Miracle-dz/UniFAR-FTUs huggingface dataset:
University of Groningen Human FXR Regulates SHP Expression through Direct Binding to an LRH-1 Binding Site, Independent of an IR-1 and LRH-1 Hoeke,

Background: Farnesoid X receptor/retinoid X receptor-alpha (FXR/RXRa) is the master transcriptional regulator of bile salt synthesis and transport in liver and intestine. FXR is activated by bile acids, RXRa by the vitamin A–derivative 9-cis retinoic acid (9cRA). Remarkably, 9cRA inhibits binding of FXR/RXRa to its response element, an inverted repeat-1 (IR-1). Still, most FXR/RXRa target genes are maximally expressed in the presence of both ligands, including the small heterodimer partner (SHP). Here, we revisited the FXR/RXRa-mediated regulation of human SHP. Methods: A 579-bp hSHP promoter element was analyzed to locate FXR/chenodeoxycholic acid (CDCA)and RXRa/9cRAresponsive elements. hSHP promoter constructs were analyzed in FXR/RXRa-transfected DLD-1, HEK293 and HepG2 cells exposed to CDCA, GW4064 (synthetic FXR ligand) and/or 9cRA. FXR-DNA interactions were analyzed by in vitro pull down assays. Results: hSHP promoter elements lacking the previously identified IR-1 (2291/2279) largely maintained their activation by FXR/CDCA, but were unresponsive to 9cRA. FXR-mediated activation of the hSHP promoter was primarily dependent on the 2122/269 region. Pull down assays revealed a direct binding of FXR to the 2122/269 sequence, which was abrogated by site-specific mutations in a binding site for the liver receptor homolog-1 (LRH-1) at 278/270. These mutations strongly impaired the FXR/CDCA-mediated activation, even in the context of a hSHP promoter containing the IR-1. LRH-1 did not increase FXR/RXRa-mediated activation of hSHP promoter activity. Conclusion: FXR/CDCA-activated expression of SHP is primarily mediated through direct binding to an LRH-1 binding site, which is not modulated by LRH-1 and unresponsive to 9cRA. 9cRA-induced expression of SHP requires the IR-1 that overlaps with a direct repeat-2 (DR-2) and DR-4. This establishes for the first time a co-stimulatory, but independent, action of FXR and RXRa agonists. Citation: Hoeke MO, Heegsma J, Hoekstra M, Moshage H, Faber KN (2014) Human FXR Regulates SHP Expression through Direct Binding to an LRH-1 Binding Site, Independent of an IR-1 and LRH-1. PLoS ONE 9(2): e88011. doi:10.1371/journal.pone. 0088011 Editor: Antonio Moschetta, University of Bari & Consorzio Mario Negri Sud, Italy Received October 10, 2013; Accepted January 3, 2014; Published February 3, 2014 Copyright: 2014 Hoeke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the Dutch Digestive Diseases Foundation (MLDS WS 03-38 to MOH and MLDS MWO 08-70 to MH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: k.n. faber@ umcg.nl
Effect of Chinese Herbal Medicine on the Survival of Colorectal Cancer Patients With Liver-Limited Metastases: A Retrospective Cohort Study, 2008 to 2017

Background: Colorectal cancer (CRC) remains one of the leading contributors to cancer-related mortality and morbidity worldwide. Traditional Chinese medicines have been widely employed to treat various types of cancer in China. This investigation aims to determine the association between Chinese herbal medicine (CHM) therapy and survival outcomes in CRC patients with liver-limited metastases. Methods: A retrospective cohort study was performed among patients with colorectal liver metastases at the First Affiliated Hospital of Guangzhou University of Chinese Medicine in Guangzhou, China. Data from a series of consecutive patients were collected via an electronic medical record system or telephone follow-up. We defined high exposure as a period of CHM therapy lasting more than 6 months. The primary outcome was overall survival. Results: The study included the data of 191 patients from January 2008 to December 2017; 126 patients (65.97%) met the inclusion criteria of high exposure to CHM. Multivariate analyses revealed that high exposure to CHM was associated with better overall survival (hazard ratio = 0.444, 95% confidence interval = [0.213, 0.926], P = .030). The association was further confirmed by a subgroup exploratory analysis. Conclusion: Long-term CHM therapy is correlated with improved survival outcomes in CRC patients with liver-limited metastases.
Caenorhabditis Elegans and Probiotics Interactions from a Prolongevity Perspective

