Miracle-dz/UniFAR-FTUs huggingface dataset:
Neuro-Ophthalmic Manifestations of Sarcoidosis

Background: Sarcoidosis is an idiopathic, multisystem, inflammatory disease that has central nervous system involvement in 5%–15% of cases. The presentation of neurosarcoidosis is highly variable, and the MRI findings often mimic the appearance of other central nervous system diseases. Therefore, the diagnosis can be challenging. About one-third of neurosarcoidosis cases have neuro-ophthalmic manifestations and, thus, may be evaluated by a neuro-ophthalmologist early in the disease course. Methods: We performed a retrospective review of 22 cases of biopsy-proven sarcoidosis with neuro-ophthalmic manifestations, seen at the Wilmer Eye Institute from January 2013 to September 2019, in which we described the demographic information, clinical presentations, neuroimaging findings, and diagnostic evaluations. Results: Twenty-two patients were included. Fifteen patients identified as black and 7 as white. Fifteen were women, and 7 men. Mean age at sarcoidosis diagnosis was 45.9 years (range 26–66). Neuro-ophthalmic findings included optic neuropathy in 11 (50%); proptosis/orbital inflammation in 5 (23%); abducens palsy in 5 (23%); trochlear palsy, trigeminal distribution numbness, and bitemporal hemianopia in 2 each (9%); and oculomotor palsy, facial palsy, optic perineuritis, dorsal midbrain syndrome, central vestibular nystagmus, and papilledema in 1 each (5%). Eight (36%) had a pre-existing diagnosis of sarcoidosis; however, in 14 (64%), the neuro-ophthalmic presentation led to the sarcoidosis diagnosis. Patients with a pre-existing sarcoidosis diagnosis were younger than those without this diagnosis (38.5 vs 50.1 years, P = 0.035). Brain MRI was abnormal in all but 1 case (95%). In patients without a pre-existing sarcoidosis diagnosis, all 7 tested for angiotensin converting enzyme (ACE) had normal values, and 75% of the 12 who had computed tomography (CT) chest had findings suggestive of sarcoidosis (86% of black patients vs 50% of white patients). Conclusions: Patients with neurosarcoidosis may present initially with a neuro-ophthalmic manifestation, and this presentation may be more common in older patients. MRI usually is abnormal, although findings may be nonspecific. Serum testing for ACE is not helpful. Normal CT chest does not rule out underlying sarcoidosis, particularly in white patients.
Pathogenesis guided therapeutic management of COVID-19: an immunological perspective

Abstract Lack of standardized therapeutic approaches is arguably the significant contributor to the high burden of mortality observed in the ongoing pandemic of the Coronavirus disease, 2019 (COVID-19). Evidence is accumulating on SARS-CoV-2 specific immune cell dysregulation and consequent tissue injury in COVID-19. Currently, no definite drugs or vaccines are available against the disease; however initial results of the ongoing clinical trials have raised some hope. In this article, taking insights from the emerging empirical evidence about host-virus interactions, we deliberate upon plausible pathogenic mechanisms and suitable therapeutic approaches for COVID-19.
MOTIONS OF LIMIT SETS: A SURVEY

This is a survey article, giving an expanded version of a talk delivered at the Workshop on Grothendieck-Teichmller Theories, held on July 24-30, 2016, at Nankai University, Tianjin, China. Most of the work described is joint with either Caroline Series or Ken’ichi Ohshika.
Aberrant autophagosome formation occurs upon small molecule inhibition of ULK1 kinase activity

