Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular, Morphological, and Functional Characterization of Corticotropin-Releasing Factor Receptor 1-Expressing Neurons in the Central Nucleus of the Amygdala

Abstract The central nucleus of the amygdala (CeA) is a brain region implicated in anxiety, stress-related disorders and the reinforcing effects of drugs of abuse. Corticotropin-releasing factor (CRF, Crh) acting at cognate type 1 receptors (CRF1, Crhr1) modulates inhibitory and excitatory synaptic transmission in the CeA. Here, we used CRF1:GFP reporter mice to characterize the morphological, neurochemical and electrophysiological properties of CRF1-expressing (CRF1+) and CRF1-non-expressing (CRF1–) neurons in the CeA. We assessed these two neuronal populations for distinctions in the expression of GABAergic subpopulation markers and neuropeptides, dendritic spine density and morphology, and excitatory transmission. We observed that CeA CRF1+ neurons are GABAergic but do not segregate with calbindin (CB), calretinin (CR), parvalbumin (PV), or protein kinase C-δ (PKCδ). Among the neuropeptides analyzed, Penk and Sst had the highest percentage of co-expression with Crhr1 in both the medial and lateral CeA subdivisions. Additionally, CeA CRF1+ neurons had a lower density of dendritic spines, which was offset by a higher proportion of mature spines compared to neighboring CRF1– neurons. Accordingly, there was no difference in basal spontaneous glutamatergic transmission between the two populations. Application of CRF increased overall vesicular glutamate release onto both CRF1+ and CRF1– neurons and does not affect amplitude or kinetics of EPSCs in either population. These novel data highlight important differences in the neurochemical make-up and morphology of CRF1+ compared to CRF1– neurons, which may have important implications for the transduction of CRF signaling in the CeA.
THE ASSOCIATION OF DECREASED SERUM GDNF LEVEL WITH HYPERGLYCEMIA AND DEPRESSION IN TYPE 2 DIABETES MELLITUS.

Background: Comorbidity of diabetes and depression is a critical problem. Decreased glial-derived neurotrophic factor (GDNF) has been demonstrated in depression, but no evidence of a relationship between GDNF and diabetes has been shown. The present studies were designed to investigate the relationship between GDNF and metabolism. Methods: In Study 1, we performed a case-control study inwhichsubjects with type 2 diabetes mellitus (T2DM), prediabetes (p-DM) and normal glucose tolerance (NGT)were included.And in Study 2, we performed a cross-sectional study in 296 patients having prediabetes in whom the levels of serum GDNF, blood glucose, blood lipid, and blood pressure (BP), Body Mass Index (BMI), scores from the Patient Health Questionnaire (PHQ-9), EuroQol-5 (EQ-5D) scale, Diabetes Distress Scale (DDS) were measured, as well as single-nucleotide polymorphisms (SNPs) of GDNF includingrs884344, rs3812047, and rs2075680. Results: In Study 1, serum GDNF concentration was significantly lower in the T2DM group than in the NGT group (NGT: 11.706±3.918 pg/ml, p-DM: 10.736±3.722 pg/ml, DM: 9.884 ±2.804 pg/ml, P=0.008). In Study 2, significantly decreased serum GDNF levels were observed in subjects with poor glycemic control or depression (HbA1c<7.0% without depression: 11.524±2.903 pg/ml, HbA1c≥7.0% without depression: 10.625±2.577 pg/ml, HbA1c<7.0% with depression: 10.355±2.432 pg/ml, HbA1c≥7.0% with depression: 8.824±2.102 pg/ml, P=0.008). Double-factor variance analysis showed that glycemic control and depression were independent factors for the GDNF level. Moreover, the serum GDNF level was significantly inversely associated with the Fasting plasma glucose(FPG), 2 hours postprandial plasma glucose (2hPPG), HbA1c and PHQ-9 score. Conclusion: Glycemic dysregulation was an independent factor for the GDNF level. These findings suggest GDNF level might be involved in the pathophysiology of T2DM and depression through various pathways.
Identifying the challenges of interdisciplinary research on pornography use

