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OBJECTIVE Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

Background Venous thromboembolism (VTE) contributes significantly to COVID‐19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID‐19. Whether suPAR levels identify patients with COVID‐19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID‐19 with suPAR and D‐dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine‐Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D‐dimer levels. There was a positive association between suPAR and D‐dimer (β=7.34; P =0.002). Adjusted for clinical covariables, including D‐dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51–4.75]; P Conclusions Higher suPAR was associated with incident VTE independently of D‐dimer in patients hospitalized for COVID‐19. Combining suPAR and D‐dimer identified patients at low VTE risk. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04818866.

Neuroimaging studies have demonstrated that migraine is accompanied by spontaneous brain activity alterations in specific regions. However, these findings are inconsistent, thus hindering our understanding of the potential neuropathology. Hence, we performed a quantitative whole-brain meta-analysis of relevant resting-state functional imaging studies to identify brain regions consistently involved in migraine. A systematic search of studies that investigated the differences in spontaneous brain activity patterns between migraineurs and healthy controls up to April 2022 was conducted. We then performed a whole-brain voxel-wise meta-analysis using the anisotropic effect size version of seed-based d mapping software. Complementary analyses including jackknife sensitivity analysis, heterogeneity test, publication bias test, subgroup analysis, and meta-regression analysis were conducted as well. In total, 24 studies that reported 31 datasets were finally eligible for our meta-analysis, including 748 patients and 690 controls. In contrast to healthy controls, migraineurs demonstrated consistent and robust decreased spontaneous brain activity in the angular gyrus, visual cortex, and cerebellum, while increased activity in the caudate, thalamus, pons, and prefrontal cortex. Results were robust and highly replicable in the following jackknife sensitivity analysis and subgroup analysis. Meta-regression analyses revealed that a higher visual analog scale score in the patient sample was associated with increased spontaneous brain activity in the left thalamus. These findings provided not only a comprehensive overview of spontaneous brain activity patterns impairments, but also useful insights into the pathophysiology of dysfunction in migraine.

BACKGROUND: Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target. METHODS: We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR. RESULTS: The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells. CONCLUSIONS: High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.)

Methyltransferase-like 3 (METTL3) was originally known to be responsible for N6-methyladenosine (m6A) modification of mRNA. Recent studies have found that METTL3 plays important roles in a variety of tumors by regulating the translation of oncogenes. However, the functional and regulating mechanisms of METTL3 in human gastric cancer have not yet been understood. Here we knocked down METTL3 in human gastric cancer cell lines, AGS and MKN45, by using shRNA transfection. RT-qPCR assay and western blotting verified the effectiveness of RNA interference on mRNA and protein levels, respectively. Then we found that METTL3 knockdown inhibited cell proliferation, migration and invasion in AGS and MKN45 cells. Moreover, METTL3 knockdown decreased Bcl2 and increased Bax and active Caspase-3 in gastric cancer cells, which suggested the apoptotic pathway was activated. Mechanistic investigation suggested that METTL3 led to inactivation of the AKT signaling pathway in human gastric cancer cells, including decreased phosphorylation levels of AKT and expression of down-stream effectors p70S6K and Cyclin D1. In conclusion, our study reveals that down-regulation of METTL3 inhibits the proliferation and mobility of human gastric cancer cells and leads to inactivation of the AKT signaling pathway, suggesting that METTL3 may be a potential target for the treatment of human gastric cancer.

Amphotericin B (AmB) is a very effective antifungal agent, and resistance in clinical isolates is rare. However, clinical treatment with AmB is often associated with severe side effects. Reducing the administration dose of AmB by combining it with other agents is a promising strategy to minimize this toxicity. In this study, we screened a small compound library and observed that the anti-obesity drug rimonabant exhibited synergistic antifungal action with AmB against Candida species and Cryptococcus neoformans. Moreover, the combination of AmB and rimonabant exhibited synergistic or additive effects against Candida albicans biofilm formation and cell viability in preformed biofilms. The effects of this combination were further confirmed in vivo using a murine systemic infection model. Exploration of the mechanism of synergy revealed that rimonabant enhances the fungicidal activity of AmB by increasing cellular oxidative stress and cell membrane permeability. These findings provide a foundation for the possible development of AmB–rimonabant polytherapies for fungal infections.

