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Rare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson's disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

Background and Purpose: The recently introduced Pipeline Flex Embolization Device with Shield Technology (Pipeline Shield) is the third generation of Pipeline flow-diverter devices. It has a new stent-surface modification, which reduces thrombogenicity. We aimed to evaluate clinical and radiographic (safety and efficacy) outcomes of the Pipeline Shield., Materials and Methods: The 30-day and 1-year mortality and morbidity rates and the 6- and 18-month radiographic aneurysm occlusion outcomes for procedures performed between March 2016 and January 2018 were analyzed. 3D-TOF-MRA was used for follow-up., Results: Forty-four attempted Pipeline Shield procedures were performed for 41 patients with 44 target aneurysms (total of 52 aneurysms treated). A total of 88.5% of devices were inserted in the anterior circulation, and 11.5%, in the posterior circulation; 49/52 (94.2%) aneurysms were saccular; and 1/52 (1.9%) was fusiform. One (1.9%) aneurysm was an iatrogenic pseudoaneurysm, and 1 (1.9%) was a dissecting aneurysm. Seventy-one percent (35/49) of the saccular aneurysms were wide-neck (neck, >4 mm), 34.6% (18/52) were large (≥10 mm), and 3.8% (2/52) were giant (≥25 mm). The mean aneurysm sac maximal diameter was 9.0 mm, and the mean neck width was 5.0 mm. The cumulative mortality and morbidity rates were 2.3% and 6.8% at 1 year, respectively. The adequate occlusion rate was 78.8% at 6 months and 90.3% at 18 months., Conclusions: In this pragmatic and non-industry-sponsored study, the occlusion rates and safety outcomes were similar to those seen in previously published studies with flow-diverter devices and earlier generation Pipeline Embolization Devices., (© 2019 by American Journal of Neuroradiology.)

Atypical parkinsonian disorders (APDs) comprise a group of neurodegenerative diseases with heterogeneous clinical and pathological features. Most APDs are sporadic, but rare familial forms have also been reported. Epidemiological and post-mortem studies associated APDs with oxidative stress and cellular protein aggregates. Identifying molecular mechanisms that translate stress into toxic protein aggregation and neurodegeneration in APDs is an active area of research. Recently, ribonucleic acid (RNA) stress granule (SG) pathways were discussed to be pathogenically relevant in several neurodegenerative disorders including APDs. Using whole genome sequencing, mRNA expression analysis, transfection assays and cell imaging, we investigated the genetic and molecular basis of a familial neurodegenerative atypical parkinsonian disorder. We investigated a family with six living members in two generations exhibiting clinical symptoms consistent with atypical parkinsonism. Two affected family members suffered from parkinsonism that was associated with ataxia. Magnetic resonance imaging (MRI) of these patients showed brainstem and cerebellar atrophy. Whole genome sequencing identified a heterozygous stop-gain variant (c.C811T; p.R271X) in the Poly(A) binding protein, cytoplasmic 4-like (PABPC4L) gene, which co-segregated with the disease in the family. In situ hybridization showed that the murine pabpc4l is expressed in several brain regions and in particular in the cerebellum and brainstem. To determine the functional impact of the stop-gain variant in the PABPC4L gene, we investigated the subcellular localization of PABPC4L in heterologous cells. Wild-type PABPC4L protein localized predominantly to the cell nucleus, in contrast to the truncated protein encoded by the stop-gain variant p.R271X, which was found homogeneously throughout the cell. Interestingly, the wild-type, but not the truncated protein localized to RasGAP SH3 domain Binding Protein (G3BP)-labeled cytoplasmic granules in response to oxidative stress induction. This suggests that the PABPC4L variant alters intracellular distribution and possibly the stress granule associated function of the protein, which may underlie APD in this family. In conclusion, we present genetic and molecular evidence supporting the role of a stop-gain PABPC4L variant in a rare familial APD. Our data shows that the variant results in cellular mislocalization and inability of the protein to associate with stress granules.