Abstract This paper explores some the difficulties in undertaking a large-scale systematic review of pornography research literature. Its authors come from different disciplines across the humanities and social sciences, and work within an interdisciplinary team. The research project aims to understand pornography’s relationship with its audiences, particularly considering the relationship between pornography consumption and healthy sexual development. Offering a conversational account of research experiences on the project so far, the paper illustrates some key tensions and ongoing points of discussion in research committed to interdisciplinary scholarship, featuring disciplinary perspectives that do not easily correlate. We disagree on definitions, data-gathering methods and modes of data analysis. This paper does not aim to deliver solutions to these problems but presents two different voices describing our experiences of interdisciplinary porn research so far. In order to challenge and extend our disciplinary thinking, we offer an example of dialogue, and highlight the potential of listening across disciplinary frameworks. We encourage scholars from different disciplines to work together as this generates broader research perspectives and offers challenging conditions that can usefully interrogate and extend upon traditional research practice and methods. We hope this paper will generate further reflection among research peers about how best to strengthen interdisciplinary research practice, including, but not limited to, porn research.
Neighborhood Characteristics at Birth and Positive and Negative Psychotic Symptoms in Adolescence: Findings From the ALSPAC Birth Cohort

Abstract Background Urban birth is associated with risk of non-affective psychoses, but the association with subclinical positive and negative symptoms is less clear, despite emerging evidence. Further the extent to which these findings are confounded by polygenic risk scores (PRS) for schizophrenia is also unknown. Methods Using data from the Avon Longitudinal Study of Parents and Children, linked to census geographical indicators, we examined whether various indices of urbanicity at birth were associated with negative and positive psychotic symptoms at age 16 and 18 years, respectively. We used logistic regression models, controlling for child’s ethnicity, maternal age, education, marital status, social class, depressive symptoms, other neighborhood exposures, and, in a subsample of children of white ethnicity (N = 10 283), PRS for schizophrenia. Results Amongst 11 879 adolescents, those born in the most densely populated tertile had greater odds of reporting positive psychotic experiences, after multivariable adjustment (odds ratio [OR]: 1.57, 95% confidence intervals (CIs): 1.14–2.17). Adolescents born in the most socially fragmented neighborhoods had greater odds of negative symptoms, after multivariable adjustment (OR: 1.43, 95% CI: 1.06–1.85). Although we found that greater schizophrenia PRS were associated with an increased risk of being born in more deprived and fragmented (bot not more densely populated areas), these associations were not confounded by PRS. Interpretation Birth into more densely populated and socially fragmented environments increased risk of positive and negative psychotic phenomena in adolescence, respectively, suggesting that different forms of neighborhood social adversity may impinge on different psychopathophysiologies associated with the clinical expression of psychosis.
Insight of the Interaction between 2,4-thiazolidinedione and Human Serum Albumin: A Spectroscopic, Thermodynamic and Molecular Docking Study

Thiazolidinedione derivatives (TZDs) have attracted attention because of their pharmacological effects. For example, certain TZDs have been reported to ameliorate type II diabetes by binding and activating PPARs (peroxisome proliferator-activated receptors). Nonetheless, no information is available on the interaction between the heterocyclic 2, 4-thiazolidinedione (2,4-TZD) moiety and serum albumin, which could affect the pharmacokinetics and pharmacodynamics of TZDs. In this study, we investigated the binding of 2,4-TZD to human serum albumin (HSA). Intrinsic fluorescence spectroscopy revealed a 1:1 binding stoichiometry between 2,4-TZD and HSA with a binding constant (Kb) of 1.69 ± 0.15 × 103 M−1 at 298 K. Isothermal titration calorimetry studies showed that 2,4-TZD/HSA binding was an exothermic and spontaneous reaction. Molecular docking analysis revealed that 2,4-TZD binds to HSA subdomain IB and that the complex formed is stabilized by van der Waal’s interactions and hydrogen bonds. Molecular dynamics simulation confirmed the stability of the HSA-TZD complex. Further, circular dichroism and 3D fluorescence studies showed that the global conformation of HSA was slightly altered by 2,4-TZD binding, enhancing its stability. The results obtained herein further help in understanding the pharmacokinetic properties of thiazolidinedione.
Hydroxysafflor Yellow A mitigated myocardial ischemia/reperfusion injury by inhibiting the activation of the JAK2/STAT1 pathway