Pharmacological inhibition of ULK1 with multiple and distinct small molecules does not block autophagosome initiation but does impair autophagic flux. Autophagy is a crucial homeostatic mechanism that mediates the degradation of damaged or excess intracellular components. Such components are engulfed and sequestered into double membrane autophagosomes, which deliver their contents to lysosomes for degradation. Autophagy plays a role in numerous human disorders and its pharmacological targeting by small molecules offers therapeutic potential. The serine/threonine kinase ULK1 (and its homologue ULK2) is the most upstream component of the autophagic machinery and is required for autophagy initiation. Here, we use the most selective and potent published ULK1 inhibitors to gain insights into ULK1 kinase function during autophagy. Treatment with all inhibitors blocked autophagy but also resulted in the limited formation of initial autophagosome-like structures, which appeared abnormal in size and did not traffic to lysosomes. We found that upon ULK1 inhibition, phosphatidylinositol-3-phosphate–binding proteins are still recruited to forming autophagosomes, implying that ULK1 activity is not essential for VPS34 activation. We conclude that the kinase activity of ULK1 is important in regulating autophagosome maturation, by the phosphorylation of currently unidentified key substrates.
Age, menstruation history, and the brain.

OBJECTIVES To investigate the cross-sectional association between measures of menstruation history (including menopausal status, age of menopause, age of menarche, and duration of reproductive stage) and brain volume. METHODS Women (aged 45 to 79 years) from the UK Biobank were included (n = 5,072) after excluding those who had (1) hysterectomy or bilateral oophorectomy, (2) ever used menopausal hormone therapy, (3) ever had a stroke, or (4) were perimenopausal. Multiple linear hierarchical regression models were computed to quantify the cross-sectional association between measures of menstruation history and brain volume. Sensitivity analysis based on propensity matching for age (and other demographic/health covariates) were applied to estimate differences in brain volumes between matched premenopausal and postmenopausal women. RESULTS Postmenopausal women had 1.06% (95% confidence interval [CI]; 1.05-1.06) and 2.17% (95% CI, 2.12-2.22) larger total brain volume (TBV) and hippocampal volumes (HV), respectively, than premenopausal women. Sensitivity analysis with age matched samples produced consistent results (TBV: 0.82%, 95% CI, 0.25-1.38; HV: 1.33%, 95% CI, 0.01-2.63). For every year increase in age above 45 years, postmenopausal women experienced 0.23% greater reduction in TBV than premenopausal women (95% CI, -0.60 to -0.14), which was not observed for HV. Moreover, every 1 year delayed onset of menopause after 45 was associated with 0.32% (95% CI, -0.35 to -0.28) and 0.31% (95% CI, -0.40 to -0.22) smaller TBV and HV, respectively. Every additional year in age of menarche was associated with 0.10% (95% CI, 0.04-0.16) larger TBV, which was not detected for HV. Similarly, every 1 year increase in duration of reproductive stage was associated with 0.09% smaller TBV (95% CI, -0.15 to -0.03), which was not detected for HV. CONCLUSIONS Menopause may contribute to brain volume beyond typical aging effects. Furthermore, early age of menarche, delayed age of menopause and increasing duration of reproductive stage were negatively associated with brain volume. Further research is required to determine whether the negative association between age of menopause and HV is potentially an indicator of future vulnerability for dementia.
Multiple plasmid origin‐of‐transfer regions might aid the spread of antimicrobial resistance to human pathogens

Antimicrobial resistance poses a great danger to humanity, in part due to the widespread horizontal gene transfer of plasmids via conjugation. Modeling of plasmid transfer is essential to uncovering the fundamentals of resistance transfer and for the development of predictive measures to limit the spread of resistance. However, a major limitation in the current understanding of plasmids is the incomplete characterization of the conjugative DNA transfer mechanisms, which conceals the actual potential for plasmid transfer in nature. Here, we consider that the plasmid‐borne origin‐of‐transfer substrates encode specific DNA structural properties that can facilitate finding these regions in large datasets and develop a DNA structure‐based alignment procedure for typing the transfer substrates that outperforms sequence‐based approaches. Thousands of putative DNA transfer substrates are identified, showing that plasmid mobility can be twofold higher and span almost twofold more host species than is currently known. Over half of all putative mobile plasmids contain the means for mobilization by conjugation systems belonging to different mobility groups, which can hypothetically link previously confined host ranges across ecological habitats into a robust plasmid transfer network. This hypothetical network is found to facilitate the transfer of antimicrobial resistance from environmental genetic reservoirs to human pathogens, which might be an important driver of the observed rapid resistance development in humans and thus an important point of focus for future prevention measures.
Intestinal Protozoa Infections and Associated Risk Factors in Rural Community of Samosir Island Indonesia