Background and Objective: Modern sulfonylureas like glimepiride offer effective glycemic control with extrapancreatic benefits and good tolerability. The objective of the present study was to evaluate and compare safety and efficacy of glimepiride and sitagliptin in combination with metformin in patients with type 2 diabetes mellitus (T2DM)., Methods: In this open-label, randomized, comparative, multicenter study, a total of 305 T2DM patients who were either drug naïve or uncontrolled on metformin were randomized to glimepiride 1 or 2 mg/sustained-release metformin 1000 mg once daily (glimepiride group, n = 202) or sitagliptin 50 mg/metformin 500 mg twice daily (sitagliptin group, n = 103) for 12 weeks. Primary endpoint was change in glycosylated hemoglobin (HbA1c). Secondary endpoints were change in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), body mass index (BMI) and to assess overall safety profile., Results: At 12 weeks, there was a statistically significant difference in the mean HbA1c reduction in glimepiride group (0.42%) as compared to sitagliptin group (0.30%) ( P = 0.001). Mean reduction in FPG and PPG was also statistically significant in the glimepiride group as compared to the sitagliptin group ( P = 0.008). There was no significant difference in terms of change in BMI (0.07 ± 0.39 kg/m 2 vs. 0.08 ± 0.31 kg/m 2 ) in glimepiride and sitagliptin groups, respectively, ( P = 0.644) between both the groups. The incidences of hypoglycemic events were also comparable among both the groups., Conclusion: In T2DM patients, glimepiride/metformin combination exhibited significant reduction in glycemic parameters as compared to sitagliptin/metformin combination. Moreover, there was no significant difference between both the groups in terms of change in BMI and incidence of hypoglycemia., Competing Interests: There are no conflicts of interest.

Interoception is the sensing of physiological signals originating inside the body, such as hunger, pain and heart rate. People with greater sensitivity to interoceptive signals, as measured by, for example, tests of heart beat detection, perform better in laboratory studies of risky decision-making. However, there has been little field work to determine if interoceptive sensitivity contributes to success in real-world, high-stakes risk taking. Here, we report on a study in which we quantified heartbeat detection skills in a group of financial traders working on a London trading floor. We found that traders are better able to perceive their own heartbeats than matched controls from the non-trading population. Moreover, the interoceptive ability of traders predicted their relative profitability, and strikingly, how long they survived in the financial markets. Our results suggest that signals from the body - the gut feelings of financial lore - contribute to success in the markets.

Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation., Case: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC. A detailed family history revealed her mother had died of ACC and her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 expression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1-3) in the proband and her sister., Conclusion: Our findings provide strong support for the recent proposal that ACC should be considered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes.

Background:Moringa oleifera leaf is used for diabetes due to its pharmacologic effects. Patients with hyperglycemia experience beta cell destruction. However, no research on risk awareness has been done to ascertain its safety. The present study describes the antidiabetic effect of Moringa oleifera leaf, such as the protection of pancreatic beta cells and the induction of glycogen synthesis, before addressing the secondary effects of diabetes, such as hepatic and renal toxicity. Methods: Forty‐five Wistar rats weighed 160 ± 10 g were divided into nine groups. All animal operations complied with the National Institute of Health (NIH) guidelines for the care and use of laboratory animals as approved by the Animal Ethical Committee, University of Jos. Group I was normal control and Group II was diabetic animals induced with alloxan. Insulin and extract doses of 200, 400, and 800 mg/kg were given to diabetic Groups III‐VI. Normal animals in Groups VII–IX were given extract at doses of 200, 400, and 800 mg/kg for 28 days. Tissues were retrieved for biochemical and histological investigations using standard techniques. Results: There was decrease relative body weight of diabetic animals (95.50 ± 5.50) when compared to normal control (142.75 ± 20.08) with increased levels of urea (control 6.13 ± 0.523 and diabetes 29.23 ± 1.267) and creatinine (control 0.70 ± 0.057 and diabetes 2.13 ± 0.185). Histology of the liver and pancreas also points to organ damage due to hyperglycemia. However, oral administration of extract showed antidiabetic effect with protection of pancreatic beta cells and the induction of glycogen synthesis, no glycogen was deposited in the liver, addressing the secondary effects of diabetes, such as hepatic and renal toxicity. Further discovery revealed that extract elevated antioxidant enzyme expression. Conclusion: Leaf extract from Moringa oleifera reduces blood sugar and lessens the damage caused by hyperglycemia in the pancreas and liver. [ABSTRACT FROM AUTHOR]

