Direct BMP2/4 signaling through BMP receptor IA regulates fetal thymocyte progenitor homeostasis and differentiation to CD4+CD8+double-positive cell

BMP2/4 signaling is required for embryogenesis and involved in thymus morphogenesis and T-lineage differentiation. In vitro experiments have shown that treatment of thymus explants with exogenous BMP4 negatively regulated differentiation of early thymocyte progenitors and the transition from CD4−CD8− (DN) to CD4+CD8+ (DP). Here we show that in vivo BMP2/4 signaling is required for fetal thymocyte progenitor homeostasis and expansion, but negatively regulates differentiation from DN to DP cell. Unexpectedly, conditional deletion of BMPRIA from fetal thymocytes (using the Cre-loxP system and directing excision to hematopoietic lineage cells with the Vav promoter) demonstrated that physiological levels of BMP2/4 signaling directly to thymocytes through BMPRIA are required for normal differentiation and expansion of early fetal DN thymocytes. In contrast, the arrest in early thymocyte progenitor differentiation caused by exogenous BMP4 treatment of thymus explants is induced in part by direct signaling to thymocytes through BMPRIA, and in part by indirect signaling through non-hematopoietic cells. Analysis of the transition from fetal DN to DP cell, both by ex vivo analysis of conditional BMPRIA-deficient thymocytes and by treatment of thymus explants with the BMP4-inhibitor Noggin demonstrated that BMP2/4 signaling is a negative regulator at this stage. We showed that at this stage of fetal T-cell development BMP2/4 signals directly to thymocytes through BMPRIA

Ferroelectric Nanotubes

We report the independent invention of ferroelectric nanotubes from groups in several countries. Devices have been made with three different materials: lead zirconate-titanate PbZr1-xTixO3 (PZT); barium titanate BaTiO3; and strontium bismuth tantalate SrBi2Ta2O9 (SBT). Several different deposition techniques have been used successfully, including misted CSD (chemical solution deposition) and pore wetting. Ferroelectric hysteresis and high optical nonlinearity have been demonstrated. The structures are analyzed via SEM, TEM, XRD, AFM (piezo-mode), and SHG. Applications to trenching in Si dynamic random access memories, ink-jet printers, and photonic devices are discussed. Ferroelectric filled pores as small as 20 nm in diameter have been studied

Physician and Patient Preferences for Treatment of Anemia Associated with Chronic Kidney Disease in Japan: A Survey Including Best-Worst Scaling

Sari Mishina,1 Yuichiro Ito,1 Takumi Lee,1 Toshiaki Murofushi,2 Yoshiyuki Uetake,2 Tadao Akizawa3 1Astellas Pharma Inc, Tokyo, Japan; 2INTAGE Healthcare Inc, Tokyo, Japan; 3Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, JapanCorrespondence: Sari Mishina, Astellas Pharma Inc, 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan, Tel +81-3-3244-0294, Email [email protected]: Several treatment options are available for anemia associated with chronic kidney disease (CKD); however, there remains a lack of awareness of physician and patient preferences regarding these treatments. We aimed to explore physicians’ and patients’ perceptions and preferences regarding the management of anemia of CKD in Japan.Methods: A web-based survey, including best-worst scaling (BWS), was conducted with physicians who had treated ≥ 1 patient with anemia of CKD in the preceding year, and with patients with CKD who self-reported a clinical diagnosis of anemia of CKD or low hemoglobin levels. A three-step approach was used comprising cognitive interviews, a pilot survey, and a main survey. The BWS survey results were analyzed using multinomial logit and hierarchical Bayesian models.Results: The survey was completed by 906 participants: 103 patients (average age 60.6 years; 77.7% male) and 803 physicians (166 nephrologists, 214 cardiologists, 137 diabetologists, and 286 general internists). Almost all (96.0%) physicians surveyed considered anemia of CKD to be an important condition to treat. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors had the highest treatment satisfaction among physicians, whereas patients had the highest satisfaction with both erythropoietin-stimulating agent therapy and HIF-PH inhibitors. Approximately one-third (35.9%) of patients surveyed indicated that they were receiving treatment. When comparing the relative importance of attributes and levels, physicians favored efficacy (particularly improvement in hemoglobin levels), whereas patients favored safety (particularly a lower rate of severe adverse events).Conclusion: Although a majority of physicians consider treatment of CKD-related anemia important, differences in the perceptions and usage of medications exist between medical specialties. Preferences for the management of anemia of CKD vary between physicians and patients; therefore, patient involvement in treatment decisions may help optimize outcomes.Keywords: anemia, best-worst scaling, chronic kidney disease, erythropoiesis-stimulating agents, hypoxia-inducible factor prolyl hydroxylase inhibitors, treatment preferenc

BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway

Bone morphogenetic proteins (BMPs) are known to induce ectopic bone. However, it is largely unknown how BMP signaling in osteoblasts directly regulates endogenous bone. This study investigated the mechanism by which BMP signaling through the type IA receptor (BMPR1A) regulates endogenous bone mass using an inducible Cre-loxP system. When BMPR1A in osteoblasts was conditionally disrupted during embryonic bone development, bone mass surprisingly was increased with upregulation of canonical Wnt signaling. Although levels of bone formation markers were modestly reduced, levels of resorption markers representing osteoclastogenesis were severely reduced, resulting in a net increase in bone mass. The reduction of osteoclastogenesis was primarily caused by Bmpr1a-deficiency in osteoblasts, at least through the RANKL-OPG pathway. Sclerostin (Sost) expression was downregulated by about 90% and SOST protein was undetectable in osteoblasts and osteocytes, whereas the Wnt signaling was upregulated. Treatment of Bmpr1a-deficient calvariae with sclerostin repressed the Wnt signaling and restored normal bone morphology. By gain of Smad-dependent BMPR1A signaling in mice, Sost expression was upregulated and osteoclastogenesis was increased. Finally, the Bmpr1a-deficient bone phenotype was rescued by enhancing BMPR1A signaling, with restoration of osteoclastogenesis. These findings demonstrate that BMPR1A signaling in osteoblasts restrain endogenous bone mass directly by upregulating osteoclastogenesis through the RANKL-OPG pathway, or indirectly by downregulating canonical Wnt signaling through sclerostin, a Wnt inhibitor and a bone mass mediator

A look at new therapeutic opportunities in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and is considered to be the liver manifestation of metabolic syndrome. Currently, there is no etiotropic treatment of NAFLD, so an active research for new methods of treatment is underway. In the meantime, drugs are used to treat comorbid conditions, such as dyslipidemia, arterial hypertension, obesity, type 2 diabetes, which are present in varying degrees in patients. This review considers medications that are used in patients with NAFLD and related concomitant features, and also describes new strategies for regressing changes in liver tissue in NAFLD. In our opinion, one of the promising groups of drugs are agonists of the farnesoid X receptor (FXR). FXR belongs to the group of nuclear receptors, which are ligand-activated transcription factors that regulate the genes involved in metabolism. FXR agonists can claim to be a new promising drug for the treatment of NAFLD and related diseases influencing carbohydrate metabolism, fat metabolism, bile acid metabolism, as well as inflammatory processes in the liver to ensure metabolic homeostasis

Features of clinical manifestations and diagnosis of comorbidity of disseminated pulmonary tuberculosis, coronavirus, pneumocystis and pneumococcal pneumonia in patients with late stages of HIV infection with immunodeficiency

Aim. To study the features of clinical manifestations and diagnosis of comorbidity of disseminated pulmonary tuberculosis, coronavirus, pneumocystis and pneumococcal pneumonia in patients with late stages of HIV infection with immunodeficiency. Materials and methods. The prospective study included 120 newly identified patients with disseminated pulmonary tuberculosis with Mycobacterium tuberculosis, stage IVB of HIV infection, in the phase of progression and in the absence of antiretroviral therapy, aged 2953 years, who were randomized into 1A and 2A main groups and 1B and 2B comparison groups. Group 1A included 29 patients with comorbidity and pneumocystis pneumonia and group 2A 31 patients with comorbidity of disseminated pulmonary tuberculosis, coronovirus pneumococcal pneumonia, and group 1B and 2B comprised 29 and 31 similar patients, but without coronovirus pneumonia. To diagnose coronavirus pneumonia, PCR of SARS-CoV-2 RNA was used in smears from the nasopharynx and oropharynx, in sputum or in endotracheal aspirate. To detect Pneumocystis jirovecii, the causative agent of pneumocystis pneumonia, a microscopic examination of diagnostic material from the respiratory tract with RomanovskyGiemse and GrokottGmri coloration was carried out, and to detect Streptococcus pneumoniae, the causative agent of pneumococcal pneumonia, the diagnostic material was seeded on special nutrient media with determination of the drug resistance of the resulting culture to broad-spectrum antibiotics. Statistical data processing was carried out using the Microsoft Office Excel 2019 program with the calculation of the average in the group and the standard error of the average, confidence interval. Results. The comorbidity of disseminated pulmonary tuberculosis, coronavirus, pneumocystis and pneumococcal pneumonia in patients in the late stages of HIV infection, in the phase of progression and in the absence of antiretroviral therapy was characterized by severe immunodeficiency, generalization of tuberculosis with multiple extrapulmonary lesions and severe pneumonia. This determines the similarity of clinical manifestations and respiratory symptoms, and also makes it difficult to visualize computed tomographic changes consisting of a complex simultaneous combination of four pathological syndromes: dissemination, pleural pathology, increased pulmonary pattern and adenopathy. Simultaneous layering of several pathologies with the same type of clinical manifestations and computed tomographic changes requires a comprehensive etiological diagnosis of specific diseases to prescribe timely comprehensive treatment and reduce the lethality of this heavy contingent of patients. Conclusion. Patients with disseminated pulmonary tuberculosis and HIV infection who are registered in the office of tuberculosis care for HIV-infected in the tuberculosis dispensary represent a high risk group of COVID-19 infection and the development of coronavirus pneumonia, and with severe immunodeficiency, pneumocystis and pneumococcal pneumonia, should be regularly subjected to preventive studies for timely detection of COVID-19, coronavirus, pneumocystis and pneumococcal pneumonia for the purpose of their emergency isolation and timely treatment

