Miracle-dz/UniFAR-FTUs huggingface dataset:
AR mRNA stability is increased with AR-antagonist resistance via 3′UTR variants

Advanced prostate cancer is often treated with AR antagonists which target the androgen receptor (AR) on which the growth of the tumour depends. Prostate cancer often develops AR-antagonist resistance via a plethora of mechanisms, many of which are as yet unknown, but it is thought that AR upregulation or AR ligand-binding site mutations, may be responsible. Here we describe the production of cell lines based on LNCaP and VCaP, with acquired resistance to the clinically relevant AR antagonists, bicalutamide and enzalutamide. In these resistant cells, we observed, via RNA-seq, that new variants in the 3′UTR of the AR mRNA were detectable and that the levels were increased both with AR-antagonist treatment and with hormonal starvation. Around 20% of AR transcripts showed a 3 kb deletion within the 6.7 kb 3′UTR sequence. Actinomycin D and luciferase fusion studies indicated that this shorter mRNA variant was inherently more stable in anti-androgen-resistant cell lines. Of additional interest was that the AR UTR variant could be detected in the sera of prostate cancer patients in a cohort of serum samples collected from patients of Gleason grades 6–10, with an increasing level correlated to increasing grade. We hypothesise that the shorter AR UTR variant is a survival adaptation to low hormone levels and/or AR-antagonist treatment in these cells, where a more stable mRNA may allow higher levels of AR expression under these conditions.
Manipulating charge transfer from core to shell in CdSe/CdS/Au heterojunction quantum dots.

The photophysics of charge transfer and recombination mechanisms in a heterojunction structure of CdSe/CdS/Au quantum dots (QDs) are studied by temperature-dependent steady-state photoluminescence (PL) and time-resolved PL (TRPL). We manipulate the charge transfer from core to shell surface by varying the tunneling barrier height resulted from temperature variation, and the barrier width resulted from shell thickness variation. The charge transfer process, which can be described by a tunneling transmission model, is manifested by two competitive recombination processes, an intrinsic exciton emission and a trap emission in the near-infrared (NIR) range. Our study establishes the photophysics foundation for core/shell/metal application in photocatalyst and optoelectronics.
Comparison of Inspiratory Effort, Workload and Cycling Synchronization Between Non-Invasive Proportional-Assist Ventilation and Pressure-Support Ventilation Using Different Models of Respiratory Mechanics

Background This study assessed lung models for the influence of respiratory mechanics and inspiratory effort on breathing pattern and simulator-ventilator cycling synchronization in non-invasive ventilation. Material/Methods A Respironics V60 ventilator was connected to an active lung simulator modeling mildly restrictive, severely restrictive, obstructive and mixed obstructive/restrictive profiles. Pressure-support ventilation (PSV) and proportional-assist ventilation (PAV) were set to obtain similar tidal volume (VT). PAV was applied at flow assist (FA) 40–90% of resistance (Rrs) and volume assist (VA) 40–90% of elastance (Ers). Measurements were performed with system air leak of 25–28 L/minute. Ventilator performance and simulator-ventilator asynchrony were evaluated. Results At comparable VT, PAV had slightly lower peak inspiratory flow and higher driving pressure compared with PSV. Premature cycling occurred in the obstructive, severely restrictive and mildly restrictive models. During PAV, time for airway pressure to achieve 90% of maximum during inspiration (T90) in the severely restrictive model was shorter than those of the obstructive and mixed obstructive/restrictive models and close to that measured in the PSV mode. Increasing FA level reduced inspiratory trigger workload (PTP300) in obstructive and mixed obstructive/restrictive models. Increasing FA level decreased inspiratory time (TI) and tended to aggravate premature cycling, whereas increasing VA level attenuated this effect. Conclusions PAV with an appropriate combination of FA and VA decreases work of breathing during the inspiratory phase and improves simulator-ventilator cycling synchrony. FA has greater impact than VA in the adaptation to inspiratory effort demand. High VA level might help improve cycling synchrony.
Synthesis, DFT Calculations, and In Vitro Antioxidant Study on Novel Carba-Analogs of Vitamin E

