Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease

BACKGROUND Because immune checkpoint inhibition (ICI) can cause immune-related adverse events (irAEs) mimicking immunologic diseases, patients with preexisting autoimmune disease (AID) have been excluded from clinical trials. OBJECTIVE To evaluate the safety and efficacy of ICI in patients with advanced melanoma with and without AID. DESIGN Nationwide cohort study. SETTING The Netherlands. PATIENTS 4367 patients with advanced melanoma enrolled in the Dutch Melanoma Treatment Registry (DMTR) between July 2013 and July 2018 and followed through February 2019. MEASUREMENTS Patient, clinical, and treatment characteristics; irAEs of grade 3 or higher; treatment response; and survival. RESULTS A total of 415 patients (9.5%) had AID, categorized as rheumatologic AID (n = 227), endocrine AID (n = 143), inflammatory bowel disease (IBD) (n = 55), or "other" (n = 8). Of these, 228 patients (55%) were treated with ICI (vs. 2546 [58%] without AID); 87 were treated with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), 187 with anti-programmed cell death 1 (PD-1), and 34 with the combination. The incidences of irAEs of grade 3 or higher in patients with AID were 30% (95% CI, 21% to 41%) with anti-CTLA-4, 17% (CI, 12% to 23%) with anti-PD-1, and 44% (CI, 27% to 62%) with combination therapy; for patients without AID, the incidences were 30% (CI, 27% to 33%) (n = 916), 13% (CI, 12% to 15%) (n = 1540), and 48% (CI, 43% to 53%) (n = 388), respectively. Patients with AID more often discontinued anti-PD-1 treatment because of toxicity than patients without AID (17% [CI, 12% to 23%] vs. 9% [CI, 8% to 11%]). Patients with IBD were more prone to anti-PD-1-induced colitis (6 / 31 = 19% [CI, 7% to 37%]) than patients with other AIDs (3% [CI, 0% to 6%]) and patients without AID (2% [CI, 2% to 3%]). The objective response rate was similar in patients with versus without AID who were treated with anti-CTLA-4 (10% [CI, 5% to 19%] vs. 16% [CI, 14% to 19%]), anti-PD-1 (40% [CI, 33% to 47%] vs. 44% [CI, 41% to 46%]), or the combination (39% [CI, 20% to 59%] vs. 43% [CI, 38% to 49%]). Survival did not differ between patients with and those without AID (median, 13 months [CI, 10 to 16 months] vs. 14 months [CI, 13 to 15 months]). LIMITATION Information was limited on AID severity and immunosuppressive treatment. CONCLUSION Response to ICI with anti-CTLA-4, anti-PD-1, or their combination for advanced melanoma and overall incidence of any irAEs of grade 3 or higher were similar in patients with and without preexisting AID. However, severe colitis and toxicity requiring early discontinuation of treatment occurred more frequently among patients with preexisting IBD, warranting close follow-up. PRIMARY FUNDING SOURCE The Netherlands Organization for Health Research and Development.
ORANGE Represses Chloroplast Biogenesis in Etiolated Arabidopsis Cotyledons via Interaction with TCP14[OPEN]

Arabidopsis ORANGE, a DnaJ-like zinc finger domain protein, represses chloroplast biogenesis in dark-germinated cotyledons by interacting with the transcription factor TCP14 in the nucleus. The conversion of etioplasts into chloroplasts in germinating cotyledons is a crucial transition for higher plants, enabling photoautotrophic growth upon illumination. Tight coordination of chlorophyll biosynthesis and photosynthetic complex assembly is critical for this process. ORANGE (OR), a DnaJ-like zinc finger domain-containing protein, was reported to trigger the biogenesis of carotenoid-accumulating plastids by promoting carotenoid biosynthesis and sequestration. Both nuclear and plastidic localizations of OR have been observed. Here, we show that Arabidopsis (Arabidopsis thaliana) OR physically interacts with the transcription factor TCP14 in the nucleus and represses its transactivation activity. Through this interaction, the nucleus-localized OR negatively regulates expression of EARLY LIGHT-INDUCIBLE PROTEINS (ELIPs), reduces chlorophyll biosynthesis, and delays development of thylakoid membranes in the plastids of germinating cotyledons. Nuclear abundance of OR decreased upon illumination. Together with an accumulation of TCP14 in the nucleus, this derepresses chloroplast biogenesis during de-etiolation. TCP14 is epistatic to OR and expression of ELIPs is directly regulated by the binding of TCP14 to Up1 elements in the ELIP promoter regions. Our results demonstrate that the interaction between OR and TCP14 in the nucleus leads to repression of chloroplast biogenesis in etiolated seedlings and provide new insights into the regulation of early chloroplast development.
Challenges facing users of hearing aids during the COVID-19 pandemic

