Miracle-dz/UniFAR-FTUs huggingface dataset:
Promiscuous G-Protein-Coupled Receptor Inhibition of Transient Receptor Potential Melastatin 3 Ion Channels by Gβγ Subunits

Transient receptor potential melastatin 3 (TRPM3) is a nonselective cation channel that is inhibited by Gβγ subunits liberated following activation of Gαi/o protein-coupled receptors. Here, we demonstrate that TRPM3 channels are also inhibited by Gβγ released from Gαs and Gαq. Activation of the Gs-coupled adenosine 2B receptor and the Gq-coupled muscarinic acetylcholine M1 receptor inhibited the activity of TRPM3 heterologously expressed in HEK293 cells. This inhibition was prevented when the Gβγ sink βARK1-ct (C terminus of β-adrenergic receptor kinase-1) was coexpressed with TRPM3. In neurons isolated from mouse dorsal root ganglion (DRG), native TRPM3 channels were inhibited by activating Gs-coupled prostaglandin-EP2 and Gq-coupled bradykinin B2 (BK2) receptors. The Gi/o inhibitor pertussis toxin and inhibitors of PKA and PKC had no effect on EP2- and BK2-mediated inhibition of TRPM3, demonstrating that the receptors did not act through Gαi/o or through the major protein kinases activated downstream of G-protein-coupled receptor (GPCR) activation. When DRG neurons were dialyzed with GRK2i, which sequesters free Gβγ protein, TRPM3 inhibition by EP2 and BK2 was significantly reduced. Intraplantar injections of EP2 or BK2 agonists inhibited both the nocifensive response evoked by TRPM3 agonists, and the heat hypersensitivity produced by Freund's Complete Adjuvant (FCA). Furthermore, FCA-induced heat hypersensitivity was completely reversed by the selective TRPM3 antagonist ononetin in WT mice and did not develop in Trpm3−/− mice. Our results demonstrate that TRPM3 is subject to promiscuous inhibition by Gβγ protein in heterologous expression systems, primary neurons and in vivo, and suggest a critical role for this ion channel in inflammatory heat hypersensitivity. SIGNIFICANCE STATEMENT The ion channel TRPM3 is widely expressed in the nervous system. Recent studies showed that Gαi/o-coupled GPCRs inhibit TRPM3 through a direct interaction between Gβγ subunits and TRPM3. Since Gβγ proteins can be liberated from other Gα subunits than Gαi/o, we examined whether activation of Gs- and Gq-coupled receptors also influence TRPM3 via Gβγ. Our results demonstrate that activation of Gs- and Gq-coupled GPCRs in recombinant cells and sensory neurons inhibits TRPM3 via Gβγ liberation. We also demonstrated that Gs- and Gq-coupled receptors inhibit TRPM3 in vivo, thereby reducing pain produced by activation of TRPM3, and inflammatory heat hypersensitivity. Our results identify Gβγ inhibition of TRPM3 as an effector mechanism shared by the major Gα subunits.
Barber From the Red Light District to the Red Carpet : The Gentrification of Amsterdam ’ s Red Light District and its Impact on the Democratic Citizenship Rights of Sex Workers

This paper evaluates the local policy-making processes that have a direct impact on Amsterdam‘s sex workers with reference to sexual citizenship theory and the normative model of deliberative democracy. It demonstrates how deliberation was previously incorporated as a political tool resulting in the legalization of brothels and examines the current non-deliberative gentrification efforts within the Red Light District. Ultimately, the paper argues that the gentrification of the R.L. D constitutes not only a reversal of deliberative democratic strategies but also a specific attack on the democratic rights of a sexual minority. It strongly suggests that the local policy making apparatuses be reformed in order to better protect the citizenship rights of an already marginalized population. Foreword: This paper is only a small portion of a much larger research projectthat being my dissertation. In addition to a more comprehensive exploration of the theoretical concepts that are only briefly mentioned throughout this paper, the wider project will also have support from field research and interviews that will later be analyzed using discourse analysis. In this regard, this paper is preliminary and perhaps stands as an incomplete engagement with the full breadth of the argument. Nonetheless, I am confident that the paper maintains a cohesive enough focus and argument to trigger thoughtful discussion amongst the panel‘s participants. The Complicated Nature of Sex Work: The topic of sex work is intensely complicated. My research does not attempt to clarify or ̳solve‘ (if at all possible) any of the ongoing philosophical, moral and/or political debates and/or contestations regarding sex work. Nor does it advance any one particular argument for or against sex work. Instead, I tend to further complicate such debates by inciting more ̳debate‘ and suggest a framework within which these issues can be more democratically considered. Theoretically, I place the topic of sex work at the intersections of the bodies of research on sexual minorities, sexual citizenship and democratic theory. As a result of this positioning, unique insights emerge through an interrogation of identity politics that focuses on issues of representation and democratic inclusion and specifically how democratic practices impact sex workers, the configuration of sex work and the sex industry as a whole. New issues that need to be addressed in our engagement of the larger intellectual project on sexual minorities, civil and political citizenship and power undoubtedly emerge. Indeed, this is a rich an exciting area of research and the further one explores these relationships the less one seems to know and the more research questions are brought to fore. Thus to remain on topic it is necessary to provide you with an outline so that I do not extend myself beyond the confines of this presentation.
Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