Hydroxysafflor Yellow A (HSYA) may reduce ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms remain unclear. The present study explored the effect and the mechanisms of HSYA on myocardial injury in vivo and in vitro. Myocardial infarct size was assessed by Evans blue/2,3,5-triphenyltetrazoliumchloride staining. Levels of cardiac troponin I (cTnI), interleukin-6 (IL-6), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured using commercial kits. Alteration of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation was determined by fluorescent signals. Apoptosis was detected by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling staining, flow cytometry assay and caspase-3 activity. Expression levels of the apoptosis-associated proteins were detected by reverse transcription quantitative polymerase chain reaction and western blot analysis. In vivo, animals treated with HSYA presented less severe myocardial injury and decreased janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) activity, improved antioxidant capacity and decreased apoptosis. In vitro, compared with the hypoxia (H)/reoxygenation (R) + HSYA group, AG490 and S1491 treatment decreased the releases of cTnI, IL-6 and LDH and enhanced the resistance to oxidative stress by maintaining MMP and decreasing ROS generation. In addition, AG490 and S1491 were also identified to alleviate the H/R-induced apoptosis by inhibiting caspase 3 activity and modulating the expression levels of cleaved caspase-3, tumor necrosis factor receptor superfamily member 6 (Fas), Fas ligand, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein. These data suggested that inactivation of the JAK2/STAT1 pathway strengthened the HSYA-induced protective effect in H/R-induced myocardial injury. In conclusion, the treatment of HSYA was effective in decreasing IR-induced myocardial injury, and this may be largely dependent on the JAK2/STAT1 pathway. Therefore, the present study provided a potential strategy to prevent myocardial I/R injury.
Inhibition of HER2-Positive Breast Cancer Growth by Blocking the HER2 Signaling Pathway with HER2 Glycan-Imprinted Nanoparticles.

Blocking the HER2 signaling pathway has been an effective strategy in the clinical treatment of HER2-positive breast cancer. Currently, it mainly relies on the use of monoclonal antibodies and tyrosine kinase inhibitors, which target HER2 through binding one of its domains or sub-domains. Herein we present a new strategy, nano molecularly imprinted polymer (nanoMIP). The nanoMIP was prepared by a state-of-the-art imprinting approach using all the N-glycans of HER2 as the template. The glycan-imprinted nanoMIP could bind almost all HER2 glycans and permit suppressing the dimerization of HER2 with other HER family members, resulting in blocking of the downstream signaling pathways and thereby inhibition of HER2+ breast cancer growth. In vitro experiments demonstrated that the nanoMIP specifically targeted HER2+ cells and inhibited cell proliferation at a 30% decrease. In vivo test indicated that the mean tumor volume of nanoMIP-treated group was only about a half of that of non-treated groups. This study provided not only a new possibility to the treatment of HER2+ breast cancer but also new evidence to boost further development of nanoMIPs for cancer therapy.
Long-Term Stability With the Athens Protocol (Topography-Guided Partial PRK Combined With Cross-Linking) in Pediatric Patients With Keratoconus.