Abstract Objectives To explore the difficulties and obstacles of hearing-technology users during the coronavirus disease 2019 (COVID-19) pandemic. Design Descriptive, cross-sectional study. Study sample Individuals with permanent hearing loss (n = 278) answered a questionnaire designed to identify potential obstacles caused by using hearing aids during the COVID-19 pandemic, along with the reasons and deleterious effects associated with the devices. Each category reflected challenges in communicating, learning, and working during the pandemic. Different response categories were compared using descriptive and inferential statistics. Results The duration of daily device usage before the imposed lockdown was significantly higher than that during (Z = −2.01, p < 0.05), potentially attributable to the pandemic-induced difficulties faced by hearing-technology users. Such challenges include the shortage of batteries for hearing devices, limited access to repair or programming services of said devices and accessories, termination of speech therapy sessions, and obstacles to employment and education. Conclusions Among audiologists, efficiency and professionalism are required to educate the public and private health sectors regarding the prevalent challenges and their harmful impact on hearing-technology users during the COVID-19 pandemic. To overcome these issues, awareness of telepractice and its importance in providing audiological services to hard of hearing individuals should be raised.
Antioxidant potential of family Cucurbitaceae with special emphasis on Cucurbita genus: A key to alleviate oxidative stress‐mediated disorders

Oxidative stress is the imbalance between reactive oxygen species (ROS) production, and accumulation and the ability of a biological system to clear these reactive products. This imbalance leads to cell and tissue damage causing several disorders in human body, such as neurodegeneration, metabolic problems, cardiovascular diseases, and cancer. Cucurbitaceae family consists of about 100 genera and 1,000 species of plants including mostly tropical, annual or perennial, monoecious, and dioecious herbs. The plants from Cucurbita species are rich sources of phytochemicals and act as a rich source of antioxidants. The most important phytochemicals present in the cucurbits are cucurbitacins, saponins, carotenoids, phytosterols, and polyphenols. These bioactive phyto‐constituents are responsible for the pharmacological effects including antioxidant, antitumor, antidiabetic, hepatoprotective, antimicrobial, anti‐obesity, diuretic, anti‐ulcer activity, and antigenotoxic. A wide number of in vitro and in vivo studies have ascribed these health‐promoting effects of Cucurbita genus. Results of clinical trials suggest that Cucurbita provides health benefits for diabetic patients, patients with benign prostate hyperplasia, infertile women, postmenopausal women, and stress urinary incontinence in women. The intend of the present review is to focus on the protective role of Cucurbita spp. phytochemicals on oxidative stress‐related disorders on the basis of preclinical and human studies. The review will also give insights on the in vitro and in vivo antioxidant potential of the Cucurbitaceae family as a whole.
Hepatic Gene Expression Profiling of Atlantic Cod (Gadus morhua) Liver after Exposure to Organophosphate Flame Retardants Revealed Altered Cholesterol Biosynthesis and Lipid Metabolism

