Miracle-dz/UniFAR-FTUs huggingface dataset:
Design, Synthesis and Pharmacological Evaluation of Naphthofuran Derivatives as Potent SIRT1 Activators

Diabetic nephropathy (DN) is one of the most important medical complications in diabetic patients, which is an essential cause of end-stage renal disease in diabetic patients and still lacks effective medicines. Silent information regulator 1 (SIRT1) is closely related to the occurrence and development of DN. Activation of SIRT1 could significantly improve the symptoms of DN, while the activities of SIRT1 activators need to be further improved. Based on the crystal structure of SIRT1, structure and ligand-based approaches were carried out, and a lead compound 4,456–0661 (renamed as M1) was identified. Moreover, seven M1 analogues (6a-6g) were designed using a structure-based drug design strategy followed by bioactivity evaluation with SRTR2104 used as positive drugs. Among the target molecules, compounds M1, 6b, and 6d were proved to be potent SIRT1 activators, the activities of which are comparable to SRT2104. More importantly, compounds M1, 6b, and 6d could resist high glucose-induced apoptosis of HK-2 cells by activating SIRT1 and deacetylation of p53. Apart from the beneficial effect on apoptosis of DN, these compounds also alleviated high glucose stimulating inflammation response in HK-2 cells through SIRT1/NF-κB (p65) pathway. Consequently, M1, 6b, and 6d could be promising drug candidates for SIRT1 related diseases.
Case Report: Responsive Neurostimulation of the Centromedian Thalamic Nucleus for the Detection and Treatment of Seizures in Pediatric Primary Generalized Epilepsy

Up to 20% of pediatric patients with primary generalized epilepsy (PGE) will not respond effectively to medication for seizure control. Responsive neurostimulation (RNS) is a promising therapy for pediatric patients with drug-resistant epilepsy and has been shown to be an effective therapy for reducing seizure frequency and severity in adult patients. RNS of the centromedian nucleus of the thalamus may help to prevent loss of awareness during seizure activity in PGE patients with absence seizures. Here we present a 16-year-old male, with drug-resistant PGE with absence seizures, characterized by 3 Hz spike-and-slow-wave discharges on EEG, who achieved a 75% reduction in seizure frequency following bilateral RNS of the centromedian nuclei. At 6-months post-implant, this patient reported complete resolution of the baseline daily absence seizure activity, and decrease from 3–4 generalized convulsive seizures per month to 1 per month. RNS recordings showed well-formed 3 Hz spike-wave discharges in bilateral CM nuclei, further supporting the notion that clinically relevant ictal discharges in PGE can be detected in CM. This report demonstrates that CM RNS can detect PGE-related seizures in the CM nucleus and deliver therapeutic stimulation.
A Bibliometrics Analysis of Metformin Development From 1980 to 2019

Metformin, the first-line oral blood glucose-lowering agent to manage type 2 diabetes, has gained growing popularity on both clinical application and basic research since early 1980s. A thorough and systematic knowledge map of metformin is pertinent to evaluate the research frontier and determine knowledge gaps. To this end, 20, 526 publications were analyzed by bibliometrics and data visualization to demonstrate the current global research status, potential hotspots, and perspectives on future research directions. In addition, the metformin development along the historical line was illustrated over the last 40 years. In sum, this study provides a comprehensive analysis that delineates the evolution of the historical milestones of metformin development, and we discuss the future research directions based on objective data analysis from a wide spectrum of metformin research areas.
Structures of active melanocortin-4 receptor–Gs-protein complexes with NDP-α-MSH and setmelanotide

The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R–Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor–Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs.
MALDI-TOF Mass Spectrometry Fingerprinting Performance Versus 16S rDNA Sequencing to Identify Bacterial Microflora From Seafood Products and Sea Water Samples