Intestinal Protozoa Infections and Associated Risk Factors in the Community of Samosir Island Indonesia Hemma Yulfi 1 , Dewi Masyithah Darlan 1 , Toni Wandra 2 , Akira Ito 3 1 Department of Parasitology, Medical Faculty of Universitas Sumatera Utara 2 Directorate General of Disease Control and Environlmental Health, Ministry of Health of Indonesia 3 Department of Parasitology, Asahikawa University ABSTRACT Background: Intestinal protozoa infections are still a major health concern in tropical countries, including Indonesia. Giardia lamblia as one of the human protozoa can cause significant morbidity. It is associated with personal hygiene and environmental sanitation, such as the use of proper toilet, the habit of handwashing, the safe supply of household water, and the safe handling of foods. Some other protozoa such as Balantidium coli and Blastocystis hominis are correlated with the safe farming. However, information on the prevalence is still scarce in Indonesia, Therefore, this study was conducted to determine the correlation between the risk factors and the prevalence of protozoa infections among the community in Samosir Island, the island in the centre of Lake Toba, North Sumatera, Indonesia. Method: This is an analytical study using cross-sectional design, conducted in 2015. The fecal samples were collected from 217 participants and then examined microscopically for qualitative analysis. Demographic data and and risk factors were also collected using questionnaires, which was then analysed using computer statistical analysis program for data description and correlation. Results: The study found that 21.7% of fecal samples were positive for intestinal protozoa. Giardia lamblia was the most common infection (11.1%), followed by Blastocystis hominis (5.1%) and Entamoeba coli (4.1%). There were also mix infections between species, each comprises less than 5%. The use of proper toilet, washing hands with soap before eating and after defecating, pig farming, household water source, and drinking water showed strong correlation, all of which with p value > 0.05. However there was no correlation showed with cattle farming. Conclusion: The study showed moderate prevalence of intestinal protozoa in the island community. The risk factors suggest that contaminated water play important role in transmission. Key words: intestinal protozoa, personal hygiene, sanitation, Samosir, toilet, washing hands
INVESTIGATION OF THE RELATIONSHIP BETWEEN PERCEIVED SOCIAL SUPPORT LEVEL AND RISKY BEHAVIOURS

The sample of the research in which the relationship between the perceived social support level and the risky behaviours of high school students’ consists of 433 high school students going on studying in different types of high school in the district of Şehitkamil and Şahinbey, in Gaziantep. The research was figured according to descriptive methods and relational screening model. In order to collect data, “Perceived Social Support Scale (PSSS)” developed by Yıldırım (2004), “Risky Behaviours Scale (RBS)” developed by Gençtanırım Kuru (2010), was used by the researcher. And “Personal Info Form” was used by the researcher in order to get demographic information. In the study, the normality of the data was tested, and the Mann-Whitney U Test, Kruskal Wallis Test, and Spearman Brown Sequence Differences Correlation Coefficient were used. In consequence of the analysis of the data, it was observed that there was a negative relationship between the total points of SPSS and the points obtained by its subscales and the total points of SRB and the points obtained by its subscales. However, a significant relationship wasn't observed between the points of one of SPSS's subscales, the level of social support perceived by a friend, and the points of one of SRB's subscales, alcohol use, smoking and feeding behaviour.
Moving beyond trophic groups: evaluating fishing‑induced changes to temperate reef food webs