Since the phasing out and eventual ban on the production of organohalogen flame retardants, the use of organophosphate flame retardants (OPFRs) has increased rapidly. This has led to the detection of OPFRs in various environments including the Arctic. Two of the most prevalent OPFRs found in the Arctic are tris(2‐chloroisopropyl) phosphate (TCPP), and 2‐ethylhexyl diphenyl phosphate (EHDPP). The impacts of exposure to OPFRs on Arctic organisms is poorly understood. The objective of the present study was to determine the effects of exposure to TCPP, EHDPP, and a mixture of OPFRs on gene expression patterns in Atlantic cod, Gadus morhua. Precision‐cut liver slices from Atlantic cod in vitro were exposed to either TCPP or EHDPP alone or in a mixture and sampled at 2 different time points to quantify gene expression patterns using RNA sequencing. We exposed the liver slices to 2 concentrations of TCPP and EHDPP, one of which was chosen based on the levels found in the Arctic environment. The RNA sequencing results demonstrated differential expression of hundreds of genes in response to exposure. The genes representing cholesterol biosynthesis and lipid metabolism pathway were significantly enriched in all the treatment groups. Almost all the cholesterol biosynthesis genes were significantly down‐regulated in response to OPFR exposure. The effects on these pathways could involve various physiological processes including reproduction, growth, and behavior as well as adaptation to changing temperatures. Membrane fluidity is an important adaptive mechanism among aquatic organisms. Altered cholesterol homeostasis could have long‐term consequences by altering the adaptive potential of aquatic organisms to changing water temperatures, particularly those living in polar environments. These results suggest that OPFRs could have unique effects on the organisms living in the Arctic compared with other environments. Further studies are needed to understand the long‐term impacts of exposure to environmentally realistic concentrations using laboratory and field‐based studies. Environ Toxicol Chem 2021;40:1639–1648. © 2021 SETAC
De novo design of new chemical entities for SARS-CoV-2 using artificial intelligence

Background: The novel coronavirus SARS-CoV-2 has severely affected the health and economy of several countries. Multiple studies are in progress to design novel therapeutics against the potential target proteins in SARS-CoV-2, including 3CL protease, an essential protein for virus replication. Materials & methods: In this study we employed deep neural network-based generative and predictive models for de novo design of small molecules capable of inhibiting the 3CL protease. The generative model was optimized using transfer learning and reinforcement learning to focus around the chemical space corresponding to the protease inhibitors. Multiple physicochemical property filters and virtual screening score were used for the final screening. Conclusion: We have identified 33 potential compounds as ideal candidates for further synthesis and testing against SARS-CoV-2.
Uniparental Genome Elimination in Australian Carp Gudgeons

Abstract Metazoans usually reproduce sexually, blending the unique identity of parental genomes for the next generation through functional crossing-over and recombination in meiosis. However, some metazoan lineages have evolved reproductive systems where offspring are either full (clonal) or partial (hemiclonal) genetic replicas. In the latter group, the process of uniparental genome elimination selectively eliminates either the maternal or paternal genome from germ cells, and only one parental genome is selected for transmission. Although fairly common in plants, hybridogenesis (i.e., clonal haploidization via chromosome elimination) remains a poorly understood process in animals. Here, we explore the proximal cytogenomic mechanisms of somatic and germ cell chromosomes in sexual and hybrid genotypes of Australian carp gudgeons (Hypseleotris) by tracing the fate of each set during mitosis (in somatic tissues) and meiosis (in gonads). Our comparative study of diploid hybrid and sexual individuals revealed visually functional gonads in male and female hybrid genotypes and generally high karyotype variability, although the number of chromosome arms remains constant. Our results delivered direct evidence for classic hybridogenesis as a reproductive mode in carp gudgeons. Two parental sets with integral structure in the hybrid soma (the F1 constitution) contrasted with uniparental chromosomal inheritance detected in gonads. The inheritance mode happens through premeiotic genome duplication of the parental genome to be transmitted, whereas the second parental genome is likely gradually eliminated already in juvenile individuals. The role of metacentric chromosomes in hybrid evolution is also discussed.
Factors associated with parenting self‐efficacy: A systematic review