Near-threshold voltage can effectively reduce the dynamic power of the clock tree, but at a lower voltage the timing of clock tree is more susceptible to process variations. We propose a timing-based and balanced register clustering framework (TBRCF) to enhance the robustness of the clock tree to process variations. Timing-related registers are grouped into the same cluster as much as possible, which increases the public clock path of these registers. Moreover the load capacitance of each cluster is balanced by merging clusters and appropriate buffers are allocated to each cluster according to the load of clusters. In this paper, ISCAS89 benchmark and ARM Cortex M0 and M3 microprocessor are implemented in SMIC 40nm technology and verified by Monte Carlo simulation using HSPICE software at 0.55v voltage. Compared with the traditional clock tree synthesis flow using leading commercial tool, register clustering based clock tree synthesis can reduce clock skew and standard deviation of skew.

Compared with clock tree working under super voltage region, near-threshold-voltage (NTV) clock tree suffers greater timing variation caused by technical parameter variation. Because clock buffers have a vital impact on clock skew and its variation under NTV, a symmetrical clock tree topology is adopted in this work to ensure better skew in nominal condition. To minimize skew variation, a buffer-library-oriented concurrent buffer insertion and sizing strategy is proposed. The buffering problem is later solved by generic algorithm in this work. Experimental result shows that σ skew is reduced by 117% and buffer area is reduced by 72% with wire length 107% increasement overhead on average compared with reproductive results at 0.55V.

CD133 (AC133/prominin-1) has been identified as a stem cell marker and a putative cancer stem cell marker in many solid tumors. Its biologic function and molecular mechanisms remain largely elusive. Here, we show that a fly mutant for prominin-like, a homolog of mammalian CD133, shows a larger body size and excess weight accompanied with higher fat deposits as compared with the wild type. The expression levels of prominin-like are mediated by ecdysone signaling where its protein levels increase dramatically in the fat body during metamorphosis. Prominin-like mutants exhibit higher Drosophila insulin-like peptide 6 (di lp6) levels during nonfeeding stages and increased Akt/ Drosophila target of rapamycin (dTOR) signaling. On an amino acid-restricted diet, prominin-like mutants exhibit a significantly larger body size than the wild type does, similar to that which occurs upon the activation of the dTOR pathway in the fat body. Our data suggest that prominin-like functions by suppressing TOR and dilp6 signaling to control body size and weight. The identification of the physiologic function of prominin-like in Drosophila may provide valuable insight into the understanding of the metabolic function of CD133 in mammals.-Zheng, H., Zhang, Y., Chen, Y., Guo, P., Wang, X., Yuan, X., Ge, W., Yang, R., Yan, Q., Yang, X., Xi, Y. Prominin-like, a homolog of mammalian CD133, suppresses di lp6 and TOR signaling to maintain body size and weight in Drosophila.

Background Antiangiogenic agents are commonly used in lung and colon cancer treatments, however, rapid development of drug resistance limits their efficacy. Methods Lentinan (LNT) is a biologically active compound extracted from Lentinus edodes. The effects of LNT on tumor angiogenesis were evaluated by immunohistochemistry in murine LAP0297 lung and CT26 colorectal tumor models. The impacts of LNT on immune cells and gene expression in tumor tissues were determined by flow cytometry, qPCR, and ELISA. Nude mice and IFNγ blockade were used to investigate the mechanism of LNT affecting on tumor angiogenesis. The data sets were compared using two-tailed student’s t tests or ANOVA. Results We found that LNT inhibited tumor angiogenesis and the growth of lung and colon cancers. LNT treatments elevated the expression of angiostatic factors such as IFNγ and also increased tumor infiltration of IFNγ-expressing T cells and myeloid cells. Interestingly, IFNγ blockade, but not T cell deficiency, reversed the effects of LNT treatments on tumor blood vessels. Moreover, long-lasting LNT administration persistently suppressed tumor angiogenesis and inhibited tumor growth. Conclusions LNT inhibits tumor angiogenesis by increasing IFNγ production and in a T cell-independent manner. Our findings suggest that LNT could be developed as a new antiangiogenic agent for long-term treatment of lung and colon cancers.