Photometrical observations and shape modeling of space debris in medium Earth orbits

The circular medium Earth orbits with a period of about half a day in the inclination range from 50° to 70° are used by various global navigation satellite systems (GNSS), such as GLONASS, GPS, Beidou, Galileo. GNSS operating orbits are one of the important areas in near-Earth space. The information about the space debris (SD) existing in this region and its characteristics is important for risk assessments and mitigation. We report the results of photometrical observations of SD objects in the vicinity of GNSS orbits obtained with the 1.6-meter AZT-33IK telescope of ISTP SB RAS Sayan Solar Observatory in 2018–2023. We show how SD objects existing in this region are distributed relative to GNSS objects. We derive time and phase dependences of the apparent brightness of all measured SD objects. Folded light curves are constructed, rotation periods and their dynamics are determined. The results of modeling the light curve inherent for several SD objects from the GNSS orbital are presented. We suggest a possible space object shape and parameters of proper rotation, which correspond to the observed light curve

A practical and open source implementation of IEC 61850-7-2 for IED monitoring applications

A new open source mapping of IEC 61850-7-2 to web services has been defined and implemented. This work is useful for rapidly implementing user interfaces—particularly web-based interfaces—for monitoring and controlling Intelligent Electronic Devices (IEDs) from multiple vendors. The web service mapping has been implemented using the Hypertext Transfer Protocol (HTTP), with a message format in JavaScript Object Notation (JSON). This approach requires a simple and ubiquitous software stack for its implementation, which is a significant advantage over existing client-server communications mappings. The use of an open source paradigm allows for the rapid iteration and refinement of the design, implementation, and testing of the internal details of the proposed protocol stack, in a collaborative manner. These developments are of immediate interest to users of IEC 61850 and are particularly relevant to the IEC 61850 standardization process

Association of insulin resistance and non-alcoholic fatty liver disease

BACKGROUND: The number of patients with chronic metabolic disorders such as obesity, type 2 diabetes mellitus (T2D) and non-alcoholic fatty liver disease (NAFLD) is growing at an alarming rate worldwide in both developed and developing countries. In the world, the prevalence of NAFLD is approaching 25%. Among patients with T2D, 70–80% are diagnosed with NAFLD. Insulin resistance (IR) is recognized as one of the main pathogenetic factors in the development of the most common chronic liver disease — NAFLD.AIM: Our search work was aimed at determining the contribution of the degree of IR to the progression of NAFLD; compare the gold standard for the determination of IR (clamp) and the mathematical model (HOMA-IR).METHODS: An observational one-stage open comparative study was conducted on the basis of the case-control principle. The objects of the study were overweight and obese patients who had not previously been diagnosed carbohydrate metabolism disorders, without secondary causes of fat accumulation in the liver. During the examination, clinical and laboratory studies were carried out, IR indices (M-index, HOMA-IR index) were obtained, a diagnosis of carbohydrate metabolism disturbance (or its absence) was made, a liver biopsy was made, morphological and clinical diagnoses were made.RESULTS: The analysis included information about 60 patients, they are divided into 3 groups: without NAFLD (7 people), with steatosis (18 people), with non-alcoholic steatohepatitis (NASH) (35 people), groups are comparable by age, gender, and body mass index (BMI), glycated hemoglobin. When assessing the degree of IR using the hyperinsulinemic euglycemic clamp test, 19 showed a severe degree of IR, 28 had a moderate degree, 8 had a mild degree, and 5 had no IR. In the three studied groups, the median IR corresponded to an average degree and did not significantly differ. When comparing the gold standard for determining IR and the mathematical model (HOMA-IR) in the studied groups, an negative significant correlation was revealed (p = 0,0001).CONCLUSIONS: In the course of our study, no correlation was found between the degree of IR and the severity of NAFLD. This result allows us to think about other pathogenetic factors that affect the progression of NAFLD