Hyperinsulinemic milieu elicits glomerular podocyte impairment and dysfunction via inducing GSK3beta hyperactivity

Background: Epidemiological evidence suggests that hyperinsulinemia or insulin resistance is a significant risk factor for the development of diabetic complications such as DKD. However, whether hyperinsulinemia per se plays a causative role in the development of diabetic kidney injury is unknown and was explored here. Methods: Pre-diabetic db/db mice were examined for serum insulin levels, urinary albumin to creatinine ratios and renal histology. Conditionally immortalized mouse podocytes were cultured under non-permissive conditions and exposed to high ambient insulin conditions, following GSK3beta silencing, ectopic expression of a constitutively active GSK3beta mutant (S9A), or treatment with a small molecule GSK3beta inhibitor tideglusib. Podocyte injury was assessed and signaling pathways examined.  Results: In pre-diabetic db/db mice, hyperinsulinemia was evident and associated with microalbuminuria and early signs of podocyte impairment, including diminished expression of homeostatic marker proteins like synaptopodin, as compared with db/m littermates. In vitro, prolonged exposure of differentiated podocytes to high ambient insulin induced podocytopathic changes, including cellular hypertrophy, loss of synaptopodin, and disruption of actin cytoskeleton integrity. This was associated with a desensitized insulin signaling and diminished inhibitory phosphorylation of GSK3beta, denoting GSK3beta hyperactivity. In pre-diabetic db/db mice, GSK3beta hyperactivity was confirmed in glomerular podocytes, correlating with the level of hyperinsulinemia or microalbuminuria. In cultured podocytes, ectopic expression of S9A caused podocyte hypertrophy and podocytopathic changes, reminiscent of the harmful effect of the hyperinsulinemic milieu. Conversely, GSK3beta knockdown mitigates podocyte injury elicited by hyperinsulinemic milieu. This protective effect was mimicked by the small molecule inhibitor tideglusib. Conclusions: GSK3beta hyperactivity is required and sufficient for Hyperinsulinemic milieu-elicited glomerular podocyte impairment and dysfunction.       &nbsp

Penalty-based Methods for Simple Bilevel Optimization under H\"{o}lderian Error Bounds

This paper investigates simple bilevel optimization problems where the upper-level objective minimizes a composite convex function over the optimal solutions of a composite convex lower-level problem. Existing methods for such problems either only guarantee asymptotic convergence, have slow sublinear rates, or require strong assumptions. To address these challenges, we develop a novel penalty-based approach that employs the accelerated proximal gradient (APG) method. Under an $\alpha$-H\"{o}lderian error bound condition on the lower-level objective, our algorithm attains an $(\epsilon,l_F^{-\beta}\epsilon^{\beta})$-optimal solution for any $\beta>0$ within $\mathcal{O}\left(\sqrt{\frac{L_{f_1}}{\epsilon }}\right)+\mathcal{O}\left(\sqrt{\frac{l_F^{\max\{\alpha,\beta\}}L_{g_1}}{\epsilon^{\max\{\alpha,\beta\}}}}\right)$ iterations, where $l_F$, $L_{f_1}$ and $L_{g_1}$ denote the Lipschitz constants of the upper-level objective, the gradients of the smooth parts of the upper- and lower-level objectives, respectively. If the smooth part of the upper-level objective is strongly convex, the result improves further. We also establish the complexity results when both upper- and lower-level objectives are general convex nonsmooth functions. Numerical experiments demonstrate the effectiveness of our algorithms

Lower-level Duality Based Reformulation and Majorization Minimization Algorithm for Hyperparameter Optimization

Hyperparameter tuning is an important task of machine learning, which can be formulated as a bilevel program (BLP). However, most existing algorithms are not applicable for BLP with non-smooth lower-level problems. To address this, we propose a single-level reformulation of the BLP based on lower-level duality without involving any implicit value function. To solve the reformulation, we propose a majorization minimization algorithm that marjorizes the constraint in each iteration. Furthermore, we show that the subproblems of the proposed algorithm for several widely used hyperparameter turning models can be reformulated into conic programs that can be efficiently solved by the off-the-shelf solvers. We theoretically prove the convergence of the proposed algorithm and demonstrate its superiority through numerical experiments.Comment: Accepted by AISTATS 202

The presence of pesticide residue in farmer market produce: thiabendazole residues in various produce sold at local farmers’ markets

Background: Thiabendazole is a pesticide that is mainly used after harvesting and directly applied to produce such as citrus fruits, apples, pears, bananas, mangos, corn, carrots and potatoes in the form of a spray or dip. The most common and most likely route of exposure to pesticide for the average person is through their diet. Studies have shown that the health risk of regular consumption of pesticide residue through produce is linked with disruption to various functions in the body, such as reproductive, developmental and hormone irregularity. The following study tests whether fruits and vegetables sold at farmers markets contain Thiabendazole and if they are below the acceptable Maximum Residue Limits (MRLs) set by Health Canada. Methods: A QuEChERS method and solid phase extraction was used to recover Thiabendazole from various fruits and vegetables. The gas chromatography was used to analyze all samples and a calibration curve was produced to identify the concentration of Thiabendazole. Results: Thiabendazole was detected in all of the citrus fruit samples, but was below detectable limits for all other fruits and vegetables. All Thiabendazole levels were below the Maximum Residue Level allowed by Health Canada. Conclusion: The various fruits and vegetables analyzed are all below the MRL, with only the citrus fruits having detectable concentrations. However, since the citrus fruits were imported, further studies are required on different pesticide compounds to determine if locally grown produce meet the MRL for other pesticide compounds. &nbsp

