Miracle-dz/UniFAR-FTUs huggingface dataset:
Diacylglycerol kinases regulate TRPV1 channel activity

The transient receptor potential vanilloid 1 (TRPV1) channel is activated by heat and by capsaicin, the pungent compound in chili peppers. Calcium influx through TRPV1 has been shown to activate a calcium-sensitive phospholipase C (PLC) enzyme and to lead to a robust decrease in phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] levels, which is a major contributor to channel desensitization. Diacylglycerol (DAG), the product of the PLC-catalyzed PI(4,5)P2 hydrolysis, activates protein kinase C (PKC). PKC is known to potentiate TRPV1 activity during activation of G protein–coupled receptors, but it is not known whether DAG modulates TRPV1 during desensitization. We found here that inhibition of diacylglycerol kinase (DAGK) enzymes reduces desensitization of native TRPV1 in dorsal root ganglion neurons as well as of recombinant TRPV1 expressed in HEK293 cells. The effect of DAGK inhibition was eliminated by mutating two PKC-targeted phosphorylation sites, Ser-502 and Ser-800, indicating involvement of PKC. TRPV1 activation induced only a small and transient increase in DAG levels, unlike the robust and more sustained increase induced by muscarinic receptor activation. DAGK inhibition substantially increased the DAG signal evoked by TRPV1 activation but not that evoked by M1 muscarinic receptor activation. Our results show that Ca2+ influx through TRPV1 activates PLC and DAGK enzymes and that the latter limits formation of DAG and negatively regulates TRPV1 channel activity. Our findings uncover a role of DAGK in ion channel regulation.
Elastin-Like Polypeptides for Biomedical Applications.

Elastin-like polypeptides (ELPs) are stimulus-responsive biopolymers derived from human elastin. Their unique properties-including lower critical solution temperature phase behavior and minimal immunogenicity-make them attractive materials for a variety of biomedical applications. ELPs also benefit from recombinant synthesis and genetically encoded design; these enable control over the molecular weight and precise incorporation of peptides and pharmacological agents into the sequence. Because their size and sequence are defined, ELPs benefit from exquisite control over their structure and function, qualities that cannot be matched by synthetic polymers. As such, ELPs have been engineered to assemble into unique architectures and display bioactive agents for a variety of applications. This review discusses the design and representative biomedical applications of ELPs, focusing primarily on their use in tissue engineering and drug delivery. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 22 is June 4, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Mutation of Hydrophobic Residues in the C-Terminal Domain of the Marburg Virus Matrix Protein VP40 Disrupts Trafficking to the Plasma Membrane

Marburg virus (MARV) is a lipid-enveloped negative sense single stranded RNA virus, which can cause a deadly hemorrhagic fever. MARV encodes seven proteins, including VP40 (mVP40), a matrix protein that interacts with the cytoplasmic leaflet of the host cell plasma membrane. VP40 traffics to the plasma membrane inner leaflet, where it assembles to facilitate the budding of viral particles. VP40 is a multifunctional protein that interacts with several host proteins and lipids to complete the viral replication cycle, but many of these host interactions remain unknown or are poorly characterized. In this study, we investigated the role of a hydrophobic loop region in the carboxy-terminal domain (CTD) of mVP40 that shares sequence similarity with the CTD of Ebola virus VP40 (eVP40). These conserved hydrophobic residues in eVP40 have been previously shown to be critical to plasma membrane localization and membrane insertion. An array of cellular experiments and confirmatory in vitro work strongly suggests proper orientation and hydrophobic residues (Phe281, Leu283, and Phe286) in the mVP40 CTD are critical to plasma membrane localization. In line with the different functions proposed for eVP40 and mVP40 CTD hydrophobic residues, molecular dynamics simulations demonstrate large flexibility of residues in the EBOV CTD whereas conserved mVP40 hydrophobic residues are more restricted in their flexibility. This study sheds further light on important amino acids and structural features in mVP40 required for its plasma membrane localization as well as differences in the functional role of CTD amino acids in eVP40 and mVP40.
Local Ca2+ signals couple activation of TRPV1 and ANO1 sensory ion channels