Building envelopes and indoor environments exhibit thermal inertia, forming a virtual energy storage system in conjunction with the building air conditioner (AC) system. This system represents a current demand response resource for building electricity use. Thus, this study centers on the CatBoost algorithm within machine learning (ML) technology, utilizing the LASSO regression model for feature selection and applying the Optuna framework for hyperparameter optimization (HPO) to develop a cost-optimal control method for minimizing building AC loads. This method addresses the challenges associated with traditional load forecasting and control methods, which are often impacted by environmental temperature, building parameters, and user behavior uncertainties. These methods struggle to accurately capture the complex dynamics and nonlinear relationships of AC operations, making it difficult to devise AC operation and virtual energy storage scheduling strategies effectively. The proposed method was applied and validated using a case study of an office building in Nanjing, China. The prediction results showed coefficient of variation in root mean square error (CV-RMSE) values of 6.4% and 2.2%. Compared with the original operating conditions, the indoor temperature remained within a comfortable range, the AC load was reduced by 5.25%, and the operating energy costs were reduced by 24.94%. These results demonstrate that the proposed method offers improved computational efficiency, enhanced model performance, and economic benefits. [ABSTRACT FROM AUTHOR]

In recent years, research has noted the increasing prevalence of mental health problems among university students. The current mental health needs of the university population, along with the multitude of stressors they face, have increased the importance of examining their psychological well-being and determining the personal resources that effectively promote it. In this context, the present research aims to analyze the roles of psychological capital (PsyCap) and coping strategies as personal resources that are significantly related to the psychological well-being (PWB) of university students. Specifically, the mediating roles of various coping strategies (both adaptive and maladaptive) in the relationship between PsyCap and PWB are explored. The study involves 391 university students from Spain. The results show partial mediation effects of adaptive coping strategies (cognitive restructuring and social support) on the relationship between PsyCap and PWB. Likewise, PsyCap is shown to be a direct positive predictor of adaptive coping strategies and PWB, as well as a direct negative predictor of maladaptive coping strategies (self-criticism). Therefore, it is concluded that PsyCap and some adaptive coping strategies serve as valuable personal resources that predict PWB in university students. PsyCap is also associated with a lower tendency to engage in maladaptive coping strategies, such as self-criticism. Similarly, the use of cognitive restructuring and/or social support is related to high levels of PWB among university students. [ABSTRACT FROM AUTHOR]

Background: Coccoloba uvifera L. (Family: Polygonaceae) known as sea grape is natively distributed in middle and south America. The aqueous leaf extract showed inhibitory activities against α-glucosidase and α-amylase in previous reports. Moreover, the hydroalcoholic leaves extract ameliorated hyperglycemia in the oral glucose tolerance test. Despite these promising results, the extracts used in these studies were not standardized, nor was their mechanism of action elucidated. The current study aims to standardize the ethanolic C. uvifera leaves extract (CU) using markers, and assess its ameliorative activity against diabetes and its hepatoprotective activity against diabetic complications. Results: Standardized leaves' ethanolic extract contained 0.09 ± 0.00057 and 0.23 ± 0.0011 mg/g gallic acid and rutin, respectively, as estimated by HPLC. Administration of CU (100, 200 and 400 mg/kg) for 6 weeks ameliorated DM manifestations in STZ-induced diabetic rats in a dose-dependent manner. The ethanolic extract reduced fasting blood glucose, increased serum insulin and reduced elevated liver enzymes. CU counteracted oxidative stress, promoted glucose metabolizing enzymes and reduced gluconeogenesis enzymes. The underlying mechanism involved increased expression of IR, IRS-1, IRS-2 and GLUT2 in liver tissue through activation of PI3K/AKT signaling. The histopathological study demonstrated reduced inflammation and hepatocyte degeneration. Conclusion: CU could be used as a promising antidiabetic drug with hepatoprotective activity in diabetes hepatic complications. The standardized CU ethanolic extract should be further assessed clinically alone or in combination with other antidiabetic remedies. [ABSTRACT FROM AUTHOR]

