Takshan/R1 huggingface dataset:
Novel overlapping subgraph clustering for the detection of antigen epitopes.

Motivation: Antigens that contain overlapping epitopes have been occasionally reported. As current algorithms mainly take a one-antigen-one-epitope approach to the prediction of epitopes, they are not capable of detecting these multiple and overlapping epitopes accurately, or even those multiple and separated epitopes existing in some other antigens. Results: We introduce a novel subgraph clustering algorithm for more accurate detection of epitopes. This algorithm takes graph partitions as seeds, and expands the seeds to merge overlapping subgraphs based on the term frequency-inverse document frequency (TF-IDF) featured similarity. Then, the merged subgraphs are each classified as an epitope or non-epitope. Tests of our algorithm were conducted on three newly collected datasets of antigens. In the first dataset, each antigen contains only a single epitope; in the second, each antigen contains only multiple and separated epitopes; and in the third, each antigen contains overlapping epitopes. The prediction performance of our algorithm is significantly better than the state-of-art methods. The lifts of the averaged f-scores on top of the best existing methods are 60, 75 and 22% for the single epitope detection, the multiple and separated epitopes detection, and the overlapping epitopes detection, respectively. Availability and implementation: The source code is available at github.com/lzhlab/glep/. Supplementary information: Supplementary data are available at Bioinformatics online.
Processing of Candida albicans Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence.

Candida albicans is an opportunistic fungal pathogen responsible for superficial and life-threatening infections in humans. During mucosal infection, C. albicans undergoes a morphological transition from yeast to invasive filamentous hyphae that secrete candidalysin, a 31-amino-acid peptide toxin required for virulence. Candidalysin damages epithelial cell plasma membranes and stimulates the activating protein 1 (AP-1) transcription factor c-Fos (via p38-mitogen-activated protein kinase [MAPK]), and the MAPK phosphatase MKP1 (via extracellular signal-regulated kinases 1 and 2 [ERK1/2]-MAPK), which trigger and regulate proinflammatory cytokine responses, respectively. The candidalysin toxin resides as a discrete cryptic sequence within a larger 271-amino-acid parental preproprotein, Ece1p. Here, we demonstrate that kexin-like proteinases, but not secreted aspartyl proteinases, initiate a two-step posttranslational processing of Ece1p to produce candidalysin. Kex2p-mediated proteolysis of Ece1p after Arg61 and Arg93, but not after other processing sites within Ece1p, is required to generate immature candidalysin from Ece1p, followed by Kex1p-mediated removal of a carboxyl arginine residue to generate mature candidalysin. C. albicans strains harboring mutations of Arg61 and/or Arg93 did not secrete candidalysin, were unable to induce epithelial damage and inflammatory responses in vitro, and showed attenuated virulence in vivo in a murine model of oropharyngeal candidiasis. These observations identify enzymatic processing of C. albicans Ece1p by kexin-like proteinases as crucial steps required for candidalysin production and fungal pathogenicity. IMPORTANCECandida albicans is an opportunistic fungal pathogen that causes mucosal infection in millions of individuals worldwide. Successful infection requires the secretion of candidalysin, the first cytolytic peptide toxin identified in any human fungal pathogen. Candidalysin is derived from its parent protein Ece1p. Here, we identify two key amino acids within Ece1p vital for processing and production of candidalysin. Mutations of these residues render C. albicans incapable of causing epithelial damage and markedly reduce mucosal infection in vivo Importantly, candidalysin production requires two individual enzymatic events. The first involves processing of Ece1p by Kex2p, yielding immature candidalysin, which is then further processed by Kex1p to produce the mature toxin. These observations identify important steps for C. albicans pathogenicity at mucosal surfaces.
Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study.

BACKGROUND: Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin-piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports. METHODS: We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2-3 piperaquine resistance locus. FINDINGS: We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin-piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia. INTERPRETATION: The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin-piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia. FUNDING: Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.
Health Differences between Roma and Non-Roma in the Slovak Dialyzed Population.

BACKGROUND: Roma health has not been studied systematically. Thus far, it has been shown that Roma compared to non-Roma have a significantly higher likelihood of getting end-stage renal disease and that their chances for survival on dialysis are lower. Evidence is lacking regarding morbidity between Roma and non-Roma. The aim was to compare the health status of dialyzed Roma and non-Roma using the Charlson comorbidity index (CCI). All Slovak dialysis centers for adults were asked to fill in a questionaire with demographic and clinical data, including comorbidity. Cross-sectional analysis of 2082 patients with an average age of 63.8 ± 13.8 years was performed. Comorbidity was expressed as the CCI, and ethnic differences were calculated. Linear regression was performed to adjust for differences in gender and age in both ethnic groups. Roma represented 13.0% of the whole dialyzed population (n = 270). Comorbidity expressed as CCI was significantly lower in the Roma population (p < 0.001). After adjusting for gender and age, ethnicity failed to be associated with the CCI in the linear regression analysis (p = 0.965, variance of the model-adjusted R² 38.6%). The health status of dialyzed Slovak Roma does not differ cross-sectionally when adjusted for age and gender from the health status of dialyzed non-Roma.
Blessing of dimensionality: mathematical foundations of the statistical physics of data.