Objective To study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD). Methods An open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4–<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity. Results Oral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0–mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy. Conclusions Daily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study. Classification of evidence This study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.
Adolescent Sexuality Education in Contemporary Nigeria and its Implication for Pastoral Counselling

Adolescents’ sexuality has become an issue of controversy between the family, school and the church with each of the agents pointing accusing fingers at each other. The church could be a powerful force for social and behavioural change, particularly in the current efforts to combat the HIV/AIDS pandemic. Anecdotal evidence suggests that church youths are sexually active but few studies have documented the sexual practices of these youths in the church. The purpose of the study was to examine adolescents and sexuality education and the implication for pastoral counselling in the contemporary situation of Nigeria. Scholars are of the opinion that attitudinal and behavioural practices are formed most times based on social trends that are in vogue within an environment. The concern of educationists and counsellors is to re-orientate adolescents’ for adequate understanding of their nature and character that are susceptible factors culminant through exposure, learning, peer influence which truncate their understanding of social issues, especially sexuality. More might be achieved by a more proactive engagement of the church in young people sexual and reproductive health matters. It is therefore recommended that pastoral counsellors should recreate consciousness of right awareness, attitude, behaviour, and appropriate sensitivity to sexuality and all there are for the benefits of the youth cluster group and human common good. The adolescents require right education through counselling concerning the adverse repercussion of wrong behavioural practices on sexuality that violates and devastates human dignity.
Prevalence and Characteristics of Chronic Spinal Pain Patients with Different Hopes (Treatment Goals) for Ongoing Chiropractic Care.

Objectives: The treatment goals of patients successfully using ongoing provider-based care for chronic spinal pain can help inform health policy related to this care. Design: Multinomial logistical hierarchical linear models were used to examine the characteristics of patients with different treatment goals for their ongoing care. Settings/Location: Observational data from a large national sample of patients from 125 chiropractic clinics clustered in 6 U.S. regions. Subjects: Patients with nonwork-injury-related nonspecific chronic low-back pain (CLBP) and chronic neck pain (CNP). Interventions: All were receiving ongoing chiropractic care. Outcome measures: Primary outcomes were patient endorsement of one of four goals for their treatment. Explanatory variables included pain characteristics, pain beliefs, goals for mobility/flexibility, demographics, and other psychological variables. Results: Across our sample of 1614 patients (885 with CLBP and 729 with CNP) just under one-third endorsed a treatment goal of having their pain go away permanently (cure). The rest had goals of preventing their pain from coming back (22% CLBP, 16% CNP); preventing their pain from getting worse (14% CLBP, 12% CNP); or temporarily relieving their pain (31% CLBP, 41% CNP). In univariate analysis across these goals, patients differed significantly on almost all variables. In the multinomial logistic models, a goal of cure was associated with shorter pain duration and more belief in a medical cure; a goal of preventing pain from coming back was associated with lower pain levels; and those with goals of preventing their pain from getting worse or temporarily relieving pain were similar, including in having their pain longer. Conclusions: Although much of health policy follows a curative model, the majority of these CLBP and CNP patients have goals of pain management (using ongoing care) rather than "cure" (care with a specific end) for their chiropractic care. This information could be useful in crafting policy for patients facing provider-based nonpharmacologic care for chronic pain.
Isothiocyanate-Functionalized Mesoporous Silica Nanoparticles as Building Blocks for the Design of Nanovehicles with Optimized Drug Release Profile