We evaluated the performance of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) associated with the Bruker BioTyperTM V7.0. 0 database for the identification of 713 bacterial strains isolated from seafood products and sea water samples (ANSES B3PA collection) under culture conditions that may have been significantly different from those used to create the reference spectrum vs. the 16S rDNA sequencing. We identified 78.8% of seafood isolates with 46.7% at the species level (Bruker score above 2) and 21.2% (Bruker score between 1.7 and 2) at the genus level by the two identification methods, except for 3.8% of isolates with a difference of identification between the two methods (Bruker score between 1.7 and 2). There were 41.9% isolates (Bruker score below 1.7) with the identification at the genus level. We identified 94.4% of seafood isolates with 16S rDNA sequencing. The MALDI-TOF allowed a better strain identification to the species level contrary to the 16s rDNA sequencing, which allowed an identification mainly to the genus level. MALDI-TOF MS in association with the Bruker database and 16S rDNA sequencing are powerful tools to identify a wide variety of bacteria from seafood but require further identification by biochemical, molecular technique or other conventional tests.
Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by the Interplay Between ORAI1 and InsP3 Receptors

Ca2+ signaling plays an essential role in T cell activation, which is a key step to start an adaptive immune response. During the transition from a quiescent to a fully activated state, Ca2+ microdomains characterized by reduced spatial and temporal extents are observed in the junctions between the plasma membrane (PM) and the endoplasmic reticulum (ER). Such Ca2+ responses can also occur in response to T cell adhesion to other cells or extracellular matrix proteins in otherwise unstimulated T cells. These non-TCR/CD3-dependent Ca2+ microdomains rely on d-myo-inositol 1,4,5-trisphosphate (IP3) signaling and subsequent store operated Ca2+ entry (SOCE) via the ORAI/STIM system. The detailed molecular mechanism of adhesion-dependent Ca2+ microdomain formation remains to be fully elucidated. We used mathematical modeling to investigate the spatiotemporal characteristics of T cell Ca2+ microdomains and their molecular regulators. We developed a reaction-diffusion model using COMSOL Multiphysics to describe the evolution of cytosolic and ER Ca2+ concentrations in a three-dimensional ER-PM junction. Equations are based on a previously proposed realistic description of the junction, which is extended to take into account IP3 receptors (IP3R) that are located next to the junction. The first model only considered the ORAI channels and the SERCA pumps. Taking into account the existence of preformed clusters of ORAI1 and STIM2, ORAI1 slightly opens in conditions of a full ER. These simulated Ca2+ microdomains are too small as compared to those observed in unstimulated T cells. When considering the opening of the IP3Rs located near the junction, the local depletion of ER Ca2+ allows for larger Ca2+ fluxes through the ORAI1 channels and hence larger local Ca2+ concentrations. Computational results moreover show that Ca2+ diffusion in the ER has a major impact on the Ca2+ changes in the junction, by affecting the local Ca2+ gradients in the sub-PM ER. Besides pointing out the likely involvement of the spontaneous openings of IP3Rs in the activation of SOCE in conditions of T cell adhesion prior to full activation, the model provides a tool to investigate how Ca2+ microdomains extent and interact in response to T cell receptor activation.
Cannabidiol Isolated From Cannabis sativa L. Protects Intestinal Barrier From In Vitro Inflammation and Oxidative Stress

The relevance and incidence of intestinal bowel diseases (IBD) have been increasing over the last 50 years and the current therapies are characterized by severe side effects, making essential the development of new strategies that combine efficacy and safety in the management of human IBD. Herbal products are highly considered in research aimed at discovering new approaches for IBD therapy and, among others, Cannabis sativa L. has been traditionally used for centuries as an analgesic and anti-inflammatory remedy also in different gastrointestinal disorders. This study aims to investigate the effects of different C. sativa isolated compounds in an in vitro model of intestinal epithelium. The ability of treatments to modulate markers of intestinal dysfunctions was tested on Caco-2 intestinal cell monolayers. Our results, obtained by evaluation of ROS production, TEER and paracellular permeability measurements and tight junctions evaluation show Cannabidiol as the most promising compound against intestinal inflammatory condition. Cannabidiol is able to inhibit ROS production and restore epithelial permeability during inflammatory and oxidative stress conditions, suggesting its possible application as adjuvant in IBD management.
Health Risks Associated With Excessive Exposure to Solar Ultraviolet Radiation Among Outdoor Workers in South Africa: An Overview