Probiotics exert beneficial effects on host health through different mechanisms of action, such as production of antimicrobial substances, competition with pathogens, enhancement of host mucosal barrier integrity and immunomodulation. In the context of ageing, which is characterized by several physiological alterations leading to a low grade inflammatory status called inflammageing, evidences suggest a potential prolongevity role of probiotics. Unraveling the mechanisms underlying anti-ageing effects requires the use of simple model systems. To this respect, the nematode Caenorhabditis elegans represents a suitable model organism for the study of both host-microbe interactions and for ageing studies, because of conserved signaling pathways and host defense mechanisms involved in the regulation of its lifespan. Therefore, this review analyses the impact of probiotics on C. elegans age-related parameters, with particular emphasis on oxidative stress, immunity, inflammation and protection from pathogen infections. The picture emerging from our analysis highlights that several probiotic strains are able to exert anti-ageing effects in nematodes by acting on common molecular pathways, such as insulin/insulin-like growth factor-1 (IIS) and p38 mitogen-activated protein kinase (p38 MAPK). In this perspective, C. elegans appears to be advantageous for shedding light on key mechanisms involved in host prolongevity in response to probiotics supplementation.
Cell‐of‐origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B‐cell lymphoma

The tumor cells in diffuse large B‐cell lymphomas (DLBCL) are considered to originate from germinal center derived B‐cells (GCB) or activated B‐cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC‐based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non‐GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression‐free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression‐free survival differed significantly. Importantly, patients assigned as non‐GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.
Mild stimulation improves neuronal survival in an in vitro model of the ischemic penumbra

Objective. In the core of a brain infarct, characterized by severely reduced blood supply, loss of neuronal function is rapidly followed by neuronal death. In peripheral areas of the infarct, the penumbra, damage is initially reversible, and neuronal activity is typically reduced due to ischemia-induced synaptic failure. There is limited understanding of factors governing neuronal recovery or the transition to irreversible damage. Neuronal activity has been shown to be crucial for survival. Consequently, hypoxia induced neuronal inactivity may contribute to cell death, and activation of penumbral neurons possibly improves survival. Adversely, activation increases ATP demand, and a balance should be found between the available energy and sufficient activity. Approach. We monitored activity and viability of neurons in an in vitro model of the penumbra, consisting of (rat) neuronal networks on micro electrode arrays (MEAs) under controlled hypoxic conditions. We tested effects of optogenetic and electrical activation during hypoxia. Main results. Mild stimulation yielded significantly better recovery of activity immediately after re-oxygenation, compared with no stimulation, and a 60%–70% higher survival rate after 5 d. Stronger stimulation was not associated with better recovery than no stimulation, suggesting that beneficial effects depend on a delicate balance between sufficient activity and available energy. Significance. We show that mild activation during hypoxia/ischemia is beneficial for cell survival in an in vitro model of the penumbra. This finding opposes the current common belief that suppression of neuronal activity is the cornerstone of neuroprotection during cerebral ischemia, and may open new possibilities for the treatment of secondary brain damage after stroke.
Effects of Membrane and Biological Target on the Structural and Allosteric Properties of Recoverin: A Computational Approach