PURPOSE To evaluate the safety, efficacy, and stability of topography-guided partial PRK combined with corneal cross-linking (CXL) (the Athens Protocol [AP]) in pediatric patients with keratoconus over a 4-year follow-up period. METHODS This prospective study included 39 keratoconic eyes of 21 patients younger than 18 years with clinical and imaging evidence of keratoconus progression. Partial topography-guided excimer laser ablation in conjunction with high-fluence CXL was performed in all patients according to the AP. Uncorrected distance visual acuity, corrected distance visual acuity, refraction, keratometry, endothelial cell density, topography, and tomography using both Scheimpflug and optical coherence tomography (OCT) were evaluated for 4 years postoperatively. RESULTS At 4 years postoperative, there was significant improvement in mean uncorrected distance visual acuity from 0.51 ± 0.31 (decimal) to 0.65 ± 0.26 (decimal; P < 0.05). Mean corrected distance visual acuity improved from 0.71 ± 0.22 (decimal) preoperatively to 0.81 ± 0.19 (decimal; P < 0.05), respectively. Mean flat keratometry (K1) and mean steep keratometry (K2) readings reduced from 44.95 ± 3.71 D and 49.32 ± 5.05 D, respectively, preoperatively to 43.14 ± 2.95 D and 46.28 ± 4.87 D, respectively, (P < 0.05) at 4 years. The mean anterior maximum keratometry (Kmax) reading reduced from 56.81 ± 2.94 D preoperatively to 48.11 ± 3.17 D at 48 months. The mean index of height decentration was 0.105 ± 0.054 μm preoperatively and 0.049 ± 0.024 (P < 0.05) at 4 years postoperative. Mean preoperative corneal thickness at the thinnest point was 436.7 ± 42.6 μm preoperatively, 392.50 ± 45.68 μm at 12 months postoperative, and 418.42 ± 17.01 μm at 4-year follow-up. Late-onset deep corneal haze, a potential intrinsic complication of this technique in pediatric patients, was encountered in 2 cases at least 1 year after the procedure. CONCLUSIONS Long-term results of the AP seem to be safe and effective in pediatric patients, with marked improvement in visual function and keratometric symmetry indices.
MALDI Mass Spectrometry Imaging Linked with Top-Down Proteomics as a Tool to Study the Non-Small-Cell Lung Cancer Tumor Microenvironment

Advanced non-small-cell lung cancer (NSCLC) is generally linked with a poor prognosis and is one of the leading causes of cancer-related deaths worldwide. Since only a minority of the patients respond well to chemotherapy and/or targeted therapies, immunotherapy might be a valid alternative in the lung cancer treatment field, as immunotherapy attempts to strengthen the body’s own immune response to recognize and eliminate malignant tumor cells. However, positive response patterns to immunotherapy remain unclear. In this study, we demonstrate how immune-related factors could be visualized from single NSCLC tissue sections (Biobank@UZA) while retaining their spatial information by using matrix assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI), in order to unravel the molecular profile of NSCLC patients. In this way, different regions in lung cancerous tissues could be discriminated based on the molecular composition. In addition, we linked visualization (MALDI MSI) and identification (based on liquid chromatography higher resolution mass spectrometry) of the molecules of interest for the correct biological interpretation of the observed molecular differences within the area in which these molecules are detected. This is of major importance to fully understand the underlying molecular profile of the NSCLC tumor microenvironment.
Efficacy and Safety of Dolutegravir plus Boosted-Darunavir Dual Therapy among Highly Treatment-Experienced Patients

Background Dual therapies decrease toxicity, pill-burden and treatment-associated cost. The combination of high genetic barrier drugs such as dolutegravir plus boosted-darunavir may be suitable as simplification regimen for patients harbouring multidrug-resistant virus. Methods Patients switched to a once-daily regimen consisting of dolutegravir plus darunavir, boosted with cobicistat or ritonavir, were included in this cohort study. The primary end point was the proportion of patients with HIV RNA viral load <37 copies/ml at week 48 (NCT02491242). Results Overall, 51 patients were enrolled. At baseline, all patients had failed to ≥2 antiretroviral classes. Genotypic resistance profiles showed a mean of primary mutations of 1.2 for non-nucleoside reverse transcriptase inhibitors, 2.4 for nucleoside/nucleotide reverse transcriptase inhibitors and 3.5 for protease inhibitors (PIs), but they were virologically suppressed for a median of 33 months (IQR 12–60). Only five patients had reduced sensitivity to darunavir and mean genotypic susceptibility score of dual therapy was 1.95 over 2. At week 48, there were no virological failures, three patients discontinued the regimen due to neuropsychiatric adverse events, two were lost to follow-up, and therefore the efficacy was 90% (95% CI, 82, 99%, intention-to-treat analysis). Mean estimated glomerular filtration rate decreased by 8.8 ml/min/1.73 m2, though kidney tubular parameters, high density lipoprotein-cholesterol and triglycerides levels improved after switching to dual therapy. Conclusions In highly treatment-experienced patients who were virologically suppressed, switching to the combination of dolutegravir plus boosted-darunavir dual therapy was effective and well tolerated, improving lipid and renal parameters.
Risk of infection associated with intravenous iron preparations: protocol for updating a systematic review

