Miracle-dz/UniFAR-FTUs huggingface dataset:
Early adult mental health, functional and neuropsychological outcomes of young people who have reported psychotic experiences: a 10-year longitudinal study

Abstract Background Psychotic experiences (PE) are highly prevalent in childhood and are known to be associated with co-morbid mental health disorders and functional difficulties in adolescence. However, little is known about the long-term outcomes of young people who report PE. Methods As part of the Adolescent Brain Development Study, 211 young people were recruited in childhood (mean age 11.7 years) and underwent detailed clinical interviews, with 25% reporting PE. A 10 year follow-up study was completed and 103 participants returned (mean age 20.9 years). Structured clinical interviews for DSM-5 (SCID-5) and interviewer-rated assessments of functioning were conducted. A detailed neuropsychological battery was also administered. Analyses investigated group differences between those who had ever reported PE and controls in early adulthood. Results The PE group was at a significantly higher risk of meeting DSM-5 criteria for a current (OR 4.08, CI 1.16–14.29, p = 0.03) and lifetime psychiatric disorder (OR 3.27, CI 1.43–7.47, p = 0.005). They were also at a significantly higher risk of multi-morbid lifetime psychiatric disorders. Significantly lower scores on current social and global functioning measures were observed for the PE group. Overall, there were no differences in neuropsychological performance between groups apart from significantly lower scores on the Stroop Word task and the Purdue Pegboard task for the PE group. Conclusions Our findings suggest that reports of PE are associated with poorer mental health and functional outcomes in early adulthood, with some persisting cognitive and motor deficits. Young people who report such symptoms could be considered a target group for interventions to aid functional outcomes.
Linguistic translation and validation of the Menopause-specific Quality of Life (MENQOL) questionnaire in Greek menopausal women.

OBJECTIVE The objective of this study was to translate the Menopause-specific Quality of Life (MENQOL) questionnaire in Greek and validate it for usage in the Greek population both in written and electronic form. METHODS The original English questionnaire MENQOL with 1-month recall period was translated by our team. According to instructions by Mapi Research Trust, the questionnaire was forward and back-translated, followed by patient testing and proofreading. Then it was transcripted electronically. Validation was performed with the following tests: internal consistency (reliability), stability (test-retest reliability) with Cronbach's alpha correlations, independent and paired t tests, and Pearson's correlation coefficients. RESULTS A total of 105 women, the majority recently menopausal, participated in the study. Internal consistency using the Cronbach's alpha showed high reliability ranging between 0.833 (physical domain) and 0.896 (vasomotor domain) for the written, and 0.720 (physical domain) and 0.868 (vasomotor domain) for the online form. Test-retest reliability was also high for both forms. The sexual domain of MENQOL had the higher mean, indicating the highest impact on quality of life (3.80 ± 2.35). CONCLUSIONS The Greek version of MENQOL is a reliable instrument for evaluating menopausal women. Availability of an online form will allow wider dissemination of the questionnaire. Further use of the questionnaire in Greece may lead to better understanding of the bothersome symptoms of menopause; a prerequisite to develop intervention studies for amelioration of quality of life.
Clinical, Molecular, Functional, and Structural Characterization of CYP17A1 Mutations in Brazilian Patients with 17-Hydroxylase Deficiency

