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In nephrotic syndrome, the podocyte filtration structures are damaged in a process called foot process effacement. This is mediated by the actin cytoskeleton; however, which actins are involved and how they interact with other filtration components, like the basement membrane, remains poorly understood. Here, we used the well-established Drosophila pericardial nephrocyte—the equivalent of podocytes in flies—knockdown models (RNAi) to study the interplay of the actin cytoskeleton (Act5C, Act57B, Act42A, and Act87E), alpha- and beta-integrin (basement membrane), and the slit diaphragm (Sns and Pyd). Knockdown of an actin gene led to variations of formation of actin stress fibers, the internalization of Sns, and a disrupted slit diaphragm cortical pattern. Notably, deficiency of Act5C, which resulted in complete absence of nephrocytes, could be partially mitigated by overexpressing Act42A or Act87E, suggesting at least partial functional redundancy. Integrin localized near the actin cytoskeleton as well as slit diaphragm components, but when the nephrocyte cytoskeleton or slit diaphragm was disrupted, this switched to colocalization, both at the surface and internalized in aggregates. Altogether, the data show that the interdependence of the slit diaphragm, actin cytoskeleton, and integrins is key to the structure and function of the Drosophila nephrocyte. [ABSTRACT FROM AUTHOR]

Objective: The molecular era of glioma diagnosis and treatment has arrived, and a single rapid histopathology is no longer sufficient for surgery. This study sought to present an automatic integrated gene detection system (AIGS), which enables rapid intraoperative detection of IDH/TERTp mutations. Methods: A total of 78 patients with gliomas were included in this study. IDH/TERTp mutations were detected intraoperatively using AIGS in 41 of these patients, and they were guided to surgical resection (AIGS detection group). The remaining 37 underwent histopathology‐guided conventional surgical resection (non‐AIGS detection group). The clinical utility of this technique was evaluated by comparing the accuracy of glioma subtype diagnosis before and after TERTp mutation results were obtained by pathologists and the extent of resection (EOR) and patient prognosis for molecular pathology‐guided glioma surgery. Results: With NGS/Sanger sequencing and chromosome detection as the gold standard, the accuracy of AIGS results was 100%. And the timing was well matched to the intraoperative rapid pathology report. After obtaining the TERTp mutation detection results, the accuracy of the glioma subtype diagnosis made by the pathologists increased by 19.51%. Molecular pathology‐guided surgical resection of gliomas significantly increased EOR (99.06% vs. 93.73%, p < 0.0001) and also improved median OS (26.77 vs. 13.47 months, p = 0.0289) and median PFS (15.90 vs. 10.57 months, p = 0.0181) in patients with glioblastoma. Interpretation: Using AIGS intraoperatively to detect IDH/TERTp mutations to accurately diagnose glioma subtypes can help achieve maximum safe resection of gliomas, which in turn improves the survival prognosis of patients. [ABSTRACT FROM AUTHOR]

Mitochondria are crucial for cellular ATP production. They are highly dynamic organelles, whose morphology and function are controlled through mitochondrial fusion and fission. The specific roles of mitochondria in podocytes, the highly specialized cells of the kidney glomerulus, remain less understood. Given the significant structural, functional, and molecular similarities between mammalian podocytes and Drosophila nephrocytes, we employed fly nephrocytes to explore the roles of mitochondria in cellular function. Our study revealed that alterations in the Pink1–Park (mammalian PINK1–PRKN) pathway can disrupt mitochondrial dynamics in Drosophila nephrocytes. This disruption led to either fragmented or enlarged mitochondria, both of which impaired mitochondrial function. The mitochondrial dysfunction subsequently triggered defective intracellular endocytosis, protein aggregation, and cellular damage. These findings underscore the critical roles of mitochondria in nephrocyte functionality. [ABSTRACT FROM AUTHOR]