Vitamin E is the most active natural lipophilic antioxidant with a broad spectrum of biological activity. α-Tocopherol (α-T), the main representative of the vitamin E family, is a strong inhibitor of lipid peroxidation as a chain-breaking antioxidant. Antioxidant and antiradical properties of vitamin E result from the presence of a phenolic hydroxyl group at the C-6 position. Due to stereoelectronic effects in the dihydropyranyl ring, the dissociation enthalpy for phenolic O–H bond (BDEOH) is reduced. The high chain-breaking reactivity of α-T is mainly attributed to orbital overlapping of the 2p-type lone pair on the oxygen atom (O1) in para position to the phenolic group, and the aromatic π-electron system. The influence of the O1 atom on the antioxidant activity of vitamin E was estimated quantitatively. The all-rac-1-carba-α-tocopherol was synthesized for the first time. Along with model compounds, 1-carba-analog of Trolox and its methyl ester were screened for their in vitro antioxidant activity by inhibition of styrene oxidation, and for the radical-reducing properties by means of 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) scavenging assay. To study the antioxidant activity, density functional theory (DFT) was also applied. Reaction enthalpies related to HAT (hydrogen atom transfer), SET–PT (sequential electron transfer—proton transfer), and SPLET (sequential proton loss—electron transfer) mechanisms were calculated.
Lipophilicity Determination of Antifungal Isoxazolo[3,4-b]pyridin-3(1H)-ones and Their N1-Substituted Derivatives with Chromatographic and Computational Methods

The lipophilicity of a molecule is a well-recognized as a crucial physicochemical factor that conditions the biological activity of a drug candidate. This study was aimed to evaluate the lipophilicity of isoxazolo[3,4-b]pyridine-3(1H)-ones and their N1-substituted derivatives, which demonstrated pronounced antifungal activities. Several methods, including reversed-phase thin layer chromatography (RP-TLC), reversed phase high-performance liquid chromatography (RP-HPLC), and micellar electrokinetic chromatography (MEKC), were employed. Furthermore, the calculated logP values were estimated using various freely and commercially available software packages and online platforms, as well as density functional theory computations (DFT). Similarities and dissimilarities between the determined lipophilicity indices were assessed using several chemometric approaches. Principal component analysis (PCA) indicated that other features beside lipophilicity affect antifungal activities of the investigated derivatives. Quantitative-structure-retention-relationship (QSRR) analysis by means of genetic algorithm—partial least squares (GA-PLS)—was implemented to rationalize the link between the physicochemical descriptors and lipophilicity. Among the studied compounds, structure 16 should be considered as the best starting structure for further studies, since it demonstrated the lowest lipophilic character within the series while retaining biological activity. Sum of ranking differences (SRD) analysis indicated that the chromatographic approach, regardless of the technique employed, should be considered as the best approach for lipophilicity assessment of isoxazolones.
Urea Transporters Identified as a Novel Diuretic Drug Target.

BACKGROUND Urea Transporters are a family of membrane channel proteins that facilitate the passive transport of urea across the plasma membrane. UTs are divided into two subgroups, UT-A and UT-B. UT-As are primarily located in renal tubule epithelia and UT-B is highly expressed in renal descending vasa recta and extrarenal multiple tissues. Various urea transporter knockout mice exhibit low urine concentrating ability, which suggests that UTs are a novel diuretic target. With high-throughput screening of small molecule drug-like compound libraries, various potent UT inhibitors with IC50 at nanomolar level were identified. Furthermore, selective UT inhibitors exhibit diuretic activity without disturbing electrolyte and metabolism balance, which confirms the potential of UTs as a diuretic target and UT inhibitors as novel diuretics that do not cause electrolyte imbalance. OBJECTIVE This review article summarizes the identification and validation of urea transporter as a potential diuretic target and the discovery of small molecule UT inhibitors as a novel type of diuretics. CONCLUSION UTs are a potential diuretic target. UT inhibitors play significant diuresis and would be developed to diuretics without disturbing electrolyte balance.
A comparative analysis of gene expression induced by the embryo in the caprine endometrium

