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The predictive nature of the hippocampus is thought to be useful for memory-guided cognitive behaviors. Inspired by the reinforcement learning literature, this notion has been formalized as a predictive map called the successor representation (SR). The SR captures a number of observations about hippocampal activity. However, the algorithm does not provide a neural mechanism for how such representations arise. Here, we show the dynamics of a recurrent neural network naturally calculate the SR when the synaptic weights match the transition probability matrix. Interestingly, the predictive horizon can be flexibly modulated simply by changing the network gain. We derive simple, biologically plausible learning rules to learn the SR in a recurrent network. We test our model with realistic inputs and match hippocampal data recorded during random foraging. Taken together, our results suggest that the SR is more accessible in neural circuits than previously thought and can support a broad range of cognitive functions.

Background: The binding of anti-phospholipase A2 receptor (anti-PLA2R) antibody to podocyte and complement activation is the mechanisms of idiopathic membranous nephropathy (IMN). C5a, a complement activation end product, is a strong inflammatory cell stimulator and can influence the behavior of T cells and dendritic cells. This study examined the etiology–disease relationship and significance of auto-antibody and C5a with short-term remission. Method: Plasma anti-PLA2R antibody and C5a were measured with the blood samples that were collected when patients were admitted for renal biopsy. The deposition of IgA, IgG, IgM, C1q and C3c in glomerulus was graded according to immunofluorescence staining. The relationship of anti-PLA2R antibody with C5a, glomerular immunoglobulin and complement deposition was examined. Antibody and C5a levels as predictors of short-term remission were also examined. Results: In 72 IMN patients, 50 patients had positive plasma anti-PLA2R antibody. The antibody had positive correlation to proteinuria. Patients with high grade IgG or C3c, but not IgA/IgM/C1q, deposition had higher anti-PLA2R antibody titers. C5a was increased in IMN patients, but had no correlation with anti-PLA2R antibody or proteinuria. The analysis revealed that C5a, not initial anti-PLA2R antibody, was a predictor associated with 12-month remission in patients receiving immunosuppression with multivariate-adjusted OR 0.74 (95% CI, 0.58–0.94, P = 0.01). Conclusion: This study provides indirect evidences of etiology–disease relationship of anti-PLA2R antibody in IMN patients. The role of C5a, a predictor of remission, in the disease course of MN and the influences on inflammatory cells in MN patients is worth to be clarified. Keywords: C5a, Disease activity, Membranous nephropathy, Anti-phospholipase A2 receptor antibody, Prognosis

Sarcopenia is characterized as an age-related loss of muscle mass that results in negative health consequences such as decreased strength, insulin resistance, slowed metabolism, increased body fat mass, and a substantially diminished quality of life. Additionally, conditions such as high blood sugar are known to further exacerbate muscle degeneration. Skeletal muscle development and regeneration following injury or disease are based on myoblast differentiation. Bioactive peptides are biologically active peptides found in foods that could have pharmacological functions. The aim of this paper was to investigate the effect of decapeptide DI-10 from the potato alcalase hydrolysate on myoblast differentiation, muscle protein synthesis, and mitochondrial biogenesis in vitro. The treatment of C2C12 myoblasts with DI-10 (10 µg/mL) did not induce cell death. DI-10 treatment in C2C12 myoblast cells accelerates the phosphorylation of promyogenic kinases such as ERK, Akt and mTOR proteins in a dose-dependent manner. DI-10 improves myotubes differentiation and upregulates the expression of myosin heavy chain (MyHC) protein in myoblast cells under differentiation medium with high glucose. DI-10 effectively increased the phosphorylation of promyogenic kinases Akt, mTOR, and mitochondrial-related transcription factors AMPK and PGC1α expression under hyperglycemic conditions. Further, decapeptide DI-10 decreased the expression of Murf1 and MAFbx proteins, which are involved in protein degradation and muscle atrophy. Our reports support that decapeptide DI-10 could be potentially used as a therapeutic candidate for preventing muscle degeneration in sarcopenia.