Recoverin (Rec) is a prototypical calcium sensor protein primarily expressed in the vertebrate retina. The binding of two Ca2+ ions to the functional EF-hand motifs induces the extrusion of a myristoyl group that increases the affinity of Rec for the membrane and leads to the formation of a complex with rhodopsin kinase (GRK1). Here, unbiased all-atom molecular dynamics simulations were performed to monitor the spontaneous insertion of the myristoyl group into a model multicomponent biological membrane for both isolated Rec and for its complex with a peptide from the GRK1 target. It was found that the functional membrane anchoring of the myristoyl group is triggered by persistent electrostatic protein-membrane interactions. In particular, salt bridges between Arg43, Arg46 and polar heads of phosphatidylserine lipids are necessary to enhance the myristoyl hydrophobic packing in the Rec-GRK1 assembly. The long-distance communication between Ca2+-binding EF-hands and residues at the interface with GRK1 is significantly influenced by the presence of the membrane, which leads to dramatic changes in the connectivity of amino acids mediating the highest number of persistent interactions (hubs). In conclusion, specific membrane composition and allosteric interactions are both necessary for the correct assembly and dynamics of functional Rec-GRK1 complex.
Photodetector based on heterostructure of two-dimensional WSe2/In2Se3

Heterojunctions formed by two-dimensional (2D) layered semiconducting materials have been studied extensively in the past few years. These van der Waals (vdW) structures have shown great potential for future electronic and optoelectronic devices. However, the optoelectronic performance of these devices is limited by the indirect band gap of multilayer materials and low light absorption of single layer materials. Here, we fabricate photodetectors based on heterojunctions composed of n-type multilayer α-indium selenide (In2Se3) and p-type tungsten diselenide (WSe2) for the first time. The direct band gap of multilayer α-In2Se3 and type-II band alignment of the WSe2/In2Se3 heterojunction enable high optoelectronic performance of the devices at room temperature in the air. Without light illumination, the dark current is effectively suppressed to 10−13 A under −1 V bias and a high rectification ratio of 7.37 × 103 is observed. Upon laser illumination with a wavelength of 650 nm, the typical heterojunction device exhibits a photocurrent on/off ratio exceeding 1.24 × 105, a maximum photo responsivity of 26 mA W−1 and a short photoresponse time of 2.22 ms. Moreover, the heterojunction photodetectors show obvious light response in the wavelength range from 650 nm to 900 nm. The present 2D vdW heterojunctions composed of direct band gap multilayer materials show great potential for future optoelectronic devices.
Inducible Cardiac-Specific Deletion of Sirt1 in Male Mice Reveals Progressive Cardiac Dysfunction and Sensitization of the Heart to Pressure Overload

Heart failure is associated with profound alterations of energy metabolism thought to play a major role in the progression of this syndrome. SIRT1 is a metabolic sensor of cellular energy and exerts essential functions on energy metabolism, oxidative stress response, apoptosis, or aging. Importantly, SIRT1 deacetylates the peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), the master regulator of energy metabolism involved in mitochondrial biogenesis and fatty acid utilization. However, the exact role of SIRT1 in controlling cardiac energy metabolism is still incompletely understood and conflicting results have been obtained. We generated a cardio-specific inducible model of Sirt1 gene deletion in mice (Sirt1ciKO) to decipher the role of SIRT1 in control conditions and following cardiac stress induced by pressure overload. SIRT1 deficiency induced a progressive cardiac dysfunction, without overt alteration in mitochondrial content or properties. Sixteen weeks after Sirt1 deletion an increase in mitochondrial reactive oxygen species (ROS) production and a higher rate of oxidative damage were observed, suggesting disruption of the ROS production/detoxification balance. Following pressure overload, cardiac dysfunction and alteration in mitochondrial properties were exacerbated in Sirt1ciKO mice. Overall the results demonstrate that SIRT1 plays a cardioprotective role on cardiac energy metabolism and thereby on cardiac function.
Intravenous Immunoglobulin Therapy in Superantigen-Mediated Toxic Shock Syndrome