Summary Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young individuals. A potential role of mtDNA mutations in HCM is known. However, the underlying molecular mechanisms linking mtDNA mutations to HCM remain poorly understood due to lack of cell and animal models. Here, we generated induced pluripotent stem cell-derived cardiomyocytes (HCM-iPSC-CMs) from human patients in a maternally inherited HCM family who carry the m.2336T>C mutation in the mitochondrial 16S rRNA gene (MT-RNR2). The results showed that the m.2336T>C mutation resulted in mitochondrial dysfunctions and ultrastructure defects by decreasing the stability of 16S rRNA, which led to reduced levels of mitochondrial proteins. The ATP/ADP ratio and mitochondrial membrane potential were also reduced, thereby elevating the intracellular Ca2+ concentration, which was associated with numerous HCM-specific electrophysiological abnormalities. Our findings therefore provide an innovative insight into the pathogenesis of maternally inherited HCM., Highlights • Generation of HCM-specific iPSC-CMs carrying the m.2336T>C mutation in MT-RNR2 • m.2336T>C mutation results in mitochondrial dysfunctions • Mitochondrial dysfunctions lead to increased [Ca2+]i and decreased ICaL • Abnormal Ca2+ homeostasis is associated with HCM-specific abnormalities, In this article, Yan Q, Liu Z, Huang W, and colleagues show that patient-specific iPSCs as well as their derived cardiomyocytes carrying the m.2336T>C mutation in MT-RNR2 were generated to understand the pathogenic mechanism of maternally inherited HCM. MT-RNR2 mutation resulted in mitochondrial dysfunctions and ultrastructure defects, which induced abnormal Ca2+ homeostasis, then HCM-specific cellular and electrophysiological characteristics in iPSC-CMs.

Objective To identify the differences among preinvasive lesions, minimally invasive adenocarcinomas (MIAs) and invasive pulmonary adenocarcinomas (IPAs) based on radiomic feature analysis with computed tomography (CT). Methods A total of 109 patients with ground-glass opacity lesions (GGOs) in the lungs determined by CT examinations were enrolled, all of whom had received a pathologic diagnosis. After the manual delineation and segmentation of the GGOs as regions of interest (ROIs), the patients were subdivided into three groups based on pathologic analyses: the preinvasive lesions (including atypical adenomatous hyperplasia and adenocarcinoma in situ) subgroup, the MIA subgroup and the IPA subgroup. Next, we obtained the texture features of the GGOs. The data analysis was aimed at finding both the differences between each pair of the groups and predictors to distinguish any two pathologic subtypes using logistic regression. Finally, a receiver operating characteristic (ROC) curve was applied to accurately evaluate the performances of the regression models. Results We found that the voxel count feature (P

The β-functionalized porphyrin containing an additional electron-withdrawing unit, 2,3-diphenylquinoxaline( DPQ ) for LP-5 or 2,1,3-benzothiadiazole ( BTD) for LP-6 with different electron-withdrawing abilities, between the porphyrin core and the anchoring group and the reference porphyrin dye ( LP-4 ) have been designed and synthesized for DSCs. The influence of the additional electron-withdrawing units on molecular properties as well as photovoltaic performance of the corresponding DSCs was investigated systematically. Compared with LP-4 , the introduction of additional electron-deficient unit at the porphyrin β π-linker in LP-5 and LP-6 decreases the lowest unoccupied molecular orbital (LUMO) energy levels, resulting in the broader absorption spectra and significantly improved IPCE spectra in the region 350–500 nm, which ensures the better light-harvesting properties and the higher short-circuit current density ( J sc ). On the other hand, the introduction of additional acceptors of LP-5 and LP-6 induces dye aggregation and reduces the lifetime of the charge–separated states, which decreases the open–circuit voltage ( V oc ). Interestingly, the loss in V oc is overcompensated by the improvement in J sc . The study provides not only an alternative approach to design novel porphyrin sensitizers, but also an insight into how to manipulate the LUMO energy levels of porphyrin sensitizers via the β-linker modifications for the optimal photovoltaic applications.

