Abstract Anchor is a structural element as part of foundation that can take a variety of forms. Over the past four decades a wide variety of foundation anchor systems have been developed to satisfy ...the increasing demand for foundations with ever-higher pullout resistance. Some kind of soils have problem of cavity deforms inside it, and the reason of these cavities belong to two main reasons, natural cavities because of some chemical actions inside the soil and artificial reasons as human made like old building inside the soils. Experimental modeling was carried to study the capacity of anchor plate under effect of cavity inside the soil, small scale anchor embedded in sandy soil was carried in laboratory to study the capacity and the displacement for loaded plate anchor, the result for test shows reduced capacity for the plate capacity under appearance of cavity inside the effective soil area for the anchor.
Monitoring of cardiopulmonary activity is a challenge when attempted under adverse conditions, including different sleeping postures, environmental settings, and an unclear region of interest (ROI). ...This study proposes an efficient remote imaging system based on a Microsoft Kinect v2 sensor for the observation of cardiopulmonary-signal-and-detection-related abnormal cardiopulmonary events (e.g., tachycardia, bradycardia, tachypnea, bradypnea, and central apnoea) in many possible sleeping postures within varying environmental settings including in total darkness and whether the subject is covered by a blanket or not. The proposed system extracts the signal from the abdominal-thoracic region where cardiopulmonary activity is most pronounced, using a real-time image sequence captured by Kinect v2 sensor. The proposed system shows promising results in any sleep posture, regardless of illumination conditions and unclear ROI even in the presence of a blanket, whilst being reliable, safe, and cost-effective.
Approximately 15% of all human tumors harbor mutant KRAS, a membrane-associated small GTPase and notorious oncogene. Mutations that render KRAS constitutively active will lead to uncontrolled cell ...growth and cancer. However, despite aggressive efforts in recent years, there are no drugs on the market that directly target KRAS and inhibit its aberrant functions. In the current work, we combined structure-based design with a battery of cell and biophysical assays to discover a novel pyrazolopyrimidine-based allosteric KRAS inhibitor that binds to activated KRAS with sub-micromolar affinity and disrupts effector binding, thereby inhibiting KRAS signaling and cancer cell growth. These results show that pyrazolopyrimidine-based compounds may represent a first-in-class allosteric noncovalent inhibitors of KRAS. Moreover, by studying two of its analogues, we identified key chemical features of the compound that interact with a set of specific residues at the switch regions of KRAS and play critical roles for its high-affinity binding and unique mode of action, thus providing a blueprint for future optimization efforts.
So far, many methods have been proposed to classify items based on ABC analysis, but the results of these methods have had relatively low compliance with the principles of ABC. More precisely, ...collective value and sometimes the number of items belonging to each category in the methods provided do not meet the basic requirements of ABC called Pareto’s principle. In this study, a number of hybrid methodologies including Shannon’s entropy, TOPSIS (the technique for order preference by similarity to ideal solution) and goal programming are respectively used for determining the weight of criteria which are effective in the inventory items classification, calculations of each item value and its classification based on Pareto’s principle. To this end, the value of each item as well as classification of inventory items is calculated based on Pareto’s principle. The performance of the proposed method is evaluated through (1) statistical analysis, (2) checking the percentage of similarity with other methods and (3) comparison with another method in terms of the number and value allocated to each class. The results confirm the capability of the listed method.
Beta cell replacement has the potential to restore euglycemia in patients with insulin-dependent diabetes. Although great progress has been made in establishing allogeneic islet transplantation from ...deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association in collaboration with the Harvard Stem Cell Institute, the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward the clinical application of stem cell-derived beta cells.
Dedifferentiation of pancreatic β-cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown.
We ...employed single-cell RNAseq to detail the maturation program of α- and β-cells during human ontogeny. We also compared islets from non-diabetic and T2D individuals.
Both α- and β-cells mature in part by repressing non-endocrine genes; however, α-cells retain hallmarks of an immature state, while β-cells attain a full β-cell specific gene expression program. In islets from T2D donors, both α- and β-cells have a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes and increasing expression of exocytosis, inflammation and stress response signalling pathways. These changes are consistent with the increased proportion of β-cells displaying suboptimal function observed in T2D islets.
These findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics.