Toxic shock syndrome (TSS) is a serious acute bacterial disease characterized by fever, diffuse erythematous rash, hypotension, multiorgan involvement, and desquamation of the skin one to two weeks after onset. Various immunomodulatory agents and antisuperantigen therapeutic strategies have been proposed. One such strategy includes the administration of intravenous polyspecific immunoglobulin (IVIG). This chapter reviews the mechanistic actions and use of IVIG as adjunctive therapy for TSS. Patients were considered to have streptococcal TSS if they had hypotension in combination with two or more of the following: acute renal failure, coagulation abnormalities, liver abnormalities, adult respiratory distress syndrome (ARDS), generalized rash, and necrotizing fasciitis. The observation that staphylococcal TSS patients normally do not have detectable bacteremia, yet the patients demonstrate significant systemic features, suggested that TSS was the result of a toxemia. Most Streptococcus pyogenes strains express several different superantigens, and strains harbor in general genes encoding three to five of the superantigens, but the repertoire of genes varies between strains. S. pyogenes and Staphylococcus aureus are major human pathogens largely due to their ability to modulate and exploit the host defense mechanisms. Conventional therapy of invasive S. pyogenes infections has consisted of antimicrobials and, when necessary in severe invasive disease, support of vital functions for those patients with streptococcal TSS and surgery for those patients with necrotizing fasciitis.
Ameliorative effect of rosiglitazone, a peroxisome proliferator gamma agonist on adriamycin‐induced cardio toxicity via suppressing oxidative stress and apoptosis

We investigated the rosiglitazone (RSG) effect on adriamycin (ADM)‐induced cardio toxicity in experimental animals. Forty adult Wistar male rats were separated into four groups as follows: normal control; RSG (10 mg/kg)‐treated; ADM (10 mg/kg)‐administered; and ADM (10 mg/kg) + RSG (10 mg/kg)‐treated. Serum lipid level, different biochemical biomarkers, histological analysis, and nuclear factor erythroid 2‐related factor/heme oxygenase‐1 (Nrf2/HO‐1), Caspase 3, B‐cell lymphoma 2 (Bcl‐2), and Bax gene expression were assessed in serum and cardiac tissue samples. Our results show that RSG treatment in ADM‐administered animals significantly diminished low‐density lipoprotein cholesterol, triglyceride, and total cholesterol, and increases high‐density lipoprotein cholesterol (HDL‐c) in comparison with the ADM group. RSG treatment reduced the effect of ADM administration on cardiac dysfunction markers such as cardiac troponin T Creatine Kinase‐MB, aspartate aminotransferase, and lactate dehydrogenase, showing the amelioration of cardio toxicity in ADM‐administered rats. Additionally, RSG treatment significantly decreased the level of malondialdehyde and nitric oxide in cardiovascular tissue. RSG‐treated rats in combination with ADM likewise showed a significant increase in reduced glutathione, superoxide dismutase, catalase content, and the activity of glutathione peroxidase (GPx) as compared with ADM group. Moreover, RSG treatment in ADM rats significantly increased an Nrf2 and HO‐1 expression in comparison with ADM group. While in apoptosis parameters, RSG treatment in ADM rats significantly diminished a cleaved caspase‐3 and Bax expression as well as expanded Bcl‐2 expression when contrasted with ADM group of rats. In conclusion, RSG is capable of protecting heart toxicity in ADM‐treated animals through defensive effects on oxidative stress and biochemical markers.
Insulin Receptor Trafficking: Consequences for Insulin Sensitivity and Diabetes

Insulin receptor (INSR) has been extensively studied in the area of cell proliferation and energy metabolism. Impaired INSR activities lead to insulin resistance, the key factor in the pathology of metabolic disorders including type 2 diabetes mellitus (T2DM). The mainstream opinion is that insulin resistance begins at a post-receptor level. The role of INSR activities and trafficking in insulin resistance pathogenesis has been largely ignored. Ligand-activated INSR is internalized and trafficked to early endosome (EE), where INSR is dephosphorylated and sorted. INSR can be subsequently conducted to lysosome for degradation or recycled back to the plasma membrane. The metabolic fate of INSR in cellular events implies the profound influence of INSR on insulin signaling pathways. Disruption of INSR-coupled activities has been identified in a wide range of insulin resistance-related diseases such as T2DM. Accumulating evidence suggests that alterations in INSR trafficking may lead to severe insulin resistance. However, there is very little understanding of how altered INSR activities undermine complex signaling pathways to the development of insulin resistance and T2DM. Here, we focus this review on summarizing previous findings on the molecular pathways of INSR trafficking in normal and diseased states. Through this review, we provide insights into the mechanistic role of INSR intracellular processes and activities in the development of insulin resistance and diabetes.
A Facile Method to Prepare Silver Doped Graphene Combined with Polyaniline for High Performances of Filter Paper Based Flexible Electrode