Abstract 17-Hydroxylase-deficiency (17OHD) is a rare form of congenital adrenal hyperplasia. The aim of the work was to study clinical, biochemical, and the follow up of 17OHD patients and evaluate the function and structure of CYP17A1 mutations. Brazilian patients (three 46, XX and four 46, XY; 17±1.9 years) with combined 17-hydroxylase/17,20-lyase deficiency were evaluated. CYP17A1 gene was sequenced. Functional analysis was performed transfecting COS7 cells, which were exposed to progesterone or 17α-hydroxypregnolone substrates. Hormones were determined by RIA or LC-MS/MS. Three-dimensional structural modeling was performed by Modeller software. All patients presented prepubertal female external genitalia, primary amenorrhea, hypergonadotrophic hypogonadism, hypokalemic hypertension, decreased cortisol, and increased ACTH and corticosterone levels. Five patients presented previously described mutations: p.W406R/p.W406R, IVS2–2A>C/p.P428L, and p.P428L/p.P428L. Two patients presented the compound heterozygous p.G478S/p.I223Nfs*10 mutations, whose CYP17A1 activity and the three dimensional structural modeling are originally studied in this paper. CYP17A1 activity of p.G478S was 13 and 58% against progesterone and 17-hydroxypregnenolone, respectively. The p.I223Nfs*10 caused a truncated inactive protein. Three-dimensional p.G478S structural modeling showed different internal hydrophobic interaction with W313 and created an additional chain side contact with L476 residue. Due to the rarity of 17OHD, the long term follow up (15.3±3.1 years) of our patients will help endocrinologists on the management of patients with 17OHD. The mutation p.G478S/pI223Nfs*10 led to severe 17OHD and impaired CYP17A1 structure and function. The integration of in silico and in vitro analysis showed how the amino acid changes affected the CYP17A1 activity and contributed to clarify the molecular interactions of CYP17A1.
Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

Adenosine is involved in a range of physiological and pathological effects through membrane-bound receptors linked to G proteins. There are four subtypes of adenosine receptors, described as A1AR, A2AAR, A2BAR, and A3AR, which are the center of cAMP signal pathway-based drug development. Several types of agonists, partial agonists or antagonists, and allosteric substances have been synthesized from these receptors as new therapeutic drug candidates. Research efforts surrounding A1AR and A2AAR are perhaps the most enticing because of their concentration and affinity; however, as a consequence of distressing conditions, both A2BAR and A3AR levels might accumulate. This review focuses on the biological features of each adenosine receptor as the basis of ligand production and describes clinical studies of adenosine receptor-associated pharmaceuticals in human diseases.
The 400‐year natural history of a tropical coastal mangrove‐fringed lagoon: What can we learn?

Coastal lagoon ecosystems are important natural carbon sinks but are threatened by both climate change and direct human disturbances. Yet current understanding of historical changes to lagoon ecosystems is still poor due to the extensive labor requirements and expense of quantitative analyses. In this issue, Hapsari and colleagues analyze a unique data set that reconstructs the environmental change and carbon dynamics of the past 400 years for a tropical mangrove-fringed lagoon system in Java, Indonesia. Their work provides important insights into how climate change and human land use co-regulate the vegetation and carbon cycles of a tropical lagoon system and its catchment.
Prevalence of vitamin D deficiency in urban south Indians with different grades of glucose tolerance

Abstract The present study assessed the prevalence of vitamin D deficiency in an urban south Indian population in individuals with different grades of glucose tolerance. A total of 1500 individuals (900 normal glucose tolerance (NGT), 300 prediabetes and 300 with type 2 diabetes mellitus (T2DM)) who were not on vitamin D supplementation were randomly selected from the Chennai Urban Rural Epidemiological Study follow-up study. Anthropometric, clinical examination and biochemical investigations (25-hydroxyvitamin D (25(OH)D), insulin, glycated Hb (HbA1c) and serum lipids) were measured. Vitamin D deficiency was defined as serum 25(OH)D < 20·0 ng/ml, insufficiency as 20–29·9 ng/ml and sufficiency as ≥30 ng/ml. Of the 1500 individuals studied, 45 % were males and the mean age was 46 (sd 12) years. Vitamin D levels lowered with increasing degrees of glucose tolerance (NGT: 21 (sd 11); prediabetes: 19 (sd 10); T2DM: 18 (sd 11) ng/ml, P < 0·001). The overall prevalence of vitamin D deficiency was 55 % and was significantly higher among individuals with T2DM (63 %) followed by prediabetes (58 %) and NGT (51 %) (Pfor trend < 0·001). Women had 1·6 times the risk of vitamin D deficiency compared with men (unadjusted OR 1·6 (95 % CI 1·3, 2·0) and adjusted OR 1·6 (95 % CI 1·2, 1·9)). However, there was no increasing trend observed with increasing age. The prevalence of abdominal obesity (66 v. 49 %), generalised obesity (80 v. 64 %), the metabolic syndrome (45 v. 37 %) and insulin resistance (38 v. 27 %) was significantly higher in those with vitamin D deficiency compared with those without. This study shows that vitamin D deficiency is highly prevalent in this urban south Indian population and was higher among individuals with T2DM and prediabetes compared with those with NGT.
Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19).