•Non-endocrine and developmental genes are repressed during maturation of human α- and β-cells.•Adult α-cells retain a less mature gene expression program than β-cells.•In T2D, both α- and β-cells re-establish an immature transcriptome.
Pancreatic beta cells undergo compensatory proliferation in the early phase of type 2 diabetes. While pathways such as FoxM1 are involved in regulating compensatory beta cell proliferation, given the ...lack of therapeutics effectively targeting beta cell proliferation, other targetable pathways need to be identified. Herein, we show that Pbk, a serine/threonine protein kinase, is essential for high fat diet (HFD)‐induced beta cell proliferation in vivo using a Pbk kinase deficiency knock‐in mouse model. Mechanistically, JunD recruits menin and HDAC3 complex to the Pbk promoter to reduce histone H3 acetylation, leading to epigenetic repression of Pbk expression. Moreover, menin inhibitor (MI) disrupts the menin–JunD interaction and augments Pbk transcription. Importantly, MI administration increases beta cell proliferation, ameliorating hyperglycemia, and impaired glucose tolerance (IGT) in HFD‐induced diabetic mice. Notably, Pbk is required for the MI‐induced beta cell proliferation and improvement of IGT. Together, these results demonstrate the repressive role of the menin/JunD/Pbk axis in regulating HFD‐induced compensatory beta cell proliferation and pharmacologically regulating this axis may serve as a novel strategy for type 2 diabetes therapy.
Synopsis
Pancreatic beta cells undergo compensatory proliferation in the early phase of type 2 diabetes. Understanding the mechanism and regulation of compensatory beta cell proliferation may allow for improved treatment options for diabetes. Herein we elucidated that the menin/JunD/Pbk axis is important in compensatory beta‐cell proliferation.
Pbk is crucial for regulating compensatory pancreatic beta cell proliferation of high fat diet (HFD) fed mice.
Menin and HDAC3 complex were recruited by JunD to epigenetically repress Pbk expression.
Menin‐JunD interaction was interrupted by small molecule menin inhibitors (MIs), leading to upregulating of Pbk gene expression, beta cell proliferation, and improved glucose tolerance in diet‐induced obese and diabetic mice.
Pbk is required for MI‐induced beta cell proliferation and improved glucose tolerance in HFD‐induced diabetic mice.
Pancreatic beta cells undergo compensatory proliferation in the early phase of type 2 diabetes. Understanding the mechanism and regulation of compensatory beta cell proliferation may allow for improved treatment options for diabetes. Herein we elucidated that the menin/JunD/Pbk axis is important in compensatory beta‐cell proliferation.
Context:
Islet transplantation has been shown to improve glucose counterregulation and hypoglycemia symptom recognition in patients with type 1 diabetes (T1D) complicated by severe hypoglycemia ...episodes and symptom unawareness, but long-term data are lacking.
Objective:
To assess the long-term durability of glucose counterregulation and hypoglycemia symptom responses 18 months after intrahepatic islet transplantation and associated measures of glycemic control during a 24-month follow-up period.
Design, Setting, and Participants:
Ten patients with T1D disease duration of approximately 27 years were studied longitudinally before and 6 and 18 months after transplant in the Clinical & Translational Research Center of the University of Pennsylvania and were compared to 10 nondiabetic control subjects.
Intervention:
All 10 patients underwent intrahepatic islet transplantation according to the CIT07 protocol at the Hospital of the University of Pennsylvania.
Main Outcome Measures:
Counterregulatory hormone, endogenous glucose production, and autonomic symptom responses derived from stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-2H2-glucose.
Results:
Near-normal glycemia (HbA1c ≤ 6.5%; time 70–180 mg/dL ≥ 95%) was maintained for 24 months in all patients, with one returning to low-dose insulin therapy. In response to insulin-induced hypoglycemia, glucagon secretion was incompletely restored at 6 and 18 months, epinephrine was improved at 6 months and normalized at 18 months, and endogenous glucose production and symptoms, absent before, were normalized at 6 and 18 months after transplant.
Conclusions:
In patients with T1D experiencing problematic hypoglycemia, intrahepatic islet transplantation can lead to long-term improvement of glucose counterregulation and hypoglycemia symptom recognition, physiological effects that likely contribute to glycemic stability after transplant.
This study demonstrates near-normal glycemic control and improvement in glucose counterregulation in 10 patients with type 1 diabetes during 24 months following intrahepatic islet transplantation.