A flexible filter paper based composite electrode was prepared via the convenient one-step synthesis of silver doped graphene for the first time, followed by in-situ polymerization of aniline monomers. Using L-ascorbic acid for simultaneous reduction of grapheme oxide and silver nitrate, we provided a new and green method to prepare graphene hybrid sheets without toxicity. It was found that the as-fabricated hybrid electrode formed a three-dimensional porous architecture, which not only increased the specific surface area of composite, but also facilitated the ion diffusion of the electrolyte. In addition, according to the tests of electrochemical performances, the flexible hybrid electrode subsequently exhibited exceptional specific capacitance of 437.3 F/g, energy density of 1133.5 W·h/kg and power density of 88.8 kW/kg, respectively. Meanwhile, the as-prepared hybrid demonstrated a good cycling stability with only 10.99% specific capacitance deterioration after 5000 times of cycling. This preparation technology presented here shows great potential for the development and application of wearable and portable energy storage devices, particularly for flexible supercapacitors. Moreover, this study puts forward a general, simple and low-cost route of fabricating a novel flexible electrode on a large scale, eventually for environmental protection.
World Stroke Organization (WSO): Global Stroke Fact Sheet 2019

Stroke is the second major cause of death and disability worldwide with over 13 million new cases annually. Globally, the overall incidence rates of stroke decreased from 1990 to 2016, largely due to prevention and better control of risk factors such as tobacco use and blood pressure control. Among this decline, the one group that did see an increase is the younger age groups (younger than 50 years) and prevalence rates also increased exponentially since 2005 for this group. However, the absolute number of people who had a stroke, died or remained disabled from stroke has increased from 1990 to 2016 by almost two-fold. The World Stroke Organization (WSO) lead many advocacy efforts through their membership, targeted efforts in lowand middle-income countries, and through the strong voice of Stroke Support Organizations (SSOs). Governments, system leaders, healthcare providers, and the general population need to increase efforts for raising awareness, educating individuals and populations of their risk factors, implementing effective and widely available stroke risk prevention strategies (for example, free Stroke Riskometer app supported by the WSO and already translated into 12 languages) and ensuring timely acute treatments to reduce the long-term burden of stroke. Advocacy efforts require reliable and consistent stroke data to build awareness of the scale of the disease and support for calls for urgent action at global, regional, and national levels. This WSO Global Stroke Fact Sheet 2019 provides information that can be used to inform communication with all internal and external stakeholders; all statistics have been reviewed and approved for use by the WSO Executive Committee as well as leaders from the Global Burden of Disease research group. The facts endorsed by the WSO will be updated every one to two years as new data emerges.
Maximal free-space concentration of electromagnetic waves

We derive upper bounds to free-space concentration of electromagnetic waves, mapping out the limits to maximum intensity for any spot size and optical beam-shaping device. For sub-diffraction-limited optical beams, our bounds suggest the possibility for orders-of-magnitude intensity enhancements compared to existing demonstrations, and we use inverse design to discover metasurfaces operating near these new limits. We also demonstrate that our bounds may surprisingly describe maximum concentration defined by a wide variety of metrics. Our bounds require no assumptions about symmetry, scalar waves, or weak scattering, instead relying primarily on the transformation of a quadratic program via orthogonal-projection methods. The bounds and inverse-designed structures presented here can be useful for applications from imaging to 3D printing.