Abstract. Background. Vascular endothelial dysfunction is considered a key pathophysiologic process for the development of acute lung injury. In this study, we aimed at investigating the effects of unfractionated heparin (UFH) on the lipopolysaccharide (LPS)-induced changes of vascular endothelial-cadherin (VE-cadherin) and the potential underlying mechanisms. Methods. Male C57BL/6 J mice were randomized into three groups: vehicle, LPS, and LPS + UFH groups. Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis. Mice in the LPS + UFH group received subcutaneous injection of 8 U UFH 0.5 h before LPS injection. The lung tissue of the mice was collected for assessing lung injury by measuring the lung wet/dry (W/D) weight ratio and observing histological changes. Human pulmonary microvascular endothelial cells (HPMECs) were cultured and used to analyze the effects of UFH on LPS- or tumor necrosis factor-alpha (TNF-α)-induced vascular hyperpermeability, membrane expression of VE-cadherin, p120-catenin, and phosphorylated myosin light chain (p-MLC), and F-actin remodeling, and on the LPS-induced activation of the phosphatidylinositol-3 kinase (PI3K)/serine/threonine kinase (Akt)/nuclear factor kappa-B (NF-κB) signaling pathway. Results. In vivo, UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes (neutrophil infiltration and erythrocyte effusion, alveolus pulmonis collapse, and thicker septum), decreased the lung W/D, and increased protein concentration (LPS vs. LPS + UFH: 0.57 ± 0.04 vs. 0.32 ± 0.04 mg/mL, P = 0.0092), total cell count (LPS vs. LPS + UFH: 9.57 ± 1.23 vs. 3.65 ± 0.78 × 105/mL, P = 0.0155), polymorphonuclear neutrophil percentage (LPS vs. LPS + UFH: 88.05% ± 2.88% vs. 22.20% ± 3.92%, P = 0.0002), and TNF-α (460.33 ± 23.48 vs. 189.33 ± 14.19 pg/mL, P = 0.0006) in the bronchoalveolar lavage fluid. In vitro, UFH pre-treatment prevented the LPS-induced decrease in the membrane expression of VE-cadherin (LPS vs. LPS + UFH: 0.368 ± 0.044 vs. 0.716 ± 0.064, P = 0.0114) and p120-catenin (LPS vs. LPS + UFH: 0.208 ± 0.018 vs. 0.924 ± 0.092, P = 0.0016), and the LPS-induced increase in the expression of p-MLC (LPS vs. LPS + UFH: 0.972 ± 0.092 vs. 0.293 ± 0.025, P = 0.0021). Furthermore, UFH attenuated LPS- and TNF-α-induced hyperpermeability of HPMECs (LPS vs. LPS + UFH: 8.90 ± 0.66 vs. 15.84 ± 1.09 Ω·cm2, P = 0.0056; TNF-α vs. TNF-α + UFH: 11.28 ± 0.64 vs. 18.15 ± 0.98 Ω·cm2, P = 0.0042) and F-actin remodeling (LPS vs. LPS + UFH: 56.25 ± 1.51 vs. 39.70 ± 1.98, P = 0.0027; TNF-α vs. TNF-α + UFH: 55.42 ± 1.42 vs. 36.51 ± 1.20, P = 0.0005) in vitro. Additionally, UFH decreased the phosphorylation of Akt (LPS vs. LPS + UFH: 0.977 ± 0.081 vs. 0.466 ± 0.035, P = 0.0045) and I kappa B Kinase (IKK) (LPS vs. LPS + UFH: 1.023 ± 0.070 vs. 0.578 ± 0.044, P = 0.0060), and the nuclear translocation of NF-κB (LPS vs. LPS + UFH: 1.003 ± 0.077 vs. 0.503 ± 0.065, P = 0.0078) in HPMECs, which was similar to the effect of the PI3K inhibitor, wortmannin. Conclusions. The protective effect of UFH against LPS-induced pulmonary endothelial barrier dysfunction involves VE-cadherin stabilization and PI3K/Akt/NF-κB signaling.

In view of unstable communication and poor anti-interference ability of the existing hydraulic support condition monitoring system, a hydraulic support condition monitoring system based on LoRaWAN was designed. Sensor nodes use rate adaptive technology to periodically upload data, and can actively upload data in case of abnormal conditions, and use sequential polling to reduce transmission error rate; gateways simultaneously transmit uplink and downlink commands through independent uplink and downlink channels, which reduces collision probability of uplink and downlink commands, and improves data forwarding efficiency. In order to ensure signal coverage of fully mechanized mining face, a gateway is installed at the corner of the roadway, and the LoRa wireless signal of the fully mechanized mining face is forwarded to application platform through a jump transmission. Experimental results show that the system can effectively cover the entire fully mechanized mining face and realize condition monitoring of hydraulic support,when communication distance is 150 m, the data transmission packet loss rate is 0, and the data transmission time of a single sensor node is about 0.29 s,the system acquisition cycle is within 200 s, which meets application requirements.