A Nomogram for Predicting Overall Survival of Patients With Primary Spinal Cord Glioblastoma

Objective Primary spinal cord glioblastoma (PSCGBM) is a rare malignancy with a poor prognosis. To date, no prognostic nomogram for this rare disease was established. Hence, we aimed to develop a nomogram to predict overall survival (OS) of PSCGBM. Methods Clinical data of patients with PSCGBM was retrospectively collected from the neurosurgery department of Soochow University Affiliated Second Hospital and the Surveillance Epidemiology and End Results database. Information including age, sex, race, tumor extension, extent of resection, adjuvant treatment, marital status, income, year of diagnosis and months from diagnosis to treatment were recorded. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors for PSCGBM. A nomogram was constructed to predict 1-year, 1.5-year, and 2-year OS of PSCGBM. Results A total of 132 patients were included. The 1-year, 1.5-year, and 2-year OS were 45.5%, 29.5%, and 18.9%, respectively. Four variables: age groups, tumor extension, extent of resection, and adjuvant therapy, were identified as independent prognostic factors. The nomogram showed robust discrimination with a C-index value for the prediction of 1-year OS, 1.5-year OS, and 2-year of 0.71 (95% confidence interval [CI], 0.61–0.70), 0.72 (95% CI, 0.62–0.70), and 0.70 (95% CI, 0.61–0.70), respectively. The calibration curves exhibited high consistencies between the predicted and observed survival probability in this cohort. Conclusion We have developed and internally validated a nomogram for predicting the survival outcome of PSCGBM for the first time. The nomogram has the potential to assist clinicians in making individualized predictions of survival outcome of PSCGBM

Dielectric relaxation, resonance and scaling behaviors in Sr3Co2Fe24O41 hexaferrite

The dielectric properties of Z-type hexaferrite Sr(3)Co(2)Fe(24)O(41) (SCFO) have been investigated as a function of temperature from 153 to 503 K between 1 and 2 GHz. The dielectric responses of SCFO are found to be frequency dependent and thermally activated. The relaxation-type dielectric behavior is observed to be dominating in the low frequency region and resonance-type dielectric behavior is found to be dominating above 10(8) Hz. This frequency dependence of dielectric behavior is explained by the damped harmonic oscillator model with temperature dependent coefficients. The imaginary part of impedance (Z″) and modulus (M″) spectra show that there is a distribution of relaxation times. The scaling behaviors of Z″ and M″ spectra further suggest that the distribution of relaxation times is temperature independent at low frequencies. The dielectric loss spectra at different temperatures have not shown a scaling behavior above 10(8) Hz. A comparison between the Z″ and the M″ spectra indicates that the short-range charges motion dominates at low temperatures and the long-range charges motion dominates at high temperatures. The above results indicate that the dielectric dispersion mechanism in SCFO is temperature independent at low frequencies and temperature dependent at high frequencies due to the domination of resonance behavior

Effects of different gonadotropin preparations in GnRH antagonist protocol for patients with polycystic ovary syndrome during IVF/ICSI: a retrospective cohort study

PurposeTo compare the effects of recombinant FSH alfa (rFSH-alfa), rFSH-beta, highly purified human menopausal gonadotropin (HP-hMG) and urinary FSH (uFSH) in women with polycystic ovarian syndrome who have undertaken the GnRH antagonist protocol during IVF/ICSI treatment.MethodA single-center retrospective cohort study including women with PCOS who received the GnRH antagonist protocol from January 2019 to July 2022 was conducted. Patients were divided into rFSH-alfa group, HP-hMG group, uFSH group, and rFSH-beta group, and the number of oocytes retrieved, clinical pregnancy rate of the fresh cycle (primary outcomes), embryo quality, and severe OHSS rate (secondary outcomes) were compared.ResultsNo statistical differences were found among the four groups in fresh cycle clinical pregnancy rate (p=0.426), nor in the subgroup analyses. The HP-hMG group had a smaller number of oocytes retrieved and a higher high-quality D3 embryo rate than the three FSH groups (p<0.05). No statistical differences were found among the four groups in the severe OHSS rate (p=0.083).ConclusionFor women with PCOS undergoing the GnRH antagonist protocol, the clinical pregnancy rates of fresh IVF/ICSI-ET cycle are similar for all four types of Gn. With a lower risk of OHSS and a similar number of high-quality and available embryos, HP-hMG may have an advantage in the PCOS population

Vertical Interface Induced Dielectric Relaxation in Nanocomposite (BaTiO3)1-x:(Sm2O3)x Thin Films

Vertical interfaces in vertically aligned nanocomposite thin films have been approved to be an effective method to manipulate functionalities. However, several challenges with regard to the understanding on the physical process underlying the manipulation still remain. In this work, because of the ordered interfaces and large interfacial area, heteroepitaxial (BaTiO(3))(1-x):(Sm(2)O(3))(x) thin films have been fabricated and used as a model system to investigate the relationship between vertical interfaces and dielectric properties. Due to a relatively large strain generated at the interfaces, vertical interfaces between BaTiO(3) and Sm(2)O(3) are revealed to become the sinks to attract oxygen vacancies. The movement of oxygen vacancies is confined at the interfaces and hampered by the misfit dislocations, which contributed to a relaxation behavior in (BaTiO(3))(1-x):(Sm(2)O(3))(x) thin films. This work represents an approach to further understand that how interfaces influence on dielectric properties in oxide thin films