The current study proceeded to reduce the environmental hazards spreading worldwide due to synthetic dyes. To overcome these problems, eco-friendly natural dyes are introduced as alternative sources of synthetic dyes. The present study was focused on exploring the bio-colorant of the aqueous and acidic extract of the bark of Melia azedarach L. for the dyeing of both silk and cotton samples. The results of the extraction medium specified that the aqueous extract gave maximum colorant solubility and upon fabric dyeing produced higher color strength in contrast to the acidic medium. The optimization experimentation data showed that excellent color strength of silk fabric was found at 45 min dyeing time duration, in 35:1 mL dye extract, and using 2% salt (NaCl) as an exhausting agent, whereas cotton fabric showed the maximum K/S value at 60 min dyeing time, in a 45:1 mL liquor ratio, and with the use of 2% salt. Bio-mordants produce different shades on both fabrics. Bio-mordanting experiments on silk revealed that pre-mordanting with 2% turmeric and 3% pomegranate, and post-mordanting using 3% turmeric and 2% pomegranate produced a darker shade. In the case of cotton, the pre-mordanted samples with 2% turmeric and 3% pomegranate and the post-mordanted samples with 4% turmeric and 4% pomegranate gave the highest color strengths. All the mordanted samples gave excellent fastness ratings. Overall, it has been found that Bakain bark proved to be an excellent source of tannin. The result of this study showed that it could be a cost-effective and eco-friendly dye source for textile progress. [ABSTRACT FROM AUTHOR]

Spiking neural networks and neuromorphic hardware platforms that simulate neuronal dynamics are getting wide attention and are being applied to many relevant problems using Machine Learning. Despite a well-established mathematical foundation for neural dynamics, there exists numerous software and hardware solutions and stacks whose variability makes it difficult to reproduce findings. Here, we establish a common reference frame for computations in digital neuromorphic systems, titled Neuromorphic Intermediate Representation (NIR). NIR defines a set of computational and composable model primitives as hybrid systems combining continuous-time dynamics and discrete events. By abstracting away assumptions around discretization and hardware constraints, NIR faithfully captures the computational model, while bridging differences between the evaluated implementation and the underlying mathematical formalism. NIR supports an unprecedented number of neuromorphic systems, which we demonstrate by reproducing three spiking neural network models of different complexity across 7 neuromorphic simulators and 4 digital hardware platforms. NIR decouples the development of neuromorphic hardware and software, enabling interoperability between platforms and improving accessibility to multiple neuromorphic technologies. We believe that NIR is a key next step in brain-inspired hardware-software co-evolution, enabling research towards the implementation of energy efficient computational principles of nervous systems. NIR is available at neuroir.org Neuromorphic software and hardware solutions vary widely, challenging interoperability and reproducibility. Here, authors establish a representation for neuromorphic computations in continuous time and demonstrate support across 11 platforms. [ABSTRACT FROM AUTHOR]

This study addresses the magnetohydrodynamic flow of a squeezed ternary nanofluid between two horizontal parallel Riga plates. The importance of this problem lies in understanding the complex interactions between magnetic fields, nanofluid dynamics, and heat transfer, which are crucial for optimizing thermal management systems. This study utilizes a numerical approach, specifically a collocation method implemented in MATLAB, to solve the governing equations with high precision. Key results acquired indicate that the magnetic field and Riga plate actuator significantly enhance fluid velocity, whereas the variation in thermal conductivity, radiation, and viscous dissipation increases the temperature distribution. Quantitative analysis illustrates the impact of all these factors on skin friction and Nusselt number. Sensitivity analysis using the response surface methodology exhibits the conditions for optimized heat transfer. The novelty of this work lies in its comprehensive analysis of the magnetohydrodynamic flow in the presence of a microcantilever sensor, which provides deep understanding of optimization of heat transfer rates. This research offers a detailed examination of the combined effects of various physical phenomena and also validates them through graphical comparisons with existing studies. [ABSTRACT FROM AUTHOR]

Risk taking is central to human activity. Consequently, it lies at the focal point of behavioral sciences such as neuroscience, economics, and finance. Many influential models from these sciences assume that financial risk preferences form a stable trait. Is this assumption justified and, if not, what causes the appetite for risk to fluctuate? We have previously found that traders experience a sustained increase in the stress hormone cortisol when the amount of uncertainty, in the form of market volatility, increases. Here we ask whether these elevated cortisol levels shift risk preferences. Using a double-blind, placebo-controlled, cross-over protocol we raised cortisol levels in volunteers over 8 d to the same extent previously observed in traders. We then tested for the utility and probability weighting functions underlying their risk taking and found that participants became more risk-averse. We also observed that the weighting of probabilities became more distorted among men relative to women. These results suggest that risk preferences are highly dynamic. Specifically, the stress response calibrates risk taking to our circumstances, reducing it in times of prolonged uncertainty, such as a financial crisis. Physiology-induced shifts in risk preferences may thus be an underappreciated cause of market instability.