Abstract Aims To provide an overview of the parental, child, and socio‐contextual factors related to general parenting self‐efficacy (PSE) in the general population. Design Systematic review. Data sources Medline Ovid, Web of Science, Embase, and PsycINFO Ovid were systematically searched for studies published between January 1980‐June 2020. Review Methods Studies were included if they described associations between factor(s) and PSE among parents of children aged 0–18 years old in the general population, and published in an English language peer‐reviewed journal. Studies with participants from specific populations, studies describing the development of instruments for PSE, qualitative studies, reviews, theses, conference papers and book chapters were excluded. Belsky's process model of parenting guided the data synthesis. Results Of 3,819 articles, 30 articles met the inclusion criteria. Eighty‐nine factors were identified. There was evidence of associations between child temperament, maternal parenting satisfaction, parenting stress, maternal depression, household income, perceived social support and PSE. Evidence was inconsistent for an association of educational level, parity, number of children in the household and PSE in mothers. There was no evidence of an association for child gender, age, marital status and PSE in both mothers and fathers; ethnicity, age, employment status in mothers; household income in fathers; and educational level, parenting fatigue in parents. Conclusion A range of factors studied in relation to PSE was identified in this systematic review. However, the majority of the factors was reported by one or two studies often implementing a cross‐sectional design. Impact There is some evidence for an association between some potentially modifiable factors and PSE in the general population, this information may be used by health and social professionals supporting child health and well‐being. Future longitudinal studies are recommended to study parental, child and socio‐contextual factors associated with PSE to inform the development of intervention strategies.
How Can Reasoned Transparency Enhance Co-Creation in Healthcare and Remedy the Pitfalls of Digitization in Doctor-Patient Relationships?

This article addresses transparency in the current era of digital co-creation between healthcare professionals and patients. The concept of reasoned transparency is presented as a potential tool to guide the development of digital co-creation that is rapidly growing. The aim was to reflect on how doctors can apply transparency in their daily practice, following the shift from paternalistic to more collaborative relationships. On the one hand, our contribution indicates ways to take advantage of the existing digital tools to improve efficiency and increase patient trust, including the latest trend of artificial intelligence. On the other hand, this article identifies pitfalls of digitization and proposes reasoned transparency as remedy for the challenges rose by artificial intelligence. As a result, this perspective article tackles the issue of maintaining trustful and high-quality relationships between doctors and patients, increasingly challenged by the dissemination of online information and the pressures on healthcare professionals’ accountability towards patients and the general public.
In vitro gastrointestinal digestion and fermentation models and their applications in food carbohydrates

Abstract Food nutrients plays a crucial role in human health, especially in gastrointestinal (GI) health. The effect of food nutrients on human health mainly depends on the digestion and fermentation process in the GI tract. In vitro GI digestion and fermentation models had the advantages of reproducibility, simplicity, universality, and could integrally simulate the in vivo conditions to mimic oral, gastric, small intestinal and large intestinal digestive processes. They could not only predict the relationship among material composition, structure and digestive characteristics, but also evaluate the bioavailability of material components and the impact of digestive metabolites on GI health. This review systematicly summarized the current state of the in vitro simulation models, and made detailed descriptions for their applications, advantages and disadvantages, and specially their applications in food carbohydrates. In addition, it also provided the suggestions for the improvement of in vitro models and firstly proposed to establish a set of standardized methods of in vitro dynamic digestion and fermentation conditions for food carbohydrates, which were in order to further evaluate more effects of the nutrients on human health in future.
Genetically modified attenuated salmonid alphavirus: A potential strategy for immunization of Atlantic salmon.

Pancreas disease (PD) is a serious challenge in European salmonid aquaculture caused by salmonid alphavirus (SAV). In this study, we report the effect of immunization of Atlantic salmon with three attenuated infectious SAV3 strains with targeted mutations in a glycosylation site of the envelope E2 protein and/or in a nuclear localization signal in the capsid protein. In a pilot experiment, it was shown that the mutated viral strains replicated in fish, transmitted to naïve cohabitants and that the transmission had not altered the sequences. In the main experiment, the fish were immunized with the strains and challenged with SAV3 eight weeks after immunization. Immunization resulted in infection both in injected fish and 2 weeks later in the cohabitant fish, followed by a persistent but declining load of the mutated virus variants in the hearts. The immunized fish developed clinical signs and pathology consistent with PD prior to challenge. However, fish injected with the virus mutated in both E2 and capsid showed little clinical signs and had higher average weight gain than the groups immunized with the single mutated variants. The SAV strain used for challenge was not detected in the immunized fish indicating that these fish were protected against superinfection with SAV during the 12 weeks of the experiment.
Development of models for the prediction of energy content of fresh municipal solid waste from an unsecured landfill in India