Trajectory data from connected vehicles (CVs) provide a continuous and reliable means of obtaining information that can be leveraged to optimize traffic signals. This paper proposes a real‐time traffic signal control method using CV trajectory data as the sole input. The primary goal of the proposed signal control method is to prevent queue spillover, which may significantly decrease the traffic efficiency on urban networks and induce high delays to the travelers. The proposed method formulates the signal control problem via a linear quadratic optimization model, considering the constraints related to the duration and variability of green lights in practical traffic signal control systems. Compared to conventional max‐pressure‐based methods, the optimization model offers enhanced efficiency in handling these constraints, making it highly suitable for real‐life implementation. The proposed method has undergone testing in both simulated environments and real‐world applications. In the simulation experiments, the proposed method has been demonstrated to effectively reduce spillover risks and outperform a conventional max‐pressure‐based approach even when the CV penetration rate is as low as 5%. In the real‐world experiment, the proposed method had been tested in a traffic network around the Beijing Capital International Airport for several months. The severity of spillovers, which was represented by two performance indicators, had been significantly reduced after implementing the proposed method. [ABSTRACT FROM AUTHOR]

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

Mild normobaric hypoxia (NH) and modest exercise have multiple beneficial effects on health, but the changes in physiological function induced by NH and/or exercise remain unclear. The purpose of this investigation was to examine the specific effects of NH and/or exercise on cardiac function and myocardial structure and behavior including sleep-activity and negative geotaxis in aged Drosophila. We also assessed the survival rate of flies after hypoxia and/or exercise. One-thousand wild-type w1118 virgin female flies were randomly divided into four groups and treated with NH and/or exercise from ages 3–6 weeks. We found that exercise remarkably delayed the decline of actin and myosin and the age-related changes in cardiac structure, improved abnormal cardiac contraction, and enhanced the cardiac pumping force by inducing cardiac hypertrophy and delaying deterioration of cardiac contractility and diastolic compliance, and improved abnormal heart contraction. NH also increased the content of actin and myosin, but induced a decrease in heart diameter and heart rate, as well as an increase in the number of mitochondria and deeper sleep, which may be the manifestation of energy saving under long-term hypoxia. Both NH and exercise improved sleep quality and climbing ability of aged flies, as well as extended the maximum life span, which shows the benefits of hypoxia and exercise. Finally, the superposition of NH and exercise did not impart any obvious physiological and behavior improvement. Therefore, it is necessary to further explore the appropriate combination of hypoxia and exercise.

In recent years, long-term continuous sea-ice datasets have been developed, and they cover the periods before and after the satellite era. How these datasets differ from one another before the satellite era, and whether one is more reliable than the other, is important but unclear because the sea-ice record before 1979 is sparse and not continuous. In this letter, two sets of sea-ice datasets are evaluated: one is the HadISST1 dataset from the Hadley Centre, and the other is the SIBT1850 (Gridded Monthly Sea Ice Extent and Concentration, from 1850 Onward) dataset from the National Snow and Ice Data Center (NSIDC). In view of its substantial importance for climate, the winter sea ice in the Barents and Kara seas (BKS) is of particular focus. A reconstructed BKS sea-ice extent (SIE) is developed using linear regression from the mean of observed surface air temperature at two adjacent islands, Novaya Zemlya and Franz Josef Land (proxy). One validation illustrates that the proxy is substantially coherent with the BKS sea-ice anomaly in the observations and the CMIP5 (phase 5 of the Coupled Model Intercomparison Project) historical experiments. This result indicates that the proxy is reasonable. Therefore, the establishment of the reconstructed BKS SIE is also reasonable. The evaluation results based on the proxy suggest that the sea-ice concentration prior to the satellite era in the NSIDC dataset is more realistic and reliable than that in the Hadley Centre dataset, and thus is more appropriate for use.