Exposure of outdoor workers to high levels of solar ultraviolet radiation (UVR) poses significant, well-known health risks including skin cancer and eye diseases. In South Africa, little is known about how many workers are potentially overexposed to solar UVR and what the associated impacts on their health might be. In this overview, the geography and solar UVR environment in South Africa are considered, as well as the different outdoor occupational groups likely to be affected by excessive solar UVR exposure. Sunburn, pterygium, cataract, keratinocyte cancers, and melanoma are discussed in the context of outdoor workers. Few studies in South Africa have considered these health issues and the most effective ways to reduce solar UVR exposure for those working outside. Several countries have developed policies and guidelines to support sun safety in the workplace which include training and education, in addition to the provision of personal protective equipment and managerial support. Several gaps in occupational sun protection and workplace sun safety for South Africa are identified. Legislation needs to recognize solar UVR exposure as an occupational health hazard, with sun safety guidelines and training provided for employers and employees.
Functional Characterization of Sex Pheromone Neurons and Receptors in the Armyworm, Mythimna separata (Walker)

Pheromone receptors (PRs) of moths are expressed on the dendritic membrane of odorant receptor neurons (ORNs) housed in the long trichoid sensilla (TS) of antennae and are essential to sex pheromone reception. The function of peripheral neurons of Mythimna separata in recognizing sex pheromones is still unclear. In this study, electroantennogram recordings were performed from male and female antennae of M. separata, and showed that the major component of sex pheromones, (Z)-11-hexadecenal (Z11–16:Ald), evoked the strongest response of male antennae with significant differences between sexes. Single sensillum recording was used to record responses of neurons housed in TS of male M. separata. The results revealed four types of TS with three neurons housed in each type, based on profiles of responses to sex pheromone components and pheromone analogs. ORN-B of type-I TS was specifically tuned to the major sex pheromone component Z11–16:Ald; ORN-Bs in type-III and type-IV TSs were, respectively, activated by minor components (Z)-11-hexadecen-1-yl acetate (Z11–16:OAc) and hexadecenal (16:Ald); and ORNs in type-II TS were mainly activated by the sex pheromone analogs. We further cloned full-length sequences of six putative PR genes and an Orco gene. Functional characterization of PRs in the Xenopus oocyte system demonstrated that male antennae-biased MsepPR1 responded strongly to (Z)-9-tetradecenal (Z9-14:Ald), suggesting that MsepPR1 may be expressed in type-II TS. MsepPR6 was exclusively tuned to (Z)-9-tetradecen-1-yl acetate (Z9–14:OAc). MsepPR2 and MsepPR4 showed no responses to any tested components. Female antennae-biased MespPR5 was broadly tuned to Z9–14:Ald, Z9–14:OAc, Z11–16:Ald, and (Z)-11-hexadecen-1-ol (Z11–16:OH). Our results further enriched the sex pheromone recognition mechanism in the peripheral nervous system of moth M. separata.
Glutaminolysis: A Driver of Vascular and Cardiac Remodeling in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a decimating ailment described by chronic precapillary pulmonary hypertension, an elevated mean pulmonary arterial pressure with a normal pulmonary capillary wedge pressure, and a raised pulmonary vascular resistance resulting in increased right ventricular afterload culminating in heart failure and death. Current PAH treatments regulate the vasodilatory/vasoconstrictory balance of pulmonary vessels. However, these treatment options are unable to stop the progression of, or reverse, an already established disease. Recent studies have advanced a metabolic dysregulation, featuring increased glutamine metabolism, as a mechanism driving PAH progression. Metabolic dysregulation in PAH leads to increased glutaminolysis to produce substrate to meet the high-energy requirement by hyperproliferative and apoptosis-resistant pulmonary vascular cells. This article explores the role of glutamate metabolism in PAH and how it could be targeted as an anti-remodeling therapeutic strategy.
The Development of a Multidimensional Inventory for the Assessment of Mental Pain (FESSTE 30)