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.

Background Drosophila Prominin-like is a homolog of mammalian CD133, which is recognized as a biomarker for stem cells. The interacting proteins of CD133 and their biological functions remain elusive. Results In this study, we using yeast two-hybrid assays, GST pull-down assay and co-immunoprecipitation (Co-IP) methods found that Drosophila Prominin-like interacts with ND20, a subunit of mitochondrial respiratory complex I. Bioinformatics analysis suggests that Prominin-like is a six-transmembrane glycoprotein which localizes on cellular membranes. Immunostaining and mitochondrial fractionation indicate that Drosophila Prominin-like could localize in the mitochondria. The knockdown of prominin-like in S2 cells resulted in transient mitochondrial dysfunctions as evidenced by reduced ATP production, elevated ROS generation and an accompanied reduction in mitochondrial proteins. Mitochondrial dysfunctions were detected in aged prominin-like mutant flies. Conclusion Our data indicates that Prominin-like acts to maintain mitochondrial function through its interaction with ND20 which, itself, is active in the mitochondrial electron transport chain. Our study provides insights into a novel molecular mechanism of Drosophila prominin-like and suggests a similar function of CD133 in mammals.

The speech keyword detection system is generally used to detect a specific wake-up word spoken by the user, as a simple interactive command between the user and the device, or a front end of a larger voice recognition system for determining whether to open a large speech recognition system at the back end. Yet, such keyword recognition systems are always active, hence have strict power and latency constraints. This paper proposes an implementation of an LSTM accelerator based on an iterative linear approximation scheme, which optimizes the circuit implementation while maintaining high accuracy and reliability. The scheme of this paper has been verified on the FPGA board, and real-time speech recognition power consumption is only less 150$\mu$w.

Accurately and efficiently estimate the extremely small failure rate of the SRAM cell is a challenging issue. In this paper, we develop an importance sampling with the differential evolution algorithm to extend the minimized norm importance sampling and mixture importance sampling. The key idea is searching the optimal shift vector (OSV) in the complex and nonconvex failure region using the improved differential algorithm efficiently. Then we construct a mixture of an original distribution and uniform distribution and a distort distribution based the searched OSV to estimate the failure rate of SRAM cell accurately. Our experiment results of a 40nm SRAM Cell show that the proposed method has achieved 1.31x-1.44x speedup than state-of-art methods and 7196x than Monte Carlo (MC) method with less than 2% error compared with MC result when the high accuracy is required (e.g., the relative error defined by the 99% confidence interval reaches 5%).

Immune checkpoint blockade (ICB) has shown long-term survival benefits, but only in a small fraction of cancer patients. Recent studies suggest that improved vessel perfusion by ICB positively correlates with its therapeutic outcomes. However, the underlying mechanism of such a process remains unclear. Here, we show that anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) treatment-induced tumor vessel normalization was accompanied by an increased infiltration of eosinophils into breast tumors. Eosinophil accumulation was positively correlated with the responsiveness of a breast tumor to anti-CTLA4 therapy. Depletion of eosinophils subsequently negated vessel normalization, reduced antitumor immunity and attenuated tumor growth inhibition by anti-CTLA4 therapy. Moreover, intratumoral accumulation of eosinophils relied on T lymphocytes and interferon γ production. Together, these results suggest that eosinophils partially mediate the antitumor effects of CTLA4 blockade through vascular remodeling. Our findings uncover an unidentified role of eosinophils in anti-CTLA4 therapy, providing a potential new target to improve ICB therapy and to predict its efficacy.