Abstract Transcriptomics is an established powerful tool to identify potential mRNAs and ncRNAs (non‐coding RNAs) for endometrial receptivity. In this study, the goat endometrium at estrus day 5 (ED5) and estrus day 15 (ED15) were selected to systematically analyse the differential expressed genes (DEGs) what were induced by the embryo. There were 1,847 genes which were significantly differential expressed in endometrium induced by the embryo at ED5, and 1,346 at ED15 (p‐value < .05). Secreted phosphoprotein 1 (SPP) was the responsive genes for embryo in the goat endometrium during estrus cycle, neurotensis (NTS) and pleiotrophin (PTN) were the responsive genes for embryo in the goat endometrium at ED5, Testin (TES) and Phosphate and Tension Homology Deleted on Chromsome ten (PTEN) at ED15. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analysis revealed cytoplasm and Endocytosis were indispensable for the endometrium development in dairy goat. In a word, this resulting view of the transcriptome greatly uncovered the global trends in mRNAs expression induced by the embryo in the endometrium of dairy goats.
High risk behavior investigation and syphilis infection survelliance among female sex workers and drug users in Hainan

Objective: To understand the behavior characteristic and the infection rate of syphilis/HIV among female drug users and sex workers in Hainan. Methods: 317 sex workers in Hainan Provincial Women Education Center and 276 female drug users in the Addiction Withdraw Education Houses were surveyed by questionnaire and sero-test for syphilis and HIV. Results: (1) The average age of total 593 female drug users and sex workers was 25.36 years old. 154 of 317 sex workers (48.57%) use condom frequently 28 of 276 female drug users (10.14%) shared syringes and needles with others. 271 female drug users (98.2%) had commercial sex activities and 47 sex workers had drug abuse behavior (14.83%). (2) There were 88 syphilis cases (31.88%) among 276 female drug users and 56 cases (17.67%) among 317 sex workers. Syphilis prevalence in sex workers and female drug users are much higher than normal people and syphilis infection rate in female drug users is higher than in female sex workers. Conclusion: The research find out that sex workers and female drug users are at high risk. Syphilis prevalence in this two groups is quite high. It is necessary to take effective stratege of high risk behavioral intervention on these population.
Engagement in Care, Viral Suppression, Drug Resistance, and Reasons for Nonengagement After Home-Based Same-Day Antiretroviral Therapy Initiation in Lesotho: A Two-Year Follow-up of the CASCADE Trial

Abstract Background The CASCADE trial showed that compared with usual care (UC), offering same-day (SD) antiretroviral therapy (ART) during home-based human immunodeficiency virus testing improved engagement in care and viral suppression 12 months after diagnosis. However, questions remain regarding long-term outcomes and the risk of propagating drug resistance. Methods After completion of the primary endpoint at 12 months, participants not in care in both arms were traced and encouraged to access care. At 24 months, the following outcomes were assessed in both arms: engagement in care, viral suppression, and reasons for nonengagement. Furthermore, we explored the acquisition of drug resistance mutations (DRMs) among SD arm nonlinkers. Results At 24 months, 64% (88/137) in the SD arm vs 59% (81/137) in the UC arm were in care (absolute difference [AD], 5%; 95% confidence interval [CI], −6 to16; P = .38) and 57% (78/137) vs 54% (74/137) had documented viral suppression (AD, 3%; 95% CI, −9 to 15; P = .28). Among 36 participants alive and not in care at 24 months with ascertained status, the majority rejected contact with the health system or were unwilling to take ART. Among 8 interviewed SD arm nonlinkers, 6 had not initiated ART upon enrollment, and no acquired DRMs were detected. Two had taken the initial 30-day ART supply and acquired DRMs. Conclusions SD ART resulted in higher rates of engagement in care and viral suppression at 12 months but not at 24 months. Leveling off between both arms was driven by linkage beyond 12 months in the UC arm. We did not observe compensatory long-term disengagement in the SD arm. These long-term results endorse SD ART initiation policies. Clinical Trials Registration NCT02692027.
Optimal Strategies of Product Price, Quality, and Corporate Environmental Responsibility