Background: Although the term “mental pain” is often the subject of expert opinions regarding claims for damages, there is still no standardized questionnaire in the German-speaking area to operationalize this concept. Therefore, the aim of this work is the development and validation of a self-assessment measurement for psychological pain after traumatic events (FESSTE). Methods: A first version of the questionnaire was applied on a sample of the German speaking general population (N = 425; 88% female). After performing an item analysis and exploratory factor analysis, the questionnaire was shortened and tested on a second German speaking general population sample (N = 619; 89% female). Finally, the newly developed questionnaire was related to the extent of traumatization (measured with a uniquely designed trauma checklist attached to the FESSTE) and already established instruments for the assessment of psychiatric symptom burden, which included the Brief Symptom Inventory-18 (BSI-18) and the Post-traumatic-Stress-Scale (PTSS-10). Results: The final version of the FESSTE consists of a total of 30 items and covers the subscales “Somatization,” “Depression,” “Intrusive Memories,” “Dissociation” and “Anxiety,” and a total scale “Mental Pain. ” Based on the confirmatory factor analysis, it is assumed that the latent factor structure of the FESSTE can be best described as a bifactor-model. The final version shows a satisfactory model fit, high internal consistencies, and strong positive correlations with the BSI-18 and PTSS-10, as well as the extent of traumatic experiences. Discussion: The FESSTE enables an operationalization of mental pain comprising five subscales and one total scale. What is more, the trauma checklist attached to the FESSTE allows for the standardized assessment of potentially traumatic experiences and the corresponding extent of these experiences. The results indicate that the FESSTE is a reliable and valid self-assessment procedure for mental pain, which is suitable for use in research and in expert practice.
Long Non-Coding RNA LINC00467 Correlates to Poor Prognosis and Aggressiveness of Breast Cancer

Breast cancer remains the leading cause of female cancer-related mortalities worldwide. Long non-coding RNAs (LncRNAs) have been increasingly reported to play pivotal roles in tumorigenesis and cancer progression. Herein, we focused on LINC00467, which has never been studied in breast cancer. Silence of LINC00467 suppressed proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) of breast cancer cells in vitro, whereas forced expression of LINC00467 exhibited the opposite effects. Furthermore, we demonstrated overexpression of LINC00467 promoted tumor growth, while knockdown of LINC00467 inhibited pulmonary metastasis in vivo. Mechanistically, LINC00467 down-regulated miR-138-5p by acting as a miRNA “sponge”. Besides, LINC00467 also up-regulated the protein level of lin-28 homolog B (LIN28B) via a direct interaction. A higher expression level of LINC00467 was observed in breast cancer tissues as compared to the adjacent normal counterparts and elevated LINC00467 predicted poor overall survival. Our findings suggest LINC00467 promotes progression of breast cancer through interacting with miR-138-5p and LIN28B directly. LINC00467 may serve as a potential candidate for the diagnosis and treatment of breast cancer.
Features Associated With Quality of Life Impairment in Hidradenitis Suppurativa Patients

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with an adverse impact on patients' quality of life (QoL). Objectives: To quantify QoL impairment in patients in Germany suffering from HS and to identify the parameters associated with QoL impairment. Methods: A non-interventional, cross-sectional, mono-centric study with 500 HS patients. QoL data (measured using the Dermatology Life Quality Index; DLQI) and demographic, anamnestic, clinical, and blood parameters were collected. All patients were examined by dermatologists that documented the skin alterations. QoL data from 462 HS patients were available and evaluated. Results: The mean (± standard deviation) DLQI score of HS patients was 13.18 ± 7.99. Approximately 40% and 20% of HS patients declared very large and extremely large QoL impairment, respectively. The degree of QoL disturbance correlated with the severity of skin alterations, blood leucocyte count and, in particular, with anogenital localization and the presence of nodules and fistulas. Furthermore, QoL impairment was associated with specific comorbidities, such as adiposity and back pain, but not with HS family history. QoL impairment was not influenced by whether or not the patients had undergone resection surgery or antibiotic treatment but was more severe in HS patients that had undergone abscess lancing compared to patients without such treatment in the past. Limitations: It was a mono-centric study and most data were obtained from self-administered patient questionnaires. The association of QoL with type of treatment was analyzed for abscess lancing, resection surgery, and antibiotic treatment. Further therapeutic modalities recommended in the guidelines were not investigated. Conclusion: A profound impairment in QoL was present in patients with HS, and this was higher than that observed in other studied dermatoses. The degree of impairment correlated with the extent of cutaneous and some extra-cutaneous alterations. Surgical and conventional medicamentous therapies of HS were not associated with long-lasting reduction of QoL impairment. Our data support the implementation of patient-reported outcome measures for the assessment of therapy responses.
Doxycycline Induces Apoptosis of Brucella Suis S2 Strain-Infected HMC3 Microglial Cells by Activating Calreticulin-Dependent JNK/p53 Signaling Pathway