Suggestion for the management of idiopathic membranous nephropathy (IMN) includes 6 months of observation, followed with steroid plus alkylating agent. However, delayed immunosuppression exposes the kidneys to persistent damage. This study aimed to examine the benefit of early immunosuppression in IMN patients. Methods: A retrospective study was performed. From 1993 to 2013, 161 IMN patients were enrolled. Patients receiving immunosuppression within 6 months after diagnosis were classified as initial-treatment group, whereas other patients as initial-no-treatment group. The clinical outcomes and complication were examined. Result: Patients in the initial-treatment group had lower serum albumin concentration, less diabetes, and were younger. Steroid monotherapy is the main immunosuppression (64.5%) in this group. The initial-treatment group had a higher complete and partial remission rate than the initial-no-treatment group 6 months (52.9% vs. 35.0%, p = 0.05) and 12 months (71.1% vs. 45.0%, p = 0.003) after diagnosis. A similar result was seen between initial-steroid monotherapy and initial-no-treatment patients. Early immunosuppression is an independent predictor of remission within 1 year [hazard ratio (HR) = 2.09; 95% confidence interval (CI) = 1.25–3.49; p = 0.005] and estimated glomerular filtration rate (eGFR) decline over 50% during the follow-up. (HR = 0.33; 95% CI = 0.13–0.86; p = 0.02). The initial-treatment group also had a low frequency of eGFR decline over 50% (p = 0.001) and low combined end-stage renal disease/mortality (p = 0.001) compared with the initial-no-treatment group, but without more immunosuppression-related complication. Conclusion: In contrast to Western countries, early immunosuppression (even steroid monotherapy) in our patients is associated with better remission in the 1st year and renal preserve. Further randomized controlled trials are needed to clarify the benefit of early immunosuppression in IMN patients, especially with oriental ethnic background.

Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

Abstract Loss-of-function mutations in the human gene encoding the neuron-specific Ca2+ channel CaV2.1 are linked to the neurological disease episodic ataxia type 2 (EA2), as well as neurodevelopmental disorders such as developmental delay and developmental epileptic encephalopathy. Disease-associated CaV2.1 mutants may exhibit defective proteostasis and promote endoplasmic reticulum (ER)-associated degradation of their wild-type (WT) counterpart in a dominant-negative manner. The E3 ubiquitin ligase RNF138 was previously shown to mediate EA2-related aberrant degradation of CaV2.1 at the ER. Herein we aimed to elucidate the ER proteostasis mechanism of CaV2.1. The peptidyl-prolyl cis/trans isomerase, NIMA-interacting 1 (Pin1) was identified as a novel neuronal CaV2.1 binding partner that promoted polyubiquitination and proteasomal degradation of CaV2.1. Suppression of endogenous Pin1 level with either shRNA knockdown or the Pin1 inhibitor all-trans retinoic acid (ATRA) enhanced endogenous CaV2.1 protein level in neurons, and attenuated ER-associated degradation of CaV2.1 WT and EA2-causing mutants. Detailed mutation analyses suggested that Pin1 interacted with specific phosphorylated serine/threonine-proline motifs in the intracellular II-III loop and the distal carboxy-terminal region of human CaV2.1. We further generated Pin1-insensitive CaV2.1 constructs and demonstrated that, during ER quality control, Pin1 served as an upstream regulator of CaV2.1 polyubiquitination and degradation by RNF138. Pin1 regulation was required for the dominant-negative effect of EA2 missense mutants, but not nonsense mutants, on CaV2.1 WT protein expression. Our data are consistent with the idea that CaV2.1 proteostasis at the ER, as well as dominant-negative suppression of disease-causing loss-of-function mutants on CaV2.1 WT, entail both Pin1/RNF138-dependent and -independent mechanisms.