TRPV1-mediated release of ER Ca2+ is sufficient to activate the sensory ion channel ANO1. Boosting the Ca2+ signal for nociception The Ca2+-activated Cl− channel ANO1 promotes nociception, the perception of pain. The nonselective cation channel TRPV1 has been proposed to be the source of Ca2+ that activates ANO1, but the amount of Ca2+ that TRPV1 allows into pain-transmitting DRG neurons is thought to be insufficient to activate ANO1. Shah et al. found that TRPV1 triggered Ca2+ release from the ER through an IP3 receptor isoform. Imaging techniques showed that ANO1, TRPV1, and the IP3 receptor clustered in close proximity to each other in pain-transmitting DRG neurons. These results provide insight into the molecular mechanisms underlying nociception. ANO1 (TMEM16A) is a Ca2+-activated Cl− channel (CaCC) expressed in peripheral somatosensory neurons that are activated by painful (noxious) stimuli. These neurons also express the Ca2+-permeable channel and noxious heat sensor TRPV1, which can activate ANO1. Here, we revealed an intricate mechanism of TRPV1-ANO1 channel coupling in rat dorsal root ganglion (DRG) neurons. Simultaneous optical monitoring of CaCC activity and Ca2+ dynamics revealed that the TRPV1 ligand capsaicin activated CaCCs. However, depletion of endoplasmic reticulum (ER) Ca2+ stores reduced capsaicin-induced Ca2+ increases and CaCC activation, suggesting that ER Ca2+ release contributed to TRPV1-induced CaCC activation. ER store depletion by plasma membrane–localized TRPV1 channels was demonstrated with an ER-localized Ca2+ sensor in neurons exposed to a cell-impermeable TRPV1 ligand. Proximity ligation assays established that ANO1, TRPV1, and the IP3 receptor IP3R1 were often found in close proximity to each other. Stochastic optical reconstruction microscopy (STORM) confirmed the close association between all three channels in DRG neurons. Together, our data reveal the existence of ANO1-containing multichannel nanodomains in DRG neurons and suggest that coupling between TRPV1 and ANO1 requires ER Ca2+ release, which may be necessary to enhance ANO1 activation.
Neuronal hypertrophy dampens neuronal intrinsic excitability and stress responsiveness during chronic stress

The hypothalamic‐pituitary‐adrenal (HPA) axis habituates to repeated stress exposure. We studied hypothalamic corticotropin‐releasing hormone (CRH) neurons that form the apex of the HPA axis in a mouse model of stress habituation using repeated restraint. The intrinsic excitability of CRH neurons decreased after repeated stress in a time course that coincided with the development of HPA axis habituation. This intrinsic excitability plasticity co‐developed with an expansion of surface membrane area, which increased a passive electric load and dampened membrane depolarization in response to the influx of positive charge. We report a novel structure–function relationship for intrinsic excitability plasticity as a neural correlate for HPA axis habituation.
Protection against Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice by Neferine, A Natural Product from Nelumbo nucifera Gaertn

Objective Ulcerative colitis (UC) is a long-lasting inflammatory disease of the colon. Epidemiological studies showed that the prevalence and incidence of UC are increasing worldwide in recent years. Neferine is a natural alkaloid isolated from Nelumbo nucifera Gaertn that exerts a variety of biological activities. This study was designed to evaluate the protective effect of neferine on dextran sulfate sodium (DSS)-induced experimental UC in mice. Materials and Methods In this experimental study, 4% DSS was used to induce a mice model of UC. Neferine (5 and 10 mg/kg) was administered by intraperitoneal injection (ip). Clinical symptoms and disease activity index (DAI) scores were recorded and calculated. Pathological changes of colon tissues were detected by Hematoxylin and Eosin (H&E) staining. The levels of inflammatory mediators were detected by ELISA kits. Western blotting and immunohistochemical analysis were used for the evaluation of protein expressions. Results Neferine treatment significantly alleviated DSS-induced UC by inhibiting weight loss, decreasing DAI scores, and alleviating the pathological changes in colon tissues. Furthermore, neferine significantly decreased serum levels of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 and increased serum levels of anti-inflammatory cytokine IL-10. The increased myeloperoxidase (MPO) activity and nitric oxide (NO) in colon tissues were also inhibited. In addition, neferine significantly down-regulated inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and intercellular cell adhesion molecule-1 (ICAM-1) expression in colon tissues. Conclusion These results provided evidence that neferine could protect against DSS-induced UC symptoms in an experimental mice model. This effect might be mediated through inhibition of inflammation.
High Intensity Interval Training (HIIT) Improves Cardiorespiratory Fitness (CRF) in Healthy, Overweight and Obese Adolescents: A Systematic Review and Meta-Analysis of Controlled Studies

Background: High Intensity Interval Training (HIIT) is a sustainable and effective method for improving Cardiorespiratory Fitness (CRF) in adolescents. HIIT is proven to produce equal or greater improvements in CRF when compared to moderate intensity continuous exercise (MICE) in adolescents. Methods: The studies included were considered eligible if: (1) Participants were adolescents (11–18 years old); (2) Examined changes in CRF measured either directly or indirectly; (3) Included a non-exercising control group or MICE comparison group; (4) Participants were matched at enrolment; (5) Reported HIIT protocol information; (6) Provided HIIT intensity. A meta-analysis was conducted to determine the effect of HIIT on CRF. Meta-regression and moderator analyses were performed out to quantitatively examine moderators of protocol design on CRF improvements. Results: HIIT displays a moderate effect to improve CRF (g = 0.86, 95% CI 0.518–1.106, p < 0.001). Neither study duration (weeks), nor total or weekly accumulated HIIT volume (min) displayed any significant moderation effect on pooled improvement on CRF (p > 0.05). Conclusions: HIIT is an effective method to improve CRF in adolescents, irrespective of body composition. Notably, meta regression analysis identified that prolonged high volume HIIT programs are similarly effective to short term low volume HIIT programs. This becomes of particular interest for those involved in school curricula, where short HIIT exercise may provide a pragmatic adjunct to the health benefits of Physical Education (PE) lessons.
Methods for determining equiluminance in terms of L/M cone ratios

Heterochromatic flicker photometry (HFP), minimum motion (MM), and minimally distinct border (MDB) settings have often been used to determine equiluminance, a relative intensity setting for two chromaticities that, in theory, eliminates the responses of a luminance or achromatic psychophysical mechanism. These settings have been taken to reflect the relative contribution of the long (L) and medium (M) wavelength cones to luminance, which varies widely across individuals. The present study compares HFP, MM, and MDB using stimuli that do not modulate the short (S) wavelength cones, in both practiced and naïve observers. MDB was performed with both flashed and steadily viewed stimuli. Results are represented in the (∆L/L, ∆M/M) plane of cone contrast space. Considering both practiced and naïve observers, both MM and HFP had excellent within-subject precision and high test–retest reliability, whereas HFP also had low between-subject variability. The MDB tasks were less reliable and less precise. The mean L:M contrast ratios at equiluminance were lower for the two temporal tasks (HFP and MM) compared to the spatial tasks (MDB), perhaps consistent with the existence of multiple luminance mechanisms. Overall, the results suggest that the best method for determining equiluminance is HFP, with MM being a close second.
Emergence of mosquito-borne Bunya-, toga-, and reoviruses in central Europe.

In this paper the most important ecological characteristics of arthropod-borne (arbo) viruses and the recent emergence of some pathogens in Europe are reviewed. In early July 2007 the first autochthonous Chikungunya virus outbreak occurred in Europe between July and September 2007. A local transmission cycle involving Aedes albopictus mosquitoes was demonstrated. In 2006, Bluetongue virus emerged for the first time in north-western Europe. Culicoides imicola, which is not present in north-western Europe, is the principal vector; in north-western Europe, however, other Culicoides species served as vectors. Tahyna and Sedlec bunyaviruses were first isolated in central Europe; Tahyna virus is known to be a human pathogen, Sedlec virus was isolated from a wild bird, and it is unknown whether this virus may also affect humans, farm, or pet animals. Phylogenetic analysis of Tahyna virus indicates that the central European strains of the virus are closely related to each other. Genetic investigations of Sedlec virus shows that it is a member of the Simbu group of orthobunyaviruses, and related to Oropouche virus and Akabane virus. Integrated research of entomologists, virologists and other experts is necessary to develop of early warning networks and control systems for the protection of the European human and animal populations.
Risk factors of non-invasive ventilation failure in hematopoietic stem-cell transplantation patients with acute respiratory distress syndrome

Background: Non-invasive ventilation (NIV) was one of the first-line ventilation supports for hematopoietic stem-cell transplantation (HSCT) patients with acute respiratory distress syndrome (ARDS). Successful NIV may avoid need for intubation. However, the influence NIV failure had on patients’ outcome and its risk factors were hardly known. Methods: In this retrospective observational study, we reported risk factors and incidence of NIV failure in HSCT patients who were admitted to the Intensive Care Unit (ICU) with a diagnosis of ARDS and supported with mechanical ventilation, in a 5-year period. Patient outcomes, such as ventilator-free days, ICU-free days, and ICU mortality were also reported. Results: Of all the 94 patients included, 70 patients were initially supported with NIV. NIV failure occurred in 44 (63%) patients. Male sex, elevated serum galactomannan (GM) test, (1-3)-β-D-glucan (BG) assay, or elevated serum creatinine level were risk factors for NIV failure. When compared with the NIV success group, failure of NIV was associated with much fewer ICU-free days (22 versus 0, p < 0.001, Cohen’s d = 0.62) and higher ICU mortality (9.5% versus 75.5%, p < 0.001, Pearson’s r = 0.75). There was no difference in ICU-free days, ventilator-free days and ICU mortality between NIV failure and initial invasive mechanical ventilation (IMV) groups. Patients who failed in NIV support had a higher ICU mortality (75.5%) than those who succeeded (9.5%). Conclusion: In a small cohort of HSCT patients with mainly moderate severity of ARDS, male patients with elevated serum GM/BG test or serum creatinine level had a higher risk of NIV failure. Both NIV failure and initial IMV groups were characterized by high mortality rate and extremely low ICU-free days and ventilator-free days; failure of NIV support may further aggravate patient prognosis. The reviews of this paper are available via the supplemental material section.
Surface Modification of Staple Carbon Fiber by Dopamine to Reinforce Natural Latex Composite

Carbon fiber significantly enhances the mechanical, thermal and electrical properties of rubber composites, which are widely used in aerospace, military, national defense and other cutting-edge fields. The preparation of a high-performance carbon fiber rubber composite has been a research hotspot, because the surface of carbon fiber is smooth, reactive inert and has a poor adhesion with rubber. In this paper, a high-performance rubber composite is prepared by mixing dopamine-modified staple carbon fiber with natural latex, and the mechanisms of modified carbon fiber-reinforced natural latex composite are explored. The experimental results show that the surface-modified staple carbon fiber forms uniform and widely covered polydopamine coatings, which significantly improve the interface adhesion between the carbon fiber and the rubber matrix. Meanwhile, when the concentration of dopamine is 1.5 g/L and the staple carbon fiber is modified for 6h, the carbon fiber rubber composite shows excellent conductivity, thermal conductivity, and dynamic mechanical properties, and its tensile strength is 10.6% higher than that of the unmodified sample.
Analysis of Job-Related Demands and Resources in Ambulatory Youth Welfare Services: A Qualitative and Quantitative Approach

In this study, we investigated health-relevant job characteristics of social workers in ambulatory youth welfare services, combining qualitative and quantitative methods. Based on a systematic literature review, expert workshops, and focus group discussions with 9 experts of the target group, we identified target group-specific job demands and job resources, which we compiled into a questionnaire using content-valid scales. The target group-specific survey tool comprises 9 scales for assessing job demands and 10 scales for assessing job resources. Analyses of data from 209 social workers demonstrated desirable psychometric properties and substantial correlations of the scales with coping behaviours and indicators of employee well-being. The scales for assessing job demands were negatively related to psychological well-being and job satisfaction and positively related to burnout and depressiveness. The scales for assessing job resources showed positive correlations with indicators of positive well-being and negative correlations with indicators of impaired well-being. Regression analyses revealed that job resources explained a higher amount of variance in the positive well-being indicators compared to job demands. The study identified a broad range of health-relevant job characteristics for social workers in ambulatory youth welfare. Applying the target group-specific survey tool allows organisations to derive suitable implications for the design of health promotion programs.
Incidence of Anaplastic Large Cell Lymphoma and Breast-Implant-Associated Lymphoma—An Analysis of a Certified Tumor Registry over 17 Years

Background: Breast-implant-associated anaplastic large cell lymphoma (BI-ALCL) and primary breast ALCL are rare extranodal manifestations of non-Hodgkin lymphoma. The rarity of both diseases, along with unreleased sales data on breast implants and constant updates of classification systems impede the calculation of an exact incidence. Methods: The database of the Tumor Center Regensburg in Bavaria was searched for patients with CD30-positive and ALK-negative anaplastic large cell lymphoma between 2002 and 2018. These lymphomas were identified by the ICD-O-3 morphology code “97023” and were cross-checked by searching the diagnosis by name the and ICD-10 code C84.7. Furthermore, we tried to calculate the incidence rates and corresponding 95% confidence intervals, standardized to 1,000,000 implant years of breast-implant-associated anaplastic large cell lymphoma and primary breast anaplastic large cell lymphoma. Results: Twelve ALK-negative and CD30-positive anaplastic large cell lymphomas were identified out of 170,405 malignancies. No case was found within the breast tissue and none of the patients had a previous history of breast implant placement. In five cases, lymph node involvement in close proximity to the breast was observed. Conclusion: We found a low incidence of anaplastic large cell lymphoma and no association to breast implants in these patients. A review of the current literature revealed inconsistent use of classification systems for anaplastic large cell lymphomas and potential overestimation of cases.
The Association between Serum Levels of 25[OH]D, Body Weight Changes and Body Composition Indices in Patients with Heart Failure

We try to determine the association between weight changes (WC), both loss or gain, body composition indices (BCI) and serum levels of 25[OH]D during heart failure (HF). WC was determined in 412 patients (14.3% female, aged: 53.6 ± 10.0 years, NYHA class: 2.5 ± 0.8). Body fat, fat percentage and fat-free mass determined by dual energy X-rays absorptiometry (DEXA) and serum levels of 25[OH]D were analyzed. Logistic regression was used to calculate odds ratios for 25[OH]D insufficiency (<30 ng/mL) or deficiency (<20 ng/mL) by quintiles of WC, in comparison to weight-stable subgroup. The serum 25[OH]D was lower in weight loosing than weight stable subgroup. In fully adjusted models the risk of either insufficient or deficient 25[OH]D levels was independent of BCI and HF severity markers. The risk was elevated in higher weight loss subgroups but also in weight gain subgroup. In full adjustment, the odds for 25[OH]D deficiency in the top weight loss and weight gain subgroups were 3.30; 95%CI: 1.37–7.93, p = 0.008 and 2.41; 95%CI: 0.91–6.38, p = 0.08, respectively. The risk of 25[OH]D deficiency/insufficiency was also independently associated with potential UVB exposure, but not with nutritional status and BCI. Metabolic instability in HF was reflected by edema-free WC, but not nutritional status. BCI is independently associated with deficiency/insufficiency of serum 25[OH]D.
Mycolicibacterium brumae is a Safe and Non-Toxic Immunomodulatory Agent for Cancer Treatment

Intravesical Mycobacterium bovis Bacillus Calmette–Guérin (BCG) immunotherapy remains the gold-standard treatment for non-muscle-invasive bladder cancer patients, even though half of the patients develop adverse events to this therapy. On exploring BCG-alternative therapies, Mycolicibacterium brumae, a nontuberculous mycobacterium, has shown outstanding anti-tumor and immunomodulatory capabilities. As no infections due to M. brumae in humans, animals, or plants have been described, the safety and/or toxicity of this mycobacterium have not been previously addressed. In the present study, an analysis was made of M. brumae- and BCG-intravenously-infected severe combined immunodeficient (SCID) mice, M. brumae-intravesically-treated BALB/c mice, and intrahemacoelic-infected-Galleria mellonella larvae. Organs from infected mice and the hemolymph from larvae were processed to count bacterial burden. Blood samples from mice were also taken, and a wide range of hematological and biochemical parameters were analyzed. Finally, histopathological alterations in mouse tissues were evaluated. Our results demonstrate the safety and non-toxic profile of M. brumae. Differences were observed in the biochemical, hematological and histopathological analysis between M. brumae and BCG-infected mice, as well as survival curves rates and colony forming units (CFU) counts in both animal models. M. brumae constitutes a safe therapeutic biological agent, overcoming the safety and toxicity disadvantages presented by BCG in both mice and G. mellonella animal models.