Neurobrucellosis is a chronic complication of human brucellosis that is caused by the presence of Brucella spp in the central nervous system (CNS) and the inflammation play a key role on the pathogenesis. Doxycycline (Dox) is a widely used antibiotic that induces apoptosis of bacteria-infected cells. However, the mechanisms of Brucella inhibition of microglial apoptosis and Dox induction of apoptosis are still poorly understood. In this study, we found that Brucella suis S2 strain (B. suis S2) increased calreticulin (CALR) protein levels and inhbited HMC3 cell apoptosis. Hence, we constructed two HMC3 cell line variants, one with stable overexpression (HMC3-CALR) and one with low expression of CALR (HMC3-sh-CALR). CALR was found to decrease levels of p-JNK and p-p53 proteins, as well as suppress apoptosis in HMC3 cells. These findings suggest that CALR suppresses apoptosis by inhibiting the JNK/p53 signaling pathway. Next, we treated HMC3, HMC3-CALR and HMC3-sh-CALR cell lines with B. suis S2 or Dox. Our results demonstrate that B. suis S2 restrains the JNK/p53 signaling pathway to inhibit HMC3 cell apoptosis via increasing CALR protein expression, while Dox plays the opposite role. Finally, we treated B. suis S2-infected HMC3 cells with Dox. Our results confirm that Dox induces JNK/p53-dependent apoptosis in B. suis S2-infected HMC3 cells through inhibition of CALR protein expression. Taken together, these results reveal that CALR and the JNK/p53 signaling pathway may serve as novel therapeutic targets for treatment of neurobrucellosis.
Atrioventricular Conduction in Mesial Temporal Lobe Seizures

Purpose: Asymmetric cerebral representation of autonomic function could help to stratify cardiac complications in people with epilepsy, as some seizures are associated with potentially deleterious arrhythmias including bradycardia and atrioventricular (AV) conduction block. We investigated seizure-related changes in AV conduction and ascertained whether these alterations depend on the hemisphere in mesial temporal lobe epilepsy (mTLE). Methods: EEG and ECG data of people with pharmacoresistant mTLE undergoing pre-surgical video-EEG telemetry with seizures independently arising from both hippocampi, as determined by intracranial depths electrodes were reviewed. RR and PR intervals were measured using one-lead ECG. Statistics were done with paired student's t-tests and linear regression analysis. Data are given as mean ± SD. Results: Fifty-six seizures of 14 patients (5 men, age 34.7 ± 9.8 years) were included (2 seizures per hemisphere and patient). There were no differences of absolute PR intervals and HR before and during unilateral ictal activity between left- and right-sided hippocampal seizures. Peri-ictal modulation of AV conduction, however, appeared greater with left-sided seizures, as the slope of the PR/HR correlations was significantly steeper with seizures originating in the left hippocampus. PR lengthening >200 ms or full block did not occur in any seizure. Conclusions: Our data show that on average, PR intervals shortens with mesial temporal lobe seizures with more prominent effects in seizures with left-sided onset, supporting the notion of lateralized cerebral control of cardiac function. The clinical relevance of this subtle finding is unclear but may indicate a lateralized susceptibility to seizure-related AV node dysfunction in mTLE.