Importance Virus infection has been widely described as one of the most common causes of myocarditis. However, less is known about the cardiac involvement as a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objective To describe the presentation of acute myocardial inflammation in a patient with coronavirus disease 2019 (COVID-19) who recovered from the influenzalike syndrome and developed fatigue and signs and symptoms of heart failure a week after upper respiratory tract symptoms. Design, Setting, and Participant This case report describes an otherwise healthy 53-year-old woman who tested positive for COVID-19 and was admitted to the cardiac care unit in March 2020 for acute myopericarditis with systolic dysfunction, confirmed on cardiac magnetic resonance imaging, the week after onset of fever and dry cough due to COVID-19. The patient did not show any respiratory involvement during the clinical course. Exposure Cardiac involvement with COVID-19. Main Outcomes and Measures Detection of cardiac involvement with an increase in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T, echocardiography changes, and diffuse biventricular myocardial edema and late gadolinium enhancement on cardiac magnetic resonance imaging. Results An otherwise healthy 53-year-old white woman presented to the emergency department with severe fatigue. She described fever and dry cough the week before. She was afebrile but hypotensive; electrocardiography showed diffuse ST elevation, and elevated high-sensitivity troponin T and NT-proBNP levels were detected. Findings on chest radiography were normal. There was no evidence of obstructive coronary disease on coronary angiography. Based on the COVID-19 outbreak, a nasopharyngeal swab was performed, with a positive result for SARS-CoV-2 on real-time reverse transcriptase-polymerase chain reaction assay. Cardiac magnetic resonance imaging showed increased wall thickness with diffuse biventricular hypokinesis, especially in the apical segments, and severe left ventricular dysfunction (left ventricular ejection fraction of 35%). Short tau inversion recovery and T2-mapping sequences showed marked biventricular myocardial interstitial edema, and there was also diffuse late gadolinium enhancement involving the entire biventricular wall. There was a circumferential pericardial effusion that was most notable around the right cardiac chambers. These findings were all consistent with acute myopericarditis. She was treated with dobutamine, antiviral drugs (lopinavir/ritonavir), steroids, chloroquine, and medical treatment for heart failure, with progressive clinical and instrumental stabilization. Conclusions and Relevance This case highlights cardiac involvement as a complication associated with COVID-19, even without symptoms and signs of interstitial pneumonia.
First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody–Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors

PURPOSE This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody–drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin. PATIENTS AND METHODS This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. RESULTS Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non–small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity. CONCLUSION Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.
A Rab prenyl membrane-anchor allows effector recognition to be regulated by guanine nucleotide

