Miracle-dz/UniFAR-FTUs huggingface dataset:
Kinetic analysis of the multistep aggregation pathway of human transthyretin

Significance Aggregation of amyloidogenic proteins is implicated in a number of debilitating human diseases. A mechanistic understanding of their aggregation behavior requires a quantitative description of the multistep equilibria involved in the self-assembly processes. Here we report the application of an integrative aggregation assay combining 19F-NMR and turbidity measurements to reveal the kinetics and energetics of the human transthyretin aggregation pathway. A highly sensitive trifluoroacetyl probe enables direct observation and quantification of a weakly populated aggregation intermediate and reveals the importance of hydrophobic interactions for self-association. Extension of these studies to common pathogenic variants that are associated with early onset familial disease provides insights into the effect of the mutations on the kinetics and energetics of transthyretin aggregation. Aggregation of transthyretin (TTR) is the causative agent for TTR cardiomyopathy and polyneuropathy amyloidoses. Aggregation is initiated by dissociation of the TTR tetramer into a monomeric intermediate, which self-assembles into amyloid. The coupled multiple-step equilibria and low-concentration, aggregation-prone intermediates are challenging to probe using conventional assays. We report a 19F-NMR assay that leverages a highly sensitive trifluoroacetyl probe at a strategic site that gives distinct 19F chemical shifts for the TTR tetramer and monomeric intermediate and enables direct quantification of their populations during the aggregation process. Integration of real-time 19F-NMR and turbidity measurements as a function of temperature allows kinetic and mechanistic dissection of the aggregation pathway of both wild-type and mutant TTR. At physiological temperature, the monomeric intermediate formed by wild-type TTR under mildly acidic conditions rapidly aggregates into species that are invisible to NMR, leading to loss of the NMR signal at the same rate as the turbidity increase. Lower temperature accelerates tetramer dissociation and decelerates monomer tetramerization and oligomerization via reduced hydrophobic interactions associated with packing of a phenylalanine (F87) into a neighboring protomer. As a result, the intermediate accumulates to a higher level, and formation of higher-order aggregates is delayed. Application of this assay to pathogenic (V30M, L55P, and V122I) and protective (T119M) mutants revealed significant differences in behavior. A monomeric intermediate was observed only for V122I: aggregation of V30M and L55P proceeds without an observable monomeric intermediate, whereas the protective mutant T119M remains resistant to tetramer dissociation and aggregation.
Poster: Companies' Domination in FLOSS Development - An Empirical Study of OpenStack

Commercial participation continues to grow in free/libre open source software (FLOSS) projects. Companies may take the lead in developing FLOSS rather than volunteers, which may change the nature of FLOSS development and affect the FLOSS community. Despite substantial research on commercial participation, it remains unclear whether companies dominate FLOSS development, to what extent the domination exists and whether the domination affects the FLOSS community. We therefore conduct an empirical study on OpenStack with a focus on its four main projects (Nova, Swift, Glance, and Neutron) to explore the commercial domination. We employ the development data of the four projects to quantify companies' contributions from two aspects: the developers they provided and the commits made by those developers. We find that there are nearly half of the versions, in which the four projects are dominated by one company. The dominant companies change occasionally, but the number never exceeds three for any project. We found that the commercial domination is negatively associated with the participation of companies and contributors, while it is positively associated with the productivity of contributors and the quality of issue reports. Our study contributes to the understanding of commercial domination and its impact on FLOSS community. Our findings reveal the adverse consequences brought by commercial domination in addition to its benefits.
Bacterial Colonization and Tissue Compatibility of Denture Base Resins

Currently, there is minimal clinical data regarding biofilm composition on the surface of denture bases and the clinical tissue compatibility. Therefore, the aim of this experimental study was to compare the bacterial colonization and the tissue compatibility of a hypoallergenic polyamide with a frequently used PMMA resin tested intraorally in a randomized split-mouth design. Test specimens made of polyamide (n = 10) and PMMA (n = 10) were attached over a molar band appliance in oral cavity of 10 subjects. A cytological smear test was done from palatal mucosa at baseline and after four weeks. The monolayers were inspected for micronuclei. After four weeks in situ, the appliance was removed. The test specimens were immediately cultivated on non-selective and selective nutrient media. All growing colonies were identified using VITEK-MS. The anonymized results were analyzed descriptively. A total of 110 different bacterial species could be isolated, including putative pathogens. An average of 17.8 different bacterial species grew on the PMMA specimens, and 17.3 on the polyamide specimens. The highest number of different bacterial species was n = 24, found on a PMMA specimen. On the two specimens, a similar bacterial distribution was observed. Micronuclei, as a marker for genotoxic potential of dental materials, were not detected. This study indicates that the composition of bacterial biofilm developed on these resins after four weeks is not influenced by the type of resin itself. The two materials showed no cytological differences. This investigation suggests that polyamide and PMMA are