Background Postoperative pain is one of the most common symptoms after surgery, which brings physical discomfort to patients. In addition, it may cause a series of complications, and even affect the long-term quality of life. The purpose of this prospective, randomized, double-blinded, controlled trial is to investigate the efficacy and safety of dexmedetomidine combined with sufentanil to attenuate postoperative pain in patients after laparoscopic nephrectomy. Methods Ninety patients undergoing laparoscopic nephrectomy were randomized into three groups: the control (sufentanil 0.02 μg/kg/h, Group C), sufentanil plus low dose of dexmedetomidine (0.02 μg/kg/h each, Group D1), and sufentanil plus high dose of dexmedetomidine (0.04 μg/kg/h, Group D2). The patient-controlled analgesia was programmed to deliver a bolus dose of 0.5 ml, followed by an infusion of 2 ml/h and a lockout time of 10 min. The primary goal was to calculate the cumulative amount of self-administered sufentanil; the secondary goals were to estimate pain intensity using the numerical rating scale (NRS), level of sedation, the first bowel movement, concerning adverse effects as well as duration of postoperative hospital stay. Results The total consumption of sufentanil in group D1 and D2 were significantly lower than in group C during the first 8 h after surgery (P 0.05) between group D1 and D2. Compared with group C, the NRS scores at rest during first 8 h after surgery were significantly lower in group D1 (P 0.05). The time to first flatus was shorter in group D1 compared with the control group (P

Additional file 1: Figure S1. GST pull-down assays. GST or GST-PL-1 fusion protein generated by E. coli BL21 cells was purified by glutathione agarose resin, followed by incubation of the resin with HA-TSG101(A) or HA-Hrb27C (B) protein expressed in S2 cells. After washing with PBS, the bound proteins were analyzed by Western blotting with anti-HA antibodies. Data showed that neither TSG101 nor HRB27C could be pulled down by Prominin-like. Figure S2. Images of S2 cells of prominin-like knock down and control cells. Scale bar: 50μm. Upon dsRNA treatment, the morphology of the treated cells seemed have no obvious differences between prominin-like knock down and control cells from day 1 to day 4, except for the cell density.

The introduction of an additional acceptor to a typical donor-π bridge-acceptor (D-π-A) type porphyrin sensitizer results in a D-A-π-A featured porphyrin. Two porphyrins containing an additional acceptor with different electron-withdrawing abilities such as 2,3-diphenylquinoxaline ( DPQ ) for LP-11 and 2,1,3-benzothiadiazole ( BTD ) for LP-12 between the porphyrin core and the anchoring group have been synthesized for use as sensitizers in dye-sensitized solar cells (DSCs). Compared to LP-11 , LP-12 with the stronger electron-withdrawing additional acceptor BTD possesses better light harvesting properties with regard to red-shifted Q-band absorption and a broader IPCE spectrum, resulting in a greater short circuit photocurrent density ( J sc ) output. Interestingly, the steric hindrance of the DPQ group is favorable for suppressing dye aggregation, leading to a larger open-circuit voltage ( V oc ) value for LP-11 -based cell. However, the loss in V oc of LP-12 is overcompensated by an improvement in J sc . The optimized cell based on LP-12 achieves the better performance with a J sc of 15.51 mA cm −2 , a V oc of 674 mV, a fill factor (FF) of 0.7 and an overall power conversion efficiency (PCE) of 7.37% under standard AM 1.5 G irradiation. The findings provide a guidance for the future molecular design of highly efficient porphyrin sensitizers for use in DSCs.