Significance Although proteins are commonly bound to membranes by hydrophobic transmembrane polypeptide segments, Rab family GTPases are anchored by prenyl groups. Rabs undergo conformational switching, being more active with bound GTP and less active with bound GDP. Rab-binding proteins, termed effectors, bind with higher affinity to Rab:GTP than to Rab:GDP. We now report that the prenylated yeast vacuolar Rab Ypt7 undergoes GTP/GDP switching, which is recognized by its effector HOPS (homotypic fusion and vacuole protein sorting). In contrast, transmembrane-anchored Ypt7 undergoes GTP/GDP switching, but binds and activates HOPS with either bound guanine nucleotide. A function of the Rab prenyl anchor is revealed, allowing an effector to read guanine-nucleotide-regulated Rab conformation. Membrane fusion is catalyzed by conserved proteins R, Qa, Qb, and Qc SNAREs, which form tetrameric RQaQbQc complexes between membranes; SNARE chaperones of the SM, Sec17/αSNAP, and Sec18/NSF families; Rab-GTPases (Rabs); and Rab effectors. Rabs are anchored to membranes by C-terminal prenyl groups, but can also function when anchored by an apolar polypeptide. Rabs are regulated by GTPase-activating proteins (GAPs), activating the hydrolysis of bound GTP. We have reconstituted fusion with pure components from yeast vacuoles including SNAREs, the HOPS (homotypic fusion and vacuole protein sorting) tethering and SNARE-assembly complex, and the Rab Ypt7, bound to membranes by either C-terminal prenyl groups (Ypt7-pr) or a recombinant transmembrane anchor (Ypt7-tm). We now report that HOPS-dependent fusion occurs with Ypt7 anchored by either means, but only Ypt7-pr requires GTP for activation and is inactive either with bound GDP or without bound guanine nucleotide. In contrast, Ypt7-tm is constitutively active for HOPS-dependent fusion, independent of bound guanine nucleotide. Fusion inhibition by the GAP Gyp1-46 is not limited to Ypt7-tm with bound GTP, indicating that this GAP has an additional mode of regulating fusion. Phosphorylation of HOPS by the vacuolar kinase Yck3 renders fusion strictly dependent on GTP-activated Ypt7, whether bound to membranes by prenyl or transmembrane anchor. The binding of GTP or GDP constitutes a selective switch for Ypt7, but with Ypt7-tm, this switch is only read by HOPS after phosphorylation to P-HOPS by its physiological kinase Yck3. The prenyl anchor of Ypt7 allows both HOPS and P-HOPS to be regulated by Ypt7-bound guanine nucleotide.
Carbon partitioning and lipid remodeling during phosphorus and nitrogen starvation in the marine microalga Diacronema lutheri (Haptophyta).

The domesticated marine microalga Diacronema lutheri is of great interest for producing various highly valuable molecules like lipids, particularly long-chain polyunsaturated fatty acids (LC-PUFA). In this study, we investigated the impact of phosphorus (P) and nitrogen (N) starvation on growth, carbon fixation (photosynthetic activity) and partitioning, and membrane lipid remodeling in this alga during batch culture. Our results show that the photosynthetic machinery was similarly affected by P and N stress. Under N starvation, we observed a much lower photosynthetic rate and biomass productivity. The degradation and re-use of cellular N-containing compounds contributed to triacylglycerol (TAG) accumulation. On the other hand, P-starved cells maintained pigment content and a carbon partitioning pattern more similar to the control, ensuring a high biomass. Betaine lipids constitute the major compounds of non-plastidial membranes, which are rich in eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Under P and N starvations, EPA was transferred from the recycling of membrane polar lipids, most likely contributing to TAG accumulation.
Use of indirect computed tomography lymphangiography to determine metastatic status of sentinel lymph nodes in dogs with a pre-operative diagnosis of melanoma or mast cell tumor.

Canine melanomas and mast cell tumors (MCTs) frequently metastasize to lymph nodes, worsening prognosis compared to dogs without metastasis. Sentinel lymph node (SLN) evaluation is more specific than evaluation of the lymph node closest to the tumor, which may not be the draining lymph node. Computed tomography lymphangiography (CTL) allows for SLN identification and one study of canine mammary tumors found that CTL was able to assist in determination of the metastatic status of inguinal SLNs prior to extirpation and histopathology. The objective of the present study was to evaluate CTL for use in determining metastasis to the SLN in dogs with a pre-operative diagnosis of melanoma or MCT in various locations by correlating CTL findings with histopathology. The hypothesis was that CTL would not be able to determine the metastatic status of lymph nodes, based on author experience. Dogs were prospectively enrolled and underwent CTL and subsequent SLN extirpation. Histopathology results for the primary tumor, SLN, and additional extirpated lymph nodes were recorded. Fifteen dogs were enrolled and 21 SLN were evaluated. The SLN enhancement pattern (heterogeneous, homogenous, or peripheral) was not associated with metastasis, nor was the attenuation value at 1 min, 5 min, or the change in attenuation value. No correlation was found between CTL findings and metastatic status of SLNs. Based on these results, CTL alone cannot be used to diagnose SLN metastasis. Extirpation of the SLN with histopathology is recommended to diagnose lymph node metastasis in dogs with melanoma and MCT. This article is protected by copyright. All rights reserved.
Corylin Inhibits Vascular Cell Inflammation, Proliferation and Migration and Reduces Atherosclerosis in ApoE-Deficient Mice