The concentrations of measure phenomena were discovered as the mathematical background to statistical mechanics at the end of the nineteenth/beginning of the twentieth century and have been explored in mathematics ever since. At the beginning of the twenty-first century, it became clear that the proper utilization of these phenomena in machine learning might transform the curse of dimensionality into the blessing of dimensionality This paper summarizes recently discovered phenomena of measure concentration which drastically simplify some machine learning problems in high dimension, and allow us to correct legacy artificial intelligence systems. The classical concentration of measure theorems state that i.i.d. random points are concentrated in a thin layer near a surface (a sphere or equators of a sphere, an average or median-level set of energy or another Lipschitz function, etc.). The new stochastic separation theorems describe the thin structure of these thin layers: the random points are not only concentrated in a thin layer but are all linearly separable from the rest of the set, even for exponentially large random sets. The linear functionals for separation of points can be selected in the form of the linear Fisher's discriminant. All artificial intelligence systems make errors. Non-destructive correction requires separation of the situations (samples) with errors from the samples corresponding to correct behaviour by a simple and robust classifier. The stochastic separation theorems provide us with such classifiers and determine a non-iterative (one-shot) procedure for their construction. This article is part of the theme issue 'Hilbert's sixth problem'.
Persistent Borrelia Infection in Patients with Ongoing Symptoms of Lyme Disease.

INTRODUCTION: Lyme disease is a tickborne illness that generates controversy among medical providers and researchers. One of the key topics of debate is the existence of persistent infection with the Lyme spirochete, Borreliaburgdorferi, in patients who have been treated with recommended doses of antibiotics yet remain symptomatic. Persistent spirochetal infection despite antibiotic therapy has recently been demonstrated in non-human primates. We present evidence of persistent Borrelia infection despite antibiotic therapy in patients with ongoing Lyme disease symptoms. METHODS: In this pilot study, culture of body fluids and tissues was performed in a randomly selected group of 12 patients with persistent Lyme disease symptoms who had been treated or who were being treated with antibiotics. Cultures were also performed on a group of ten control subjects without Lyme disease. The cultures were subjected to corroborative microscopic, histopathological and molecular testing for Borrelia organisms in four independent laboratories in a blinded manner. RESULTS: Motile spirochetes identified histopathologically as Borrelia were detected in culture specimens, and these spirochetes were genetically identified as Borreliaburgdorferi by three distinct polymerase chain reaction (PCR)-based approaches. Spirochetes identified as Borrelia burgdorferi were cultured from the blood of seven subjects, from the genital secretions of ten subjects, and from a skin lesion of one subject. Cultures from control subjects without Lyme disease were negative for Borrelia using these methods. CONCLUSIONS: Using multiple corroborative detection methods, we showed that patients with persistent Lyme disease symptoms may have ongoing spirochetal infection despite antibiotic treatment, similar to findings in non-human primates. The optimal treatment for persistent Borrelia infection remains to be determined.
Valuing treatment with infliximab for ankylosing spondylitis using a willingness-to-pay approach.

OBJECTIVE: To investigate willingness to pay (WTP) for treatment with infliximab by patients with ankylosing spondylitis (AS) and explore factors associated with WTP. METHODS: Data were used from 85 patients participating in the European AS Infliximab Cohort (EASIC) open-label extension of the AS Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT). WTP was included at baseline of EASIC and comprised a hypothetical scenario exploring whether the patient would be willing to pay for beneficial effects of infliximab and, if so, what amount they would be willing to pay per administration. Factors associated with WTP were explored using zero-inflated negative binomial regressions (ZINB). RESULTS: Sixty-three of 85 patients (74.1%) were willing to pay, and among these the mean amount willing to pay was €275 (median €100) [interquartile range €50-200] per administration. Multivariable ZINB analysis showed that Assessment of SpondyloArthritis international Society 20 (ASAS20) response was associated with a 7-fold lower likelihood to pay zero euros (OR=0.14, 95%-confidence interval [95%CI] 0.03-0.71) and a 3-fold increase in the amount willing to pay (exp(B)=3.32, 95%CI 1.44-7.69). In addition, country of residence was associated with lower likelihood to pay zero euros (OR = 0.07, 95% CI 0.02-0.36), while increased age was associated with the amount willing to pay (exp(B)=1.05, 95%CI 1.01-1.09). CONCLUSION: In a hypothetical scenario, three quarter of patients with AS on long-term infliximab stated to be willing to pay an out-of-pocket contribution for this treatment. Treatment response contributed to the willingness as well as to the amount patients are willing to pay. This article is protected by copyright. All rights reserved.
Bowel wall thickening: inquire or not inquire? Our guidelines.