Sphingosine 1-phosphate receptor 1 (S1PR1) plays a pivotal role in mediating trafficking and migration of immune cells. Previous reports also identify S1PR1 as an important susceptibility gene of asthma and other autoimmune disorders. However, little has been known about the regulatory mechanism of S1PR1 expression. Thus we systematically investigated the transcriptional regulation of S1PR1 in this study. Promoter activity of S1PR1 gene was carefully screened using series of pGL3-Basic reporter vectors, containing full length (range from transcription start site to upstream -1 kb region) or several truncated fragments of S1PR1 promoter. We identified an area (from -29 to -12 bp) of the S1PR1 promoter as the minimal promoter region. Bioinformatics prediction results showed that several transcription factors were recruited to these sites. EMSA and ChIP assays demonstrated the transcriptional factor STAT1 could bind to the region. We also found that the level of S1PR1 level was significantly reduced when STAT1 was knocked-down. Consistent with the reduction of S1PR1 caused by depletion of STAT1, overexpression of STAT1 resulted in up-regulation of S1PR1. In addition, both mRNA and protein levels of S1PR1 were increased when STAT1 was activated by IFN-γ, and decreased when STAT1 was inhibited by fludarabine. Besides, the levels of STAT1 and S1PR1 expression were positively correlated in peripheral blood leukocytes derived from 41 healthy individuals. Our study showed that transcription factor STAT1 could bind to upstream region of -29 bp to -12 bp of the S1PR1 promoter and stimulate the expression of S1PR1.

We report a case of a pregnant woman with nephrotic syndrome due to biopsy-proven focal segmental glomerulosclerosis (FSGS) whose fetus developed echogenic kidneys and severe oligohydramnios by 27 weeks of gestation. Maternal treatment with prednisone resulted in normalization of the amniotic fluid indices and resolution of fetal renal echogenicity. The newborn was noted to have transient renal dysfunction and proteinuria, resolving by 6 weeks postpartum. The transplacental passage of permeability factors is postulated to have caused both the fetal and newborn renal presentation, with significantly elevated levels of soluble urokinase-type plasminogen activator receptor (suPAR) noted in the cord blood. This case documents the transplacental maternal-fetal transmission of suPAR, demonstrating the potential for maternal-fetal transmission of deleterious, disease-causing entities, and adds to the differential diagnosis of fetal echogenic kidneys. Further, this is the first documentation of a fetal response to maternal systemic therapy.

Background This study explored the neural differentiation and therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) in a rat model of Parkinson's disease (PD). Methods The SHED were isolated from fresh dental pulp and were induced to differentiate to neurons and dopamine neurons by inhibiting similar mothers against dpp (SMAD) signaling with Noggin and increase conversion of dopamine neurons from SHED with CHIR99021, Sonic Hedgehog (SHH) and FGF8 in vitro. The neural-primed SHED were transplanted to the striatum of 6-hydroxydopamine (6-OHDA)–induced PD rats to evaluate their neural differentiation and functions in vivo. Results These SHED were efficiently differentiated to neurons (62.7%) and dopamine neurons (42.3%) through a newly developed method. After transplantation, the neural-induced SHED significantly improved recovery of the motor deficits of the PD rats. The grafted SHED were differentiated into neurons (61%), including dopamine neurons (22.3%), and integrated into the host rat brain by forming synaptic connections. Patch clamp analysis showed that neurons derived from grafted SHED have the same membrane potential profile as dopamine neurons, indicating these cells are dopamine neuron-like cells. The potential molecular mechanism of SHED transplantation in alleviating motor deficits of the rats is likely to be mediated by neuronal replacement and immune-modulation as we detected the transplanted dopamine neurons and released immune cytokines from SHED. Conclusion Using neural-primed SHED to treat PD showed significant restorations of motor deficits in 6-OHDA–induced rats. These observations provide further evidence that SHED can be used for cell-based therapy of PD.

Transient receptor potential channel 5 (TRPC5) is highly expressed in brain and kidney and mediates calcium influx and promotes cell migration. In the kidney, loss of TRPC5 function has been reported to benefit kidney filter dynamics by balancing podocyte cytoskeletal remodeling. However, in vivo gain-in-function studies of TRPC5 with respect to kidney function have not been reported. To address this gap, we developed two transgenic mouse models on the C57BL/6 background by overexpressing either wild-type TRPC5 or a TRPC5 ion-pore mutant. Compared with nontransgenic controls, neither transgenic model exhibited an increase in proteinuria at 8 months of age or a difference in LPS-induced albuminuria. Moreover, activation of TRPC5 by Englerin A did not stimulate proteinuria, and inhibition of TRPC5 by ML204 did not significantly lower the level of LPS-induced proteinuria in any group. Collectively, these data suggest that the overexpression or activation of the TRPC5 ion channel does not cause kidney barrier injury or aggravate such injury under pathologic conditions.