Atherosclerosis is a complex disease that includes several events, including reactive oxygen species (ROS) stress, inflammation, endothelial dysfunction, lipid deposition, and vascular smooth muscle cell (VSMC) proliferation and migration, which result in atherosclerotic plaque formation. Corylin, a flavonoid compound, is known to exhibit antioxidative, anti-inflammatory and antiproliferative effects. However, it remains unknown whether corylin could modulate atherogenesis. Here, we identified the anti-inflammatory effect of corylin in tumor necrosis factor-α (TNF-α)-induced vascular cells. In human umbilical vein endothelial cells (HUVECs), corylin suppressed TNF-α-induced monocyte adhesion to the HUVECs and transmigration by downregulating the ROS/JNK/nuclear factor-kappa beta (NF-κB) p65 pathway. In VSMCs, corylin inhibited TNF-α-induced monocyte adhesion by suppressing ROS production, mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB p65 translocation. In platelet-derived growth factor-BB (PDGF-BB)-induced VSMCs, corylin inhibited PDGF-BB-induced VSMC proliferation and migration through regulating the mammalian target of rapamycin (mTOR)/dynamin-1-like protein 1 (Drp1) signaling cascade. In addition, corylin treatment not only attenuated atherosclerotic lesions, ROS production, vascular cell adhesion protein-1 (VCAM-1) expression, monocyte adhesion and VSMC proliferation in apolipoprotein E (ApoE)-deficient mice but also inhibited neointimal hyperplasia in endothelial-denuded mice. Thus, corylin may be a potential prevention and treatment for atherosclerosis.
Artificial Intelligence Analysis of Gene Expression Data Predicted the Prognosis of Patients with Diffuse Large B-Cell Lymphoma.

OBJECTIVE We aimed to identify new biomarkers in Diffuse Large B-cell Lymphoma (DLBCL) using the deep learning technique. METHODS AND RESULTS The multilayer perceptron (MLP) analysis was performed in the GSE10846 series, divided into discovery (n = 100) and validation (n = 414) sets. The top 25 gene-probes from a total of 54,614 were selected based on their normalized importance for outcome prediction (dead/alive). By Gene Set Enrichment Analysis (GSEA) the association to unfavorable prognosis was confirmed. In the validation set, by univariate Cox regression analysis, high expression of ARHGAP19, MESD, WDCP, DIP2A, CACNA1B, TNFAIP8, POLR3H, ENO3, SERPINB8, SZRD1, KIF23 and GGA3 associated to poor, and high SFTPC, ZSCAN12, LPXN and METTL21A to favorable outcome. A multivariate analysis confirmed MESD, TNFAIP8 and ENO3 as risk factors and ZSCAN12 and LPXN as protective factors. Using a risk score formula, the 25 genes identified two groups of patients with different survival that was independent to the cell-of-origin molecular classification (5-year OS, low vs. high risk): 65% vs. 24%, respectively (Hazard Risk = 3.2, P < 0.000001). Finally, correlation with known DLBCL markers showed that high expression of all MYC, BCL2 and ENO3 associated to the worst outcome. CONCLUSION By artificial intelligence we identified a set of genes with prognostic relevance.