INTRODUCTION: Bowel wall thickening is not an uncommon finding among patient undergoing abdomen CT scan. It may be caused by neoplastic, inflammatory, infectious or ischaemic conditions but also be a normal variant. Although specific radiologic patterns may direct to a precise diagnosis, occasionally misidentification may occur. Thus, in the absence of guidelines, further and not always needed diagnostic procedures (colonoscopy, esophagogastroduodenoscopy or capsule endoscopy) are performed. PATIENTS AND METHODS: We conducted a retrospective study on data collected from May 2016 to June 2017. We selected 40 adult patients, admitted in Emergency Department with "abdominal pain" and undergone an abdomen CT scan, in which bowel wall abnormalities were founded. RESULTS: 75% patients were found to have a benign condition vs 25% a malignant condition. In the stomach group, 50% were found to have a neoplasm, whilst 33.3% presented an aspecific pattern and 16.7% had an inflammatory disease. In the small bowel cluster, 33.3% patients had an ischaemic disease, 33.3% an aspecific pattern, 22.2% an inflammatory disease and 11.1% was diagnosed with cancer. In the colon group, 36% had an inflammatory disease, 24% a colon cancer, 24% an aspecific pattern and 16% an ischaemic condition. CONCLUSIONS: We recommend to perform a further endoscopic procedure to all patients with gastric or colonic wall abnormalities on CT scan, on the basis of growing rate of cancer and IBD. Capsule endoscopy should be taken into account in patients with severe symptoms and after a previous negative endoscopic examination.
Decreased outlet angle of the superior cerebellar artery as indicator for dolichoectasia in late onset Pompe disease.

BACKGROUND: Lysosomal α-glucosidase deficiency (Pompe disease) not only leads to glycogen accumulation in skeletal muscle, but also in the cerebral arteries. Dolichoectasia of the basilar artery (BA) has been frequently reported. Therefore progression of BA dolichoectasia in late onset Pompe patients (LOPD) was studied. METHODS: BA length, diameter and volume, and cerebral lesions were analysed by MRI/TOF-MR angiography or CT/CT angiography in 20 LOPD patients and 40 controls matching in age, sex- and cardiovascular risk factors. The height of BA bifurcation was assessed semi-quantitatively using the Smoker's criteria and quantitatively by measuring the outlet angle of the superior cerebellar artery (SUCA). Nine patients were followed over 5 years. RESULTS: The height of the BA bifurcation was abnormal in 12/20 (60%) LOPD patients and in 12/40 (30%) matched controls. The SUCA outlet angle was reduced in LOPD patients compared to controls (127 ± 33° vs. 156 ± 32°, p = 0.0024). The diameter, length and volume of the BA were significantly increased in LOPD patients compared to controls. 12/20 (60%) LOPD patients and 27/40 (68%) controls presented white matter lesions. During 5 years 2/9 LOPD patients developed an abnormal height of BA bifurcation according to the Smoker's criteria and in all patients the SUCA outlet angle decreased (138 ± 34° vs. 128 ± 32°, p = 0.019). One patient with prominent basilar dolichoectasia experienced a thalamic hemorrhage. CONCLUSION: Pompe disease is associated with BA dilation, elongation and elevated bifurcation height of the BA which might result in cerebrovascular complications. The SUCA outlet angle seems to be useful for monitoring the progression of BA dolichoectasia.
Household water treatment and the nutritional status of primary-aged children in India: findings from the India human development survey.