Coenzyme Q (CoQ, aka ubiquinone) is a key component of the mitochondrial electron transport chain (ETC) and membrane-incorporated antioxidant. CoQ10 deficiencies encompass a heterogeneous spectrum of clinical phenotypes and can be caused by hereditary mutations in the biosynthesis pathway or result from pharmacological interventions such as HMG-CoA Reductase inhibitors, and statins, which are widely used to treat hypercholesterolemia and prevent cardiovascular disease. How CoQ deficiency affects individual tissues and cell types, particularly mitochondrial-rich ones such as brown adipose tissue (BAT), has remained poorly understood. Here we show that pharmacological and genetic models of BAT CoQ deficiency show altered respiration that can only in part be explained by classical roles of CoQ in the respiration chain. Instead, we found that CoQ strongly impacts brown and beige adipocyte respiration via the regulation of uncoupling protein 1 (UCP1) expression. CoQ deficiency in BAT robustly decreases UCP1 protein levels and uncoupled respiration unexpectedly, resulting in increased inner mitochondrial membrane potential and decreased ADP/ATP ratios. Suppressed UCP1 expression was also observed in a BAT-specific in vivo model of CoQ deficiency and resulted in enhanced cold sensitivity. These findings demonstrate an as yet unappreciated role of CoQ in the transcriptional regulation of key thermogenic genes and functions.

Glomerular capillary remodeling is an essential process in the development of glomerular hypertrophy. Angiopoietins, which are important regulators in angiogenesis, plays a role in the development of glomerulus during embryogenesis. Here, we evaluated the influence of angiopoietin on glomerular components and hypertrophy after uninephrectomy in adult male BALB/c mice. The actions of angiopoietin 1 or 2 were systemically antagonized by the subcutaneous administration of antagonists. We observed that the angiopoietin system was activated after uninephrectomy, and that the blockade of angiopoietin 1 or 2 decreased the activation of the angiopoietin receptor--tyrosine kinase with Ig and EGF homology domains-2--and attenuated the development of glomerular and podocyte hypertrophy. The increase in endothelial density staining (anti-CD31) following uninephrectomy was also reversed by angiopoietin 1 or 2 blockades. Glomerular basement thickness and foot process width were observed to decrease in the angiopoietin blockade groups. These changes were associated with the down regulation of the expression of genes for the glomerular matrix and basement membrane, including collagen type IV α1, collagen type IV α2, collagen type IV α5, and laminin α5. Thus, angiopoietin 1 or 2 may play an important role in the development of glomerular hypertrophy after uninephrectomy. A blockade of the angiopoietin system not only influenced the endothelium but also the podocyte, leading to diminished gene expression and morphological changes after uninephrectomy.

Impaired white adipose tissue (WAT) function has been recognized as a critical early event in obesity-driven disorders, but high buoyancy, fragility, and heterogeneity of primary adipocytes have largely prevented their use in drug discovery efforts highlighting the need for human stem cell-based approaches. Here, human stem cells are utilized to derive metabolically functional 3D adipose tissue (iADIPO) in a microphysiological system (MPS). Surprisingly, previously reported WAT differentiation approaches create insulin resistant WAT ill-suited for type-2 diabetes mellitus drug discovery. Using three independent insulin sensitivity assays, i.e., glucose and fatty acid uptake and suppression of lipolysis, as the functional readouts new differentiation conditions yielding hormonally responsive iADIPO are derived. Through concomitant optimization of an iADIPO-MPS, it is abled to obtain WAT with more unilocular and significantly larger (≈40%) lipid droplets compared to iADIPO in 2D culture, increased insulin responsiveness of glucose uptake (≈2-3 fold), fatty acid uptake (≈3-6 fold), and ≈40% suppressing of stimulated lipolysis giving a dynamic range that is competent to current in vivo and ex vivo models, allowing to identify both insulin sensitizers and desensitizers.