Fish capture has far-reaching but inadequately assessed implications for marine food webs. At the community level, such effects are typically investigated using dynamic models that rely on partially subjective categorization of species into trophic groups and that mostly overlook the substantial contribution of ontogenetic dietary variation within fish species. Here, we estimate consumption by fish communities at 376 southern Australian sites by applying a recently developed statistical model that predicts diet for individual fish based on their body size and taxonomic identity, with predicted diets then summed to estimate total community consumption. Impacts of fishing and human population density as top-down pressures on shallow reef communities were thereby resolved at fine taxonomic scales. Fishes were estimated to consume 71% more prey biomass in southern Australian no-take marine protected areas (MPAs) relative to fished sites. Consumption of algae and sessile invertebrates was unexpectedly high in MPAs, an outcome not apparent with fish species allocated into pre-defined trophic groups. Extension of this individual size-structured modelling approach provides an opportunity to fill important knowledge gaps in understanding human impacts on marine food webs.
Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress

Constitutively active extracellular signal–regulated kinase (ERK) 1/2 signaling promotes cancer cell proliferation and survival. We previously described a class of compounds containing a 1,1-dioxido-2,5-dihydrothiophen-3-yl 4-benzenesulfonate scaffold that targeted ERK2 substrate docking sites and selectively inhibited ERK1/2-dependent functions, including activator protein-1–mediated transcription and growth of cancer cells containing active ERK1/2 due to mutations in Ras G-proteins or BRAF, Proto-oncogene B-RAF (Rapidly Acclerated Fibrosarcoma) kinase. The current study identified chemical features required for biologic activity and global effects on gene and protein levels in A375 melanoma cells containing mutant BRAF (V600E). Saturation transfer difference-NMR and mass spectrometry analyses revealed interactions between a lead compound (SF-3-030) and ERK2, including the formation of a covalent adduct on cysteine 252 that is located near the docking site for ERK/FXF (DEF) motif for substrate recruitment. Cells treated with SF-3-030 showed rapid changes in immediate early gene levels, including DEF motif–containing ERK1/2 substrates in the Fos family. Analysis of transcriptome and proteome changes showed that the SF-3-030 effects overlapped with ATP-competitive or catalytic site inhibitors of MAPK/ERK Kinase 1/2 (MEK1/2) or ERK1/2. Like other ERK1/2 pathway inhibitors, SF-3-030 induced reactive oxygen species (ROS) and genes associated with oxidative stress, including nuclear factor erythroid 2–related factor 2 (NRF2). Whereas the addition of the ROS inhibitor N-acetyl cysteine reversed SF-3-030–induced ROS and inhibition of A375 cell proliferation, the addition of NRF2 inhibitors has little effect on cell proliferation. These studies provide mechanistic information on a novel chemical scaffold that selectively regulates ERK1/2-targeted transcription factors and inhibits the proliferation of A375 melanoma cells through a ROS-dependent mechanism. SIGNIFICANCE STATEMENT Constitutive activation of the extracellular signal–regulated kinase (ERK1/2) pathway drives the proliferation and survival of many cancer cell types. Given the diversity of cellular functions regulated by ERK1/2, the current studies have examined the mechanism of a novel chemical scaffold that targets ERK2 near a substrate binding site and inhibits select ERK functions. Using transcriptomic and proteomic analyses, we provide a mechanistic basis for how this class of compounds inhibits melanoma cells containing mutated BRAF and active ERK1/2.
HLA genotyping meets response to immune checkpoint inhibitors prediction: A story just started

The implementation of the immune checkpoint blockade as a therapeutic option in contemporary oncology is one of the significant immunological achievements in the last century. Constantly accumulating evidence suggests that the response to immune checkpoint inhibitors (ICIs) is not universal. Therefore, it is critical to identify determinants for response, resistance and adverse effects of immune checkpoint therapy that could be developed as prognostic and predictive markers. Recent large scale analyses of cancer genome data revealed the key role of HLA class I and class II molecules in cancer immunoediting, and it appears that HLA diversity can predict response to ICIs. In the present review, we summarize the emerging data on the role of HLA germline variations as a marker for response to ICIs.
Effectiveness of interventions for adherence to antiretroviral therapy in adults with HIV: a systematic review.