BACKGROUND: Poor water quality, one of the leading causes of diarrhea, is an issue for most developing countries. Although the health burden of poor-quality water has been studied extensively, there is a paucity of research regarding the impact of household water treatment (HWT) on children's nutritional status using data from large-scale surveys. In this research, we study the effect of HWT on the nutritional status of primary-aged children in India using a secondary data set consisting of 20,315 children between the ages of 6 and 14 (10,523 males and 9,792 females) in 12,839 households from the second wave of the India Human Development Survey (IHDS-II). METHODS: The IHDS-II is a nationally representative, household-based, comprehensive, and face-to-face survey. Households were selected using stratified random sampling, and a team consisting of one male and one female interviewer visited each household between November 2011 and October 2012. A knowledgeable member, typically the male head of household, was interviewed about the socioeconomic condition of the household. An ever-married woman between the ages of 15 and 49, typically the wife of the male head of household, answered questions related to education and health. The height and weight of all eligible household members were measured by interviewers. Correlation between HWT and nutritional status was computed first, and the estimation of a generalized simultaneous equation model, in which a binary indicator of HWT and other covariates was included, was carried out afterward. RESULTS: Bivariate analysis shows a negative association between the nutritional status of children and HWT. Additionally, findings from the generalized simultaneous equation model demonstrate that HWT increases the probability of producing normal-weighted primary-aged children by 1.7 %, while it decreases the probability of primary-aged children being thin by 2.5% and being severely thin by 1.7% in India. CONCLUSIONS: This study indicates that HWT has the potential to advance the nutritional status of primary school-aged children in India.
Few individuals with Lennox-Gastaut syndrome have autism spectrum disorder: a comparison with Dravet syndrome.

BACKGROUND: Autism spectrum disorder (ASD) in epilepsy has been a topic of increasing interest, which in general occurs in 15-35% of the patients with epilepsy, more frequently in those with intellectual disability (ID). Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are two typical forms of intractable epileptic encephalopathy associated with ID. We previously reported that ASD was diagnosed in 24.3% of patients with DS, higher in those with profound ID. Given the severe epilepsy and high frequency of ID in LGS, it is necessary to know whether ASD is a common psychomotor co-morbidity of LGS. This study evaluated the autistic behaviors and intelligence in patients with LGS and further compared that between LGS and DS, aiming to understand the complex pathogenesis of epilepsy-ASD-ID triad. METHODS: A total of 50 patients with LGS and 45 patients with DS were enrolled and followed up for at least 3 years. The clinical characteristics were analyzed, and evaluations of ASD and ID were performed. RESULTS: No patients with LGS fully met the diagnostic criteria for ASD, but three of them exhibited more or less autistic behaviors. Majority (86%) of LGS patients presented ID, among which moderate to severe ID was the most common. Early onset age and symptomatic etiology were risk predictors for ID. The prevalence of ASD in LGS was significantly lower than that in DS (0/50 vs. 10/45, p < 0.001), while the prevalence and severity of ID showed no significant difference between the two forms of epileptic encephalopathy. CONCLUSIONS: This study demonstrated a significant difference in the co-morbidity of ASD between LGS and DS, although they had a similar prevalence and severity of ID, refuting the proposal that the prevalence of ASD in epilepsy is accounted for by ID. These findings suggest that the co-morbidity of ASD, ID, and epilepsy may result from multifaceted pathogenic mechanisms.
A Systematic Review and Meta-Analysis on the Strength and Consistency of the Associations between Dupuytren Disease and Diabetes Mellitus, Liver Disease, and Epilepsy.

BACKGROUND: The role of diabetes mellitus, liver disease, and epilepsy as risk factors for Dupuytren disease remains unclear. In this systematic review and meta-analysis, the strength and consistency of these associations were examined. METHODS: The MEDLINE, EMBASE, and Web of Science databases were searched for articles reporting an association between Dupuytren disease and diabetes mellitus, liver disease, and epilepsy published before September 26, 2016. The frequencies of Dupuytren disease and diabetes mellitus, liver disease, and epilepsy were extracted, as was information on potential confounders. Generalized linear mixed models were applied to estimate pooled odds ratios, adjusted for confounders. Heterogeneity between studies was quantified using an intraclass correlation coefficient and was accounted for by a random effect for study. RESULTS: One thousand two hundred sixty unique studies were identified, of which 32 were used in the meta-analyses. An association between Dupuytren disease and diabetes mellitus was observed (OR, 3.06; 95 percent CI, 2.69 to 3.48, adjusted for age), which was stronger for type 1 diabetes mellitus than for type 2 diabetes mellitus but was not statistically significant (p = 0.24). An association between Dupuytren disease and liver disease was observed (OR, 2.92; 95 percent CI, 2.08 to 4.12, adjusted for sex). Dupuytren disease and epilepsy were associated, yielding an OR of 2.80 (95 percent CI, 2.49 to 3.15). Heterogeneity between studies was moderate to low. CONCLUSIONS: These findings demonstrate an association between Dupuytren disease and diabetes mellitus, liver disease, and epilepsy. Prospective, longitudinal studies are needed to elucidate the pathways causing these associations.