The kidneys play a vital role in the excretion of waste products and the regulation of electrolytes, maintenance of acid–base balance, regulation of blood pressure, and production of several hormones. Any alteration in the structure of the nephron (basic functional unit of the kidney) can have a major impact on the kidney’s ability to work efficiently. Progressive decline in kidney function can lead to serious illness and ultimately death if not treated by dialysis or transplantation. While there have been numerous studies that implicate lower nephron numbers as being an important factor in influencing susceptibility to developing hypertension and chronic kidney disease, a direct association has been difficult to establish because of three main limitations: 1) the large variation in nephron number observed in the human population; 2) no established reliable noninvasive methods to determine nephron complement; and 3) to date, nephron measurements have been done after death, which doesn’t adequately account for potential loss of nephrons with age or disease. In this review, we will provide an overview of kidney structure/function, discuss the current literature for both humans and other species linking nephron deficiency and cardio-renal complications, as well as describe the major molecular signaling factors involved in nephrogenesis that modulate variation in nephron number. As more detailed knowledge about the molecular determinants of nephron development and the role of nephron endowment in the cardio-renal system is obtained, it will hopefully provide clinicians the ability to accurately identify people at risk to develop CKD/hypertension and lead to a shift in patient care from disease treatment to prevention.

Cataracts are a major cause of blindness. The most common forms of cataracts are age- and UV-related and develop mostly in the elderly, while congenital cataracts appear at birth or in early childhood. The Dahl salt-sensitive (SS/Jr) rat is an extensively used model of salt-sensitive hypertension that exhibits concomitant renal disease. In the mid-1980s, cataracts appeared in a few animals in the Dahl S colony, presumably the result of a spontaneous mutation. The mutation was fixed and bred to establish the SS/Jr-Ctr substrain. The SS/Jr-Ctr substrain has been used exclusively by a single investigator to study the role of steroids and hypertension. Using a classical positional cloning approach, we localized the cataract gene with high resolution to a less than 1-Mbp region on chromosome 9 using an F1(SS/Jr-Ctr × SHR) × SHR backcross population. The 1-Mbp region contained only 13 genes, including 4 genes from the γ-crystallins (Cryg) gene family, which are known to play a role in cataract formation. All of the γ-crystallins were sequenced and a novel point mutation in the start codon (ATG → GTG) of the Crygd gene was identified. This led to the complete absence of the CRYGD protein in the eyes of the SS/Jr-Ctr strain. In summary, the identification of the genetic cause in this novel cataract model may provide an opportunity to better understand the development of cataracts, particularly in the context of hypertension.

Blood pressure high (BPH2) mice represent a novel genetic mouse model of hypertension that was derived from an 8-way cross of common inbred strains of mice. Mice derived from the original cross were segregated by blood pressure and then inbred to establish distinct mouse lines including the BPH2 line, a normotensive genetic control (blood pressure normal; BPN3) as well as a blood pressure low (BPL1) line. The goal of the present study was to test the hypothesis that the level of blood pressure in BPH2, BPN3, BPL1, and C57Bl/6 (normotensive inbred control) mice correlates with nephron endowment. Systolic blood pressure (SBP) was measured in male BPH2, BPN3, BPL1, and C57BL/6 mice (n=6/group) using tail-cuff plethysmography. SBP in BPH2, BPN3, BPL1, and C57BL/6 mice averaged 152±2, 117±1; 105±4; and 107±3 mm Hg, respectively. SBP was significantly greater (P0.05) between BPL1 and C57BL/6 mice and significantly (P0.05) in BPH2 and BPN3 mice and significantly (P