OBJECTIVE To identify the best available evidence of intervention effectiveness for adherence to antiretroviral therapy for HIV in adults. METHOD The methodology proposed by the Cochrane Collaboration was used, with search in the databases: PubMed, Embase, LILACS, CINAHL, Web of Science and SCOPUS. Randomized clinical trials of interventions to promote adherence to antiretroviral therapy for HIV, in the ≥ 18-year-old population, published from 2010 onward, were considered. The eligibility, inclusion and extraction of results were developed by two independent researchers. RESULTS The five studies included in the quantitative analysis were effective interventions that developed educational actions with the patient, especially mediated by software, the use of medication schedule reminders and the inclusion of treatment supporters that also received educational actions to develop such role. CONCLUSION The combination of interventions strengthens the promotion of adherence. There is a need for investment in the implementation of educational actions with patients, such as the inclusion of supporters, in addition to counseling and electronic devices for reminders, which must be offered in the services in an articulated and continuous manner.
Overview of global status of plastic presence in marine vertebrates

The presence of plastic in the environment is generating impacts on all habitats and has become a major global problem in marine megafauna. Macroplastics can cause entanglement, ingestion and loss of suitable habitats. In addition to entanglement problems, there is evidence that plastics are entering the food web through ingestion by marine organisms, which could ultimately be affecting humans. Much of the available information on the impact of plastic in biota is scattered and disconnected due to the use of different methodologies. Here, we review the variety of approaches and protocols followed to assess macro‐ and microplastic ingestion in marine vertebrates such as sea turtles, cetaceans and fishes in order to offer a global overview of their current status. The analysis of 112 studies indicates the highest plastic ingestion in organisms collected in the Mediterranean and Northeast Indian Ocean with significant differences among plastic types ingested by different groups of animals, including differences in colour and the type of prevalent polymers. In sea turtles, the most prevalent types of plastics are white plastics (66.60%), fibres (54.54%) and LDPE polymer (39.09%); in cetaceans, white macro‐ and microplastics (38.31%), fibres (79.95%) and PA polymer (49.60%); and in fishes, transparent plastics (45.97%), fibres (66.71%) and polyester polymer (36.20%). Overall, clear fibre microplastics are likely the most predominant types ingested by marine megafauna around the globe.
Evidence-based Classification in Track Athletics for Athletes with a Vision Impairment: A Delphi Study

Supplemental digital content is available in the text. SIGNIFICANCE The Delphi analysis presented here highlights the need for a sport-specific evidence-based classification system for track athletics for athletes with a vision impairment (VI). This system may differ for different race distances. Further research is required to develop a useful test battery of vision tests for classification. The issue of intentional misrepresentation during classification needs particular attention. PURPOSE At present, athletes with VI are placed into competition classes developed on the basis of legal definitions of VI. The International Paralympic Committee Athlete Classification Code states that all sports should have their own classification system designed to reflect the (visual) demands of that individual sport. This project gathered expert opinion on the specific requirements for an evidence-based sport-specific classification system for VI track athletics and to identify any particular issues within track athletics that require further research into their impact on sport performance. METHODS A three-round Delphi review was conducted with a panel of 17 people with expertise in VI track athletics. RESULTS The panel agreed that the current classification system in VI track athletics does not completely minimize the impact of impairment on competition outcome, highlighting the need for improvements. There was clear agreement that the existing measures of vision may fail to adequately reflect the type of vision loss that would impact running performance, with additional measures required. Intentional misrepresentation, where athletes “cheat” on classification tests, remains a serious concern. CONCLUSIONS The panel has identified measures of vision and performance that will inform the development of an evidence-based classification system by better understanding the relationship between VI and performance in track athletics. Issues such as the use of guides and whether the current class system was equitable gave rise to differing opinions within the panel, with these varying across the different running distances.