With the awakening of environmental consciousness, more and more firms desire to go “green” by shifting their focus of corporate social responsibility (CSR) from charitable contributions to environmental actions called corporate environmental responsibility (CER). We develop a monopoly differential game to depict optimal corporate strategies of product price, quality, and CER. Using the Hamilton–Jacobi–Bellman (HJB) equation, we analyze optimal feedback equilibrium strategies for pricing and investing in both quality and CER with/without government subsidies. Numerical simulations show that government subsidy can improve CER and profit.
Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design

The fitness landscape of AAV Adeno-associated virus (AAV) is an important gene therapy vector. Using tools from synthetic biology, Ogden et al. provide a comprehensive view of how sequence changes in capsid proteins affect AAV properties. After saturation mutagenesis of the AAV2 capsid gene, the resulting library was subjected to multiplexed phenotypic analyses, including virus production, immunity, thermostability, and biodistribution. The mutant distribution to major organs in mice revealed dominant trends affecting in vivo delivery. Moreover, the findings uncovered a viral accessory protein with a role in viral production. Finally, a model built from the capsid fitness landscape enabled machine-guided design of useful variants with much higher efficiency than random mutagenesis. Science, this issue p. 1139 Detailed mutagenesis analysis reveals how sequence changes affect adeno-associated virus delivery properties in vivo and in vitro. Adeno-associated virus (AAV) capsids can deliver transformative gene therapies, but our understanding of AAV biology remains incomplete. We generated the complete first-order AAV2 capsid fitness landscape, characterizing all single-codon substitutions, insertions, and deletions across multiple functions relevant for in vivo delivery. We discovered a frameshifted gene in the VP1 region that expresses a membrane-associated accessory protein that limits AAV production through competitive exclusion. Mutant biodistribution revealed the importance of both surface-exposed and buried residues, with a few phenotypic profiles characterizing most variants. Finally, we algorithmically designed and experimentally verified a diverse in vivo targeted capsid library with viability far exceeding random mutagenesis approaches. These results demonstrate the power of systematic mutagenesis for deciphering complex genomes and the potential of empirical machine-guided protein engineering.
“As I Was Walking Down the Street, Four Strange Guys Came and Took Me Under the Bridge, Where They All Raped Me”: An Interpretative Phenomenological Analysis of the Types of Rape Experienced by Men in South Africa

Globally, rape is regarded as the most demoralizing type of trauma, and it has negative implications for victims and their families. Although rape affects the community in general, there is a paucity of literature on rape victimization of men. As a result, the types of rape experienced by them are not understood, and thus it is often difficult to develop contextually relevant interventions to prevent male rape and to support male rape victims. The objective of this study was to first determine and then describe, the types of rape experienced by men. An interpretative phenomenological analysis (IPA) qualitative approach was used to collect and analyze data from a purposive sample of 11 participants, using semistructured individual interviews. The findings of the study reveal six themes and related subthemes as six types and related subtypes of rape experienced by men as follows: acquaintance rape, including familial rape; stranger rape; gang rape, including corrective-gang rape, drug-facilitated gang rape, pack-hunting rape, women retributive rape (or women vengeance) for violence experienced from men; homophobic rape; prison rape, including transactional rape and gang initiation rape; and armed rape. The findings reveal the different contexts or settings where men are vulnerable to rape. This highlights the possibilities for the development of context-specific sexual violence prevention interventions for men, which include self-defense training and awareness campaigns specific to rape victimization of men. Furthermore, future studies are recommended to expose this pandemic. Activism is advocated to stop the silence around this public and social health issue.
A chemical path to quantum information