The enormous quantities of municipal solid waste (MSW) generation in Indian cities has emerged as a serious concern. In order to reduce the negative environmental impacts of MSW accumulation in dumpsites or unsecured landfills across India, various measures have been proposed to facilitate conversion of MSW into a valuable resource. One such measure is the immense potential for utilization of MSW as a source of energy. In this study, a comprehensive estimation of the energy potential of freshly dumped MSW has been conducted at a large unsecured landfill site in Okhla, Delhi, which is the capital city of India. Multiple regression models were developed to predict gross calorific value (GCV) and net calorific value (NCV) of MSW in terms of physical composition, proximate analysis and ultimate analysis of the waste. The developed models were found to give a reasonably good prediction of energy content of freshly dumped MSW in the landfill. Food waste, inerts, textile and paper were found to be the prime constituents of fresh MSW arriving at the landfill site. Based on the statistical analysis, volatile matter content and oxygen content of MSW were found to be non-significant terms in the energy content models derived using proximate analysis and ultimate analysis, respectively. The models developed in this study can be used to predict energy content of MSW at other landfill sites in India under similar climatic conditions and disposal practices.
Sulfate is Incorporated into Cysteine to Trigger ABA Production and Stomatal Closure[OPEN]

Comprehensive genetic analysis uncovers mechanistic insights into sulfate-induced activation of ABA biosynthesis to close stomata. Plants close stomata when root water availability becomes limiting. Recent studies have demonstrated that soil-drying induces root-to-shoot sulfate transport via the xylem and that sulfate closes stomata. Here we provide evidence for a physiologically relevant signaling pathway that underlies sulfate-induced stomatal closure in Arabidopsis (Arabidopsis thaliana). We uncovered that, in the guard cells, sulfate activates NADPH oxidases to produce reactive oxygen species (ROS) and that this ROS induction is essential for sulfate-induced stomata closure. In line with the function of ROS as the second-messenger of abscisic acid (ABA) signaling, sulfate does not induce ROS in the ABA-synthesis mutant, aba3-1, and sulfate-induced ROS were ineffective at closing stomata in the ABA-insensitive mutant abi2-1 and a SLOW ANION CHANNEL1 loss-of-function mutant. We provided direct evidence for sulfate-induced accumulation of ABA in the cytosol of guard cells by application of the ABAleon2.1 ABA sensor, the ABA signaling reporter ProRAB18:GFP, and quantification of endogenous ABA marker genes. In concordance with previous studies, showing that ABA DEFICIENT3 uses Cys as the substrate for activation of the ABSCISIC ALDEHYDE OXIDASE3 (AAO3) enzyme catalyzing the last step of ABA production, we demonstrated that assimilation of sulfate into Cys is necessary for sulfate-induced stomatal closure and that sulfate-feeding or Cys-feeding induces transcription of NINE-CIS-EPOXYCAROTENOID DIOXYGENASE3, limiting the synthesis of the AAO3 substrate. Consequently, Cys synthesis-depleted mutants are sensitive to soil-drying due to enhanced water loss. Our data demonstrate that sulfate is incorporated into Cys and tunes ABA biosynthesis in leaves, promoting stomatal closure, and that this mechanism contributes to the physiological water limitation response.
Mass‐Spectrometric Observations of Argon Clusters in Nozzle Beams II. The Kinetics of Dimer Growth

Previously reported data on the growth of argon dimer in free‐jet expansions of pure argon are given a simple kinetic interpretation. A third‐order rate constant for recombination, coupled with consideration of the reverse process of dimer dissociation (assuming microscopic reversibility), is chosen for the kinetic description. The temperature–pressure–time history of the expanding gas is based on an ideal isentropic expansion to a terminal Mach number. A stepwise computer solution of the simple differential equation governing dimer growth is carried out with trial temperature‐dependent rate constants. Those rate constants which most nearly reproduce the experimental data are kf = 0.8 × 10−30 / T2 and kf = 6.5 × 10−30 / T3cm6molecules−2·sec−1. The principal conclusions are that the rate constants are strongly temperature dependent, reverse reactions are quite important, dimer continues to be formed throughout the expansion, and the best correlating parameter for dimer growth is P02d. An argument is also m.