A straightforward methodology for the synthesis of isothiocyanate-functionalized mesoporous silica nanoparticles (MSNs) by exposure of aminated MSNs to 1,1′-thiocarbonyldi-2(1H)-pyridone is reported. These nanoparticles are chemically stable, water tolerant, and readily react with primary amines without the formation of any by-product. This feature allows the easy modification of the surface of the nanoparticles for tuning their physical properties and the introduction of gatekeepers on the pore outlets. As a proof-of-concept, amino-isothiocyanate-functionalized MSNs have been used for the design of a nanocontainer able to release the drug Ataluren. The release profile of the drug can be easily fine-tuned with the careful choice of the capping amine.
Localization of 4 d N = 1 theories on D 2 × T 2

We consider 4d N = 1 gauge theories with R-symmetry on a hemisphere times a torus. We apply localization techniques to evaluate the exact partition function through a cohomological reformulation of the supersymmetry transformations. Our results represent the natural elliptic lifts of the lower dimensional analogs as well as a field theoretic derivation of the conjectured 4d holomorphic blocks, from which partition functions of compact spaces with diverse topology can be recovered through gluing. We also analyze the different boundary conditions which can naturally be imposed on the chiral multiplets, which turn out to be either Dirichlet or Robin-like. We show that different boundary conditions are related to each other by coupling the bulk to 3d N = 1 degrees of freedom on the boundary three-torus, for which we derive explicit 1-loop determinants.
Environmental Toxicology and Chemistry

Engineered aluminum oxide nanoparticles (Al2O3 NPs) having high‐grade thermal stability and water‐dispersion properties are extensively used in different industries and personal care products. Toxicological response evaluation of these NPs is indispensable in assessing the health risks and exposure limits because of their industrial disposal into the aquatic environment. We assessed and compared the developmental toxicity of Al2O3 NPs in Xenopus laevis and Danio rerio over a period of 96 h using the frog embryo teratogenic assay Xenopus and a fish embryo toxicity assay. Engineered Al2O3 NP exposure produced dose‐dependent embryonic mortality and decreased the embryo length, indicating a negative effect on growth. Moreover, Al2O3 NPs induced various malformations, such as small head size, a bent/deformed axis, edema, and gut malformation, dose‐dependently and altered the expression of heart‐ and liver‐specific genes in both X. laevis and D. rerio, as revealed by whole‐mount in‐situ hybridization and reverse transcriptase polymerase chain reaction. In conclusion, the toxicological data suggest that Al2O3 NPs are developmentally toxic and teratogenic and negatively affect the embryonic development of X. laevis and D. rerio. Our study can serve as a model for the toxicological evaluation of nanomaterial exposure on vertebrate development that is critical to ensure human and environmental safety. Environ Toxicol Chem 2019;38:2672–2681. © 2019 SETAC
Single-Stranded DNA Translocation Recordings Through Solid-State Nanopores on Glass Chips at 10-MHz Measurement Bandwidth.

Accurate and low-cost analysis of biomolecules is important for many applications. This work seeks to further improve the measurement bandwidths achievable with solid-state nanopores, which have emerged as an important platform for this analysis. We report single-stranded DNA translocation recordings at a bandwidth of 10 MHz copolymers of 80 (C20A20C20A20), 90 (C30A30C30), and 200 (C50A50C50A50) nucleotides through Si nanopores with effective diameters of 1.4 - 2.1 nm and effective membrane thickness 0.5 - 8.9 nm. By optimizing glass chips with thin nanopores and by integrating them with custom-designed amplifiers based on complementary metal-oxide-semiconductor (CMOS) technology, this work demonstrates detection of translocation events as brief as 100 ns with a signal-to-noise ratio exceeding seven at a measurement bandwidth of 10 MHz. We also report data robustness and variability across 13 pores of similar size and thickness yielding a current blockade between 30 and 60 % with a mean ionic current blockade (ΔI) of ~ 3 to 9 nA and a characteristic dwell time of ~ 2 to 21 ns per nucleotide. These measurements show that characteristic translocation rates are at least ten times faster than previously recorded. We detect transient intra-event fluctuations, multiple current levels within translocation events, and variability of DNA-translocation-event signatures and durations.
Synthesis, biological evaluation, and molecular modeling of nitrile‐containing compounds: Exploring multiple activities as anti‐Alzheimer agents

Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aβ anti‐aggregating properties. Eighty‐three nitrile‐containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 μM), MAO B (0.26 μM), and AChE (52 μM), while 32 exhibited a lead for selective MAO A (0.12 μM) inhibition coupled to AChE (48 μM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aβ1–42, was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aβ1–42 fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 μM), making it a potential lead for Alzheimer's disease application.
Hospitalizations associated with respiratory syncytial virus (RSV) and influenza in children, including children diagnosed with asthma.