Nanoscale graphene can be designed to function as a molecular qubit The second quantum revolution is rapidly transforming fields like structural biology, cryptography, and condensed matter physics. The core quantum unit is the qubit, which has an infinite number of possible configurations through the superposition of its quantum states. This quantum property provides a singular approach for solving problems in computing, sensing, and metrology (1, 2). Creating and manipulating qubits is a grand challenge, leading to a plethora of viable approaches (3). Spin-based molecular qubits are promising because they unify atomicscale spatial precision with structural customization for systems integration (4). On page 1107 of this issue, Lombardi et al. (5) exemplified this approach by constructing an electronic spin-based molecular qubit from a carefully engineered state in nanoscale graphene, providing an elegant example of atomic control over qubit design.
Development and verification of a nomogram for prediction of recurrence‐free survival in clear cell renal cell carcinoma

Nowadays, gene expression profiling has been widely used in screening out prognostic biomarkers in numerous kinds of carcinoma. Our studies attempt to construct a clinical nomogram which combines risk gene signature and clinical features for individual recurrent risk assessment and offer personalized managements for clear cell renal cell carcinoma. A total of 580 differentially expressed genes (DEGs) were identified via microarray. Functional analysis revealed that DEGs are of fundamental importance in ccRCC progression and metastasis. In our study, 338 ccRCC patients were retrospectively analysed and a risk gene signature which composed of 5 genes was obtained from a LASSO Cox regression model. Further analysis revealed that identified risk gene signature could usefully distinguish the patients with poor prognosis in training cohort (hazard ratio [HR] = 3.554, 95% confidence interval [CI] 2.261‐7.472, P < .0001, n = 107). Moreover, the prognostic value of this gene‐signature was independent of clinical features (P = .002). The efficacy of risk gene signature was verified in both internal and external cohorts. The area under receiver operating characteristic curve of this signature was 0.770, 0.765 and 0.774 in the training, testing and external validation cohorts, respectively. Finally, a nomogram was developed for clinicians and did well in the calibration plots. This nomogram based on risk gene signature and clinical features might provide a practical way for recurrence prediction and facilitating personalized managements of ccRCC patients after surgery.
Clinical impact of repeat renal biopsies in patients with lupus nephritis: Renal biopsy is essential especially later in the course of the disease.

OBJECTIVE The clinical impact of repeat renal biopsies in patients with lupus nephritis (LN) is still debatable. The aim of this retrospective analysis was to assess whether repeat renal biopsy is a reliable tool in guiding therapeutic decisions. METHODS Laboratory and histological parameters and therapeutic changes in 35 patients with LN and repeat renal biopsies were retrospectively analyzed. Biopsies were performed in the presence of clinical evidence of an active glomerular disease. Biopsy specimens were retrospectively re-assessed by two renal pathologists and were compared according to the last International Society of Nephrology/Renal Pathology Society classification. RESULTS Thirty-five patients had two, 13 had three, 5 had four, 4 had five, and 1 had six renal biopsies. Fifty-eight comparisons of renal biopsies were made. Median times between the first and second, second and third, third and fourth, and fourth and fifth biopsies were 31, 27, 34, and 28 months, respectively. The mean activity indices from the first to the fifth biopsy were 8.7, 6.6, 7.8, 9.4, and 4.7, whereas the mean chronicity indices were 1.7, 2.3, 4.3, 5.2, and 7.7, respectively. Conversion was observed in 65.5% of cases with the most frequent (21%) being between classes III and IV. Conversion to a more severe type of nephritis occurred in 19% of cases. There was no correlation of laboratory parameters to the type of nephritis upon conversion. In 79% of cases, immunosuppressive therapy was modified after repeat biopsy. CONCLUSION Repeat biopsy is a reliable tool for monitoring the activity and chronicity status of LN and for tailoring immunosuppressive therapy to the needs of the patient, especially late in the course of the disease.