Introduction The benefits and risk of intravenous iron have been documented in previous systematic reviews and continue to be the subject of randomised controlled trials (RCTs). An ongoing issue that continues to be raised is the relationship between administering iron and developing infection. This is supported by biological plausibility from animal models. We propose an update of a previously published systematic review and meta-analysis with the primary focus being infection. Methods and analysis We will include RCTs and non-randomised studies (NRS) in this review update. We will search the relevant electronic databases. Two reviewers will independently extract data. Risk of bias for RCTs and NRS will be assessed using the relevant tools recommended by The Cochrane Collaboration. Data extracted from RCTs and NRS will be analysed and reported separately. Pooled data from RCTs will be analysed using a random effects model. We will also conduct subgroup analyses to identify any patient populations that may be at increased risk of developing infection. We will provide a narrative synthesis on the definitions, sources and responsible pathogens for infection in the included studies. Overall quality of evidence on the safety outcomes of mortality and infection will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Ethics and dissemination This systematic review will only investigate published studies and therefore ethical approval is not required. The results will be broadly distributed through conference presentations and peer-reviewed publications. Trial registration number PROSPERO (CRD42018096023).
Urban meadows as an alternative to short mown grassland: effects of composition and height on biodiversity

Abstract There are increasing calls to provide greenspace in urban areas, yet the ecological quality, as well as quantity, of greenspace is important. Short mown grassland designed for recreational use is the dominant form of urban greenspace in temperate regions but requires considerable maintenance and typically provides limited habitat value for most taxa. Alternatives are increasingly proposed, but the biodiversity potential of these is not well understood. In a replicated experiment across six public urban greenspaces, we used nine different perennial meadow plantings to quantify the relative roles of floristic diversity and height of sown meadows on the richness and composition of three taxonomic groups: plants, invertebrates, and soil microbes. We found that all meadow treatments were colonized by plant species not sown in the plots, suggesting that establishing sown meadows does not preclude further locally determined grassland development if management is appropriate. Colonizing species were rarer in taller and more diverse plots, indicating competition may limit invasion rates. Urban meadow treatments contained invertebrate and microbial communities that differed from mown grassland. Invertebrate taxa responded to changes in both height and richness of meadow vegetation, but most orders were more abundant where vegetation height was longer than mown grassland. Order richness also increased in longer vegetation and Coleoptera family richness increased with plant diversity in summer. Microbial community composition seems sensitive to plant species composition at the soil surface (0–10 cm), but in deeper soils (11–20 cm) community variation was most responsive to plant height, with bacteria and fungi responding differently. In addition to improving local residents’ site satisfaction, native perennial meadow plantings can produce biologically diverse grasslands that support richer and more abundant invertebrate communities, and restructured plant, invertebrate, and soil microbial communities compared with short mown grassland. Our results suggest that diversification of urban greenspace by planting urban meadows in place of some mown amenity grassland is likely to generate substantial biodiversity benefits, with a mosaic of meadow types likely to maximize such benefits.
Crystal structure of S. aureus YlaN, an essential leucine rich protein involved in the control of cell shape

The crystal structure of a conserved leucine rich protein, YlaN, from Staphylococcus aureus has been determined by X‐ray crystallography to 2.3 Å resolution. Whilst the precise function of S. aureus YlaN is unknown its homologue in B. subtilis has been shown to be essential for cell survival and is thought to be involved in controlling cell shape. The structure of S. aureus YlaN provides the first view of its protein family, which reveals that it is a novel homodimer whose subunit architecture is comprised of an antiparallel 3 helix bundle reminiscent of the helical arrangements seen in leucine zipper proteins. Analysis of the pattern of sequence conservation on the structure has led to the identification of two connected solvent exposed patches of conserved residues in each subunit located at one end of but on opposite faces of the molecule. We suggest that YlaN has a binding role in the cell rather than a catalytic function and a search for its ligand is underway to accelerate its exploitation as a target for antibiotic discovery. Proteins 2007. © 2007 Wiley‐Liss, Inc.