BACKGROUND There is uncertainty about the burden of hospitalization associated with respiratory syncytial virus (RSV) and influenza in children, including those with underlying medical conditions. METHODS We applied previously developed methodology to HealthCare Cost and Utilization Project (HCUP) hospitalization data and additional data related to asthma diagnosis/previous history in hospitalized children to estimate RSV and influenza-associated hospitalization rates in different subpopulations of US children between 2003-2010. RESULTS The estimated average annual rates (per 100,000 children) of RSV-associated hospitalization with a respiratory cause (ICD-9 codes 460-519) present anywhere in the discharge diagnosis were 2381 (95% CI(2252,2515)) in children less than a year of age; 710.6(609.1,809.2) (age 1y); 395(327.7,462.4) (age 2y); 211.3(154.6,266.8) (age 3y); 111.1(62.4,160.1) (age 4y); 72.3(29.3,116.4) (ages 5-6y); 35.6(9.9,62.2) (ages 7-11y); and 39(17.5,60.6) (ages 12-17y). The corresponding rates of influenza-associated hospitalization were lower, ranging from 181(142.5,220.3) in age <1y to 17.9(11.7,24.2) in ages 12-17y. The relative risks for RSV-related hospitalization associated with a prior diagnosis of asthma in age groups under 5y ranged between 3.1(2.1,4.7) (age <1y) to 6.7(4.2,11.8) (age 2y); the corresponding risks for influenza-related hospitalization ranged from 2.8(2.1,4) (age <1y) to 4.9(3.8,6.4) (age 3y). CONCLUSIONS RSV-associated hospitalization rates in young children are high and decline rapidly with age. There are additional risks for both RSV and influenza hospitalization associated with a prior diagnosis of asthma, with the rates of RSV-related hospitalization in the youngest children diagnosed with asthma being particularly high.
The relationship of cardiorespiratory function, fatigue and depressive symptoms in PLHIV

ABSTRACT Fatigue and depressive symptoms are prevalent and associated with poor clinical outcomes, though the underlying physiological mechanisms of fatigue and depression are poorly understood. We examined the impact of cardiorespiratory fitness (CRF) on fatigue and depressive symptoms in one-hundred and nine PLHIV. CRF was examined by maximal cardiorespiratory stress test and determined by peak oxygen uptake. Patient-reported fatigue was examined utilizing the HIV-Related Fatigue Scale. Depressive symptoms were examined with the Beck Depression Inventory and PROMISE 29. Data was collected at baseline and six months. Generalized estimating equations were used to determine the effect of CRF on fatigue and depressive symptoms over time. Participants were approximately 53 years old, 86% African American (n = 93), and 65% male (n = 70). After controlling for age and sex, fatigue was inversely associated with CRF (β = −0.163; p = .005). Depressive symptoms were not associated with CRF as measured by the Beck Depression Inventory (p = .587) nor PROMIS 29 (p = .290), but over time, depressive symptoms decreased (p = .051). Increased CRF was associated with decreased fatigue levels, but was not associated with depressive symptoms. These results should guide future research aimed at how CRF might inform interventions to improve fatigue in PLHIV.
Comparison of Diet Quality Between Women With Chronic and Episodic Migraine

Different triggers including environmental, hormonal, and dietary factors have been introduced as migraine risk factors. There is some evidence to suggest that a high quality of diet could be effective regarding management of migraine. In this present study, we hypothesized that the diet quality of women with chronic migraine (CM) might be different from women with episodic migraine (EM).
Stability and change in social interaction style of children with autism spectrum disorder: A 4‐year follow‐up study

Children with autism spectrum disorder (ASD) show atypical social behavior but vary in their social interaction style (SIS), ranging from social aloofness to awkward social approaches. In a 4‐year follow‐up study, we examined longitudinal stability and change of SIS in children and adolescents with ASD and a normal intellectual ability (n = 55; mean age Time 1: 13 years; mean age Time 2: 17 years). Children's SIS was assessed with a parent questionnaire, the Wing Subtypes Questionnaire. As expected, most participants (69%) showed SIS stability across the 4‐year interval. Some participants (18%) shifted to a more typical or more active (but odd) SIS, while others (13%) shifted to a less typical or less active (but odd) SIS. A decrease in ASD symptoms predicted a shift toward a more typical or active SIS, but children's age and receptive verbal ability did not. SISs may be a meaningful way to create ASD subgroups and thus offer a promising research venue to further disentangle the heterogeneous autism spectrum. Autism Res 2020, 13: 74–81. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc.