Miracle-dz/UniFAR-FTUs huggingface dataset:
In Vitro and In Vivo Assessment of FK506 Analogs as Novel Antifungal Drug Candidates

FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-nuclear factor of activated T cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. ABSTRACT FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-nuclear factor of activated T cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human-pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-O-demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31-O-demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with that of FK506. The four FK506 analogs generally possessed lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against Cryptococcus neoformans and Candida albicans, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against the invasive filamentous fungus Aspergillus fumigatus. Notably, 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31-O-demethyl-FK506 for further evaluation of its in vivo antifungal efficacy in a murine model of systemic cryptococcosis. Although 9-deoxo-31-O-demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, when it was used in combination with fluconazole, it significantly extended the survival of C. neoformans-infected mice, confirming the synergistic in vivo antifungal efficacy between these two agents.
On the predictive power of database classifiers formed by a small network of interacting chemical oscillators

The predictive ability of database classifiers constructed with a network of interacting chemical oscillators is studied. Databases considered here are composed of records, where each record contains a number of parameters (predictors) characterizing the case and the output variable describing the case type. In a series of recent papers we have discussed the top-down design of database classifiers, that return output information as the number of excitations observed at a selected droplet of the network. The design is based on an evolutionary algorithm that optimizes the network to achieve maximum mutual information between the network evolution and the record types. Here we discuss results illustrating that such classifiers do have a predicting ability. They are able to give a correct classification for database records that are not included into the process of classifier training. As example databases we consider points inside a multidimensional unit cube and test if they belong to a ball located at the mid of cube.
The Protective Effects of Danggui-Baizhu-Tang on High-Fat Diet-Induced Obesity in Mice by Activating Thermogenesis

Danggui-Baizhu-Tang (DBT), a traditional Chinese medicine decoction, was used for decreasing serum TG and TC remarkably. However, effect of weight control and action mechanism remains confused. In this study, to evaluate the anti-obesity effects, different gradient concentration of DBT (0.59, 1.17 g/kg) or Orlistat (Orl, 15.6 mg/kg; positive control) were administrated by gavage for 8 weeks in C57BL/6J mice which were pretreated with chow or high fat diet (HFD) for 3 months. After administration, significant decrease of body weight and food utilization was observed. It was indicated that concentration of triacylglycerol (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST) in serum were reduced strikingly, as well as accumulation of lipid droplets in liver. Meanwhile, DBT treatment could also decrease weight of white adipose tissue (WAT) and size of adipocytes, whereas increase weight of brown adipose tissue (BAT) in mice. Moreover, it was revealed that DBT could elevate rectal temperature by raising expression of uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), which were attributed to phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, TNF-α and IL-6, obesity-related inflammatory cytokines, were decreased. In conclusion, DBT could stimulate phosphorylation of AMPK to raise expression of UCP1 and PGC-1α, and activate thermogenesis to prevent obesity.
GuessTheKarma

Popularity systems, like Twitter retweets, Reddit upvotes, and Pinterest pins have the potential to guide people toward posts that others liked. That, however, creates a feedback loop that reduces their informativeness: items marked as more popular get more attention, so that additional upvotes and retweets may simply reflect the increased attention and not independent information about the fraction of people that like the items. How much information remains? For example, how confident can we be that more people prefer item A to item B if item A had hundreds of upvotes on Reddit and item B had only a few? We investigate using an Internet game called GuessTheKarma that collects independent preference judgments (N=20,674) for 400 pairs of images, approximately 50 per pair. Unlike the rating systems that dominate social media services, GuessTheKarma is devoid of social and ranking effects that influence ratings. Overall, Reddit scores were not very good predictors of the true population preferences for items as measured by GuessTheKarma: the image with higher score was preferred by a majority of independent raters only 68% of the time. However, when one image had a low score and the other was one of the highest scoring in its subreddit, the higher scoring image was preferred nearly 90% of the time by the majority of independent raters. Similarly, Imgur view counts for the images were poor predictors except when there were orders of magnitude differences between the pairs. We conclude that popularity systems marked by feedback loops may convey a strong signal about population preferences, but only when comparing items that received vastly different popularity scores.
Chronic Hepatitis C Association with Diabetes Mellitus and Cardiovascular Risk in the Era of DAA Therapy

Patients with chronic hepatitis C have both higher prevalence of diabetes mellitus type 2 (T2DM) and increased cardiovascular risk compared to never infected people. Sustained viral response (SVR) achievement led to decreasing incidence and prevalence of T2DM during the interferon era of HCV treatment. Currently, direct-acting antiviral drugs (DAA) are the gold standard for treating HCV infection, while yielding SVR in nearly all patients. In chronic HCV patients with T2DM (prediabetes most likely too), DAA therapy is associated with both better fasting glucose and glycated hemoglobin (HbA1C) controls; thus reducing pharmacotherapy in a certain part of patients is possible. Papers mentioned in the review confirmed DAA role in both total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) increase. This alteration was accompanied by an increase in high-density lipoprotein cholesterol (HDL-C) and a decrease in triglycerides (TG) verified by most of the studies. However, the clinical significance of lipoprotein alterations caused by DAA therapy has not been explained yet. Moreover, DAA treatment of chronic hepatitis C improves hypertension control and atherosclerotic plaques. It is very likely that DAA therapeutic regimens will decrease both T2DM prevalence and cardiovascular risk in chronic hepatitis C patients; further research, however, is needed.
Carbon monoxide releasing molecule-2 protects mice against acute kidney injury through inhibition of ER stress

Acute kidney injury (AKI), which is defined as a rapid decline of renal function, becomes common and recently recognized to be closely intertwined with chronic kidney diseases. Current treatment for AKI is largely supportive, and endoplasmic reticulum (ER) stress has emerged as a novel mediator of AKI. Since carbon monoxide attenuates ER stress, the objective of the present study aimed to determine the protective effect of carbon monoxide releasing molecule-2 (CORM2) on AKI associated with ER stress. Kidney injury was induced after LPS (15 mg/kg) treatment at 12 to 24 h in C57BL/6J mice. Pretreatment of CORM2 (30 mg/kg) effectively prevented LPS-induced oxidative stress and inflammation during AKI in mice. CORM2 treatment also effectively inhibited LPS-induced ER stress in AKI mice. In order to confirm effect of CO on the pathophysiological role of tubular epithelial cells in AKI, we used mProx24 cells. Pretreatment of CORM2 attenuated LPS-induced ER stress, oxidative stress, and inflammation in mProx24 cells. These data suggest that CO therapy may prevent ER stress-mediated AKI.
Hybrid Beamforming Design and Performance with Imperfect Phase Shifters in Multiuser Millimeter Wave Systems

Hybrid beamforming (HBF) includes analog beamforming with phase shifted array in RF domain and digital beamforming in baseband domain. Phase shifted array is usually made up with a large amount of phase shifters. Limited to the manufacturing techniques, phase shifters are unavoidable to have phaseshifting error and gain error. In the paper we study the influence of imperfect phase shifters upon the performance of multiuser mmWave massive MIMO systems1 with the wireless channel modeled by Rice fading. We derive the upper bound of the achievable sum rate with imperfect phase shifters, which can be very tight when the number of the antennas at the base station is much larger than the number of users. Results show that there is a performance ceiling due to phase-shifting error and gain error. Then we propose a novel channel estimation and hybrid beamforming method to settle this problem with low training overhead. It performs well when the channel paths are few and the channel Rician K-factor is large, which can be easily satisfied in outdoor mmWave communication environment. We further make a tradeoff between the performance and the training overhead so that the algorithm can work well in more kinds of propagation environment.
Contextual Neural Model for Translating Bilingual Multi-Speaker Conversations

Recent works in neural machine translation have begun to explore document translation. However, translating online multi-speaker conversations is still an open problem. In this work, we propose the task of translating Bilingual Multi-Speaker Conversations, and explore neural architectures which exploit both source and target-side conversation histories for this task. To initiate an evaluation for this task, we introduce datasets extracted from Europarl v7 and OpenSubtitles2016. Our experiments on four language-pairs confirm the significance of leveraging conversation history, both in terms of BLEU and manual evaluation.
Rab GTPases in Osteoclastic Endomembrane Systems

Osteoclasts (OCs) are bone-resorbing cells that maintain bone homeostasis. OC differentiation, survival, and activity are regulated by numerous small GTPases, including those of the Rab family, which are involved in plasma membrane delivery and lysosomal and autophagic degradation pathways. In resorbing OCs, polarized vesicular trafficking pathways also result in formation of the ruffled membrane, the resorbing organelle, and in transcytosis.
Alcohol marketing and adolescent alcohol consumption: Results from the International Alcohol Control study (South Africa).

BACKGROUND A complete ban on alcohol advertisements has been proposed for South Africa (SA), but there has been limited local research on the association between exposure to alcohol advertisements and alcohol consumption. OBJECTIVES To examine the role of demographic factors, exposure to alcohol marketing and liking of alcohol advertisements in predicting use of alcohol in the past 6 months among older adolescents in Tshwane, Gauteng Province, SA. METHODS Participants comprised the adolescent sub-sample (N=869) of the International Alcohol Control study survey that was conducted in SA. They consisted of 408 males and 461 females aged 16 and 17 years who took part in structured interviews on their alcohol consumption and various alcohol-related attitudes and behaviours. A multiple survey logistic regression analysis of the dependent variable alcohol use in the past 6 months on the independent variables age, gender, educational status, socioeconomic status, exposure to alcohol brand marketing and liking of alcohol advertisements was used. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. RESULTS The prevalence of drinking in the past 6 months was 10.6% (95% CI 5.9 - 18.3). The number of modes of alcohol brand/product advertising to which the adolescents were exposed was positively associated with alcohol use in the past 6 months. An additional mode of alcohol brand/product advertising exposure led to a relative increase of 1.13 (95% CI 1.01 - 1.28) in the odds of alcohol use in the past 6 months (e.g. a participant who was exposed to advertisements via seven different channels was 2.08 times more likely to have used alcohol in the past 6 months than a participant with exposure via a single channel). Having a strong dislike of alcohol advertisements was associated negatively (protective) with alcohol use in the past 6 months, with the odds ratio being 0.35 (95% CI 0.19 - 0.64). Having only a moderate dislike or a liking of alcohol advertisements was positively associated with alcohol use in the past 6 months among the study participants (OR 2.90 and 2.84, respectively). Age, gender, educational status and socioeconomic status were not independently associated with alcohol consumption. CONCLUSIONS Exposure to alcohol marketing and not being strongly averse to advertisements of alcohol brands and products were associated with alcohol use among adolescents. The results have implications for policies on alcohol marketing in SA.
Addition of a polygenic risk score, mammographic density, and endogenous hormones to existing breast cancer risk prediction models: A nested case–control study

Background No prior study to our knowledge has examined the joint contribution of a polygenic risk score (PRS), mammographic density (MD), and postmenopausal endogenous hormone levels—all well-confirmed risk factors for invasive breast cancer—to existing breast cancer risk prediction models. Methods and findings We conducted a nested case–control study within the prospective Nurses’ Health Study and Nurses’ Health Study II including 4,006 cases and 7,874 controls ages 34–70 years up to 1 June 2010. We added a breast cancer PRS using 67 single nucleotide polymorphisms, MD, and circulating testosterone, estrone sulfate, and prolactin levels to existing risk models. We calculated area under the curve (AUC), controlling for age and stratified by menopausal status, for the 5-year absolute risk of invasive breast cancer. We estimated the population distribution of 5-year predicted risks for models with and without biomarkers. For the Gail model, the AUC improved (p-values < 0.001) from 55.9 to 64.1 (8.2 units) in premenopausal women (Gail + PRS + MD), from 55.5 to 66.0 (10.5 units) in postmenopausal women not using hormone therapy (HT) (Gail + PRS + MD + all hormones), and from 58.0 to 64.9 (6.9 units) in postmenopausal women using HT (Gail + PRS + MD + prolactin). For the Rosner–Colditz model, the corresponding AUCs improved (p-values < 0.001) by 5.7, 6.2, and 6.5 units. For estrogen-receptor-positive tumors, among postmenopausal women not using HT, the AUCs improved (p-values < 0.001) by 14.3 units for the Gail model and 7.3 units for the Rosner–Colditz model. Additionally, the percentage of 50-year-old women predicted to be at more than twice 5-year average risk (≥2.27%) was 0.2% for the Gail model alone and 6.6% for the Gail + PRS + MD + all hormones model. Limitations of our study included the limited racial/ethnic diversity of our cohort, and that general population exposure distributions were unavailable for some risk factors. Conclusions In this study, the addition of PRS, MD, and endogenous hormones substantially improved existing breast cancer risk prediction models. Further studies will be needed to confirm these findings and to determine whether improved risk prediction models have practical value in identifying women at higher risk who would most benefit from chemoprevention, screening, and other risk-reducing strategies.
Epidemiology of Fascioliasis in Kermanshah Province, Western Iran

Background: We aimed to determine the prevalence of fasciolosis in the definitive hosts (human and livestock) and intermediate (Lymnaea snails) hosts in Kermanshah Province, western Iran from 2014–2016. Methods: The study on animals was descriptive and retrospective one. All daily records of animals slaughtered in the abattoirs were analyzed. For the study of human fascioliasis, 975 serum samples were collected from different parts of Kermanshah Province and analyzed using ELISA based on excretory-secretory antigens. Moreover, 4400 Lymnaea snails were collected from 25 habitats. The snails were identified and examined for presence of cercariae by shedding method. Results: Fasciolosis was diagnosed in 1.7% of slaughtered animals, which was significantly greater than the other species (P<0.005). There was significant difference (P<0.001) between the prevalence of fasciolosis and seasonal pattern. As for human cases, five cases (0.5%) were positive for fascioliasis. Regarding the seropositivity to fasciolosis, no significant differences were found for age groups, sex, level of education and occupation. No Fasciola infection was seen in snails of the family Lymnaeidae. Conclusion: The prevalence of Fasciola parasite was lower compared to other provinces. This is probably due to sequential decline in rainfall and hot climate that makes conditions difficult for the snail intermediate host snails and the larval stages of fasciolid trematodes. The habitual food of people is another important point.
Risk Analysis of Colorectal Post-Polypectomy Bleeding Due to Antithrombotic Agent

Background/Aims: Post-polypectomy bleeding (PPB) is a major complication of colorectal polypectomy, and antithrombotics is one of the major risk factors of PPB. The purpose of this study was to investigate PPB risks with regard to the combinations of antithrombotic agents used. Methods: We retrospectively reviewed cases involving colonoscopic polyp resection between September 2002 and December 2014. The risk of PPB was assessed according to patient and lesion factors, including antithrombotic use. Antithrombotics were discontinued before polypectomy. Results: A total of 6,382 colonoscopies with 12,876 polypectomies were analyzed. PPB occurred in 55 patients (0.9%) and 63 lesions (0.5%). Among patients treated with antithrombotics, heparin bridging (HB) therapy was an independent risk factor of PPB (per patient, 20%, OR 33.1, p < 0.001; per lesion, 9.1%, OR 17.3, p < 0.001) compared to those without antithrombotics (per patient 0.7%; per lesion 0.4%). Among patients without HB, the combination of anticoagulant + antiplatelet agents was significantly associated with PPB (per patient, 5%, OR 7.73, p = 0.007; per lesion, 2.4%, OR 6.31, p = 0.003). Conclusion: HB therapy is a major risk factor for PPB. Among patients without HB, anticoagulant + antiplatelet therapy was a significant risk factor for PPB.
Mapping Instructions to Actions in 3D Environments with Visual Goal Prediction

We propose to decompose instruction execution to goal prediction and action generation. We design a model that maps raw visual observations to goals using LINGUNET, a language-conditioned image generation network, and then generates the actions required to complete them. Our model is trained from demonstration only without external resources. To evaluate our approach, we introduce two benchmarks for instruction following: LANI, a navigation task; and CHAI, where an agent executes household instructions. Our evaluation demonstrates the advantages of our model decomposition, and illustrates the challenges posed by our new benchmarks.
Circulating miRNAs as Diagnostic Biomarkers for Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. Its main neuropathological hallmarks are the degeneration of dopaminergic neurons in the substantia nigra and alpha-synuclein containing protein inclusions, called Lewy Bodies. The diagnosis of idiopathic PD is still based on the assessment of clinical criteria, leading to an insufficient diagnostic accuracy. Additionally, there is no biomarker available allowing the prediction of the disease course or monitoring the response to therapeutic approaches. So far, protein biomarker candidates such as alpha-synuclein have failed to improve diagnosis of PD. Circulating microRNAs (miRNAs) in body fluids are promising biomarker candidates for PD, as they are easily accessible by non- or minimally-invasive procedures and changes in their expression are associated with pathophysiological processes relevant for PD. Advances in miRNA analysis methods resulted in numerous recent publications on miRNAs as putative biomarkers. Here, we discuss the applicability of different body fluids as sources for miRNA biomarkers, highlight technical aspects of miRNA analysis and give an overview on published studies investigating circulating miRNAs as biomarker candidates for diagnosis of PD and other Parkinsonian syndromes.
Profile of the skin microbiota in a healthy Chinese population

The skin microbiota is an inseparable component of the skin barrier structure, which participates in the stabilization or impairment of the barrier function as well as the development of many skin diseases. To characterize the normal skin microbiota and its association with skin sites, age and sex, we recruited 50 volunteers divided into children, adolescents, young adults, middle‐aged adults and the elderly. The skin sites consisted of cheeks, volar forearms (representing dry environments) and upper back (representing sebaceous environments). A total of 9 574 365 high‐quality sequences of the V3 to V4 region of the 16S rRNA gene were annotated with taxonomic information related to two archaeal phyla (Thaumarchaeota and Euryarchaeota) and five dominant bacterial phyla (Actinobacteria, Proteobacteria, Firmicutes, Bacteroidetes and Cyanobacteria). The skin bacteria community structure was influenced by skin sites, and was closely related to age and sex. The upper back was dominated by Propionibacterium and Staphylococcus, and the cheeks facilitated the survival of Betaproteobacteria, while Alphaproteobacteria were prevalent on the volar forearms. Regarding the effects of age, after sexual maturity, the cheek microbiota became more similar to sebaceous sites (i.e. the upper back). The volar forearms appeared to experience the aging process earlier than the other two sites. The elderly had greater species richness and diversity and their community composition no longer had skin‐site selectivity. Males had a greater species richness than females, but the sex differences in the community structure only present at certain age groups and skin sites.