classified each tumor into the biphasic grade graph (high heterogeneity [HH]) group and the monophasic grade graph (low heterogeneity [LH]) group. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. RESULTS: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: P < 0.001 (HH:63% vs LH:91% at 10 years), and OS: P = 0.012 (HH:78% vs LH:95% at 10 years). CONCLUSION: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach of heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy.

The investigation by the integrated approach newly introduced for this study indicates that insulin resistance (IR) would develop first preferentially in the muscle tissue with a relatively low cell turnover and then progress in sequence to the subcutaneous adipose tissue, to the visceral adipose tissue, and to the liver with higher cell turnovers. Moreover, metabolic disruptions due to IR vary widely from tissue to tissue, contrary to the conventional notion that IR merely impairs glucose uptake in the whole body. This warrants that IR be divided better into four distinct tissue specific IRs: muscle insulin resistance (MIR), subcutaneous adipose insulin resistance (s-AIR), visceral adipose insulin resistance (v-AIR), and hepatic insulin resistance (HIR). Tissue-specific IRs developing in the order of MIR, s-AIR, v-AIR, and HIR – producing tissue specific metabolic disruptions – would amount to nothing but the whole body insulin resistance (WBIR) evolving in four distinctively insulin resistant stages. The four stage metabolic evolution from rapid weight gain to visceral obesity to rapid weight loss to full blown diabetes not only complies well with the natural development history of diabetes but also resolves most of the controversies regarding obesity or diabetes, including visceral obesity, obesity paradox, and dawn phenomenon that have long remained metabolic puzzles. In addition, the four-stage WBIR evolution model refutes the entrenched notion of the lipid-induced insulin resistance (LIIR) but supports instead the glycation-induced insulin resistance (GIIR) proposed in this study. A speculation is that the glycation reaction activated ever more with WBIR evolving may serve as the common thread connecting each other a cluster of disorders or diseases that are often collectively referred to as the metabolic syndrome, such as obesity, diabetes, cardio/cerebral vasculopathy, nephropathy, neuropathy, and retinopathy.

Suicide is a public health problem influenced by a variety of biological, psychological, social, and environmental factors. Recognizing the warning signs at each stage is crucial for prevention and helping those at risk. In this context, body awareness, especially interoceptive body awareness, emerges as a potentially relevant and underexplored factor. In this study, binary logistic regression and linear regression analyses were used to examine the relationship between interoceptive body awareness and suicidal orientation in Colombian university students. In addition, the bootstrap technique was used to resample and estimate the distribution of the data. The results support the idea that greater interoceptive awareness may protect against suicidal orientation by improving emotional regulation. An inverse relationship was found between interoceptive awareness and suicidal ideation. These findings are consistent with previous literature on the importance of body awareness for emotional well-being. Further longitudinal research is needed to explore this relationship in depth.

ccurate recording of growth indicators for aquaculture species at different stages is essential for evaluating aquaculture production effectiveness and the rationality of feed formulations. Due to their convenience and non-invasiveness, weight, length, and condition factor are commonly used to assess the growth of aquaculture species . However, fish growth indicators, can vary significantly with age structure and feed components(nutrition), and relying on a single indicator may lead to misjudgments . In this study we investigated the growth indicators of gibel carp (Carassius auratus gibelio var. CAS V) at different growth stages (juvenile and adult) and different feed formulations. Meanwhile, fish weight-length relationship () was used to assess the growth indicators. The results showed that the weight-length relationship of gibel carp varied significantly with age and feed formulations. Additionally, the condition factor calculated depended on the weight-length relationship was more consistent with weight/length changes than measured. Weight analysis indicated that both weight, length, height, back thickness, and carcass ration had higher weights in analyzing fish growth. Therefore, during aquaculture production, fish growth evaluating requires considering diverse indicators such as weight, length,body height, back thickness, carcass ration,as well as condition factor to avoid misjudging the actual growth situation. Meanwhile, the use of the condition factor should consider the sufficient amount of data and whether the assumptions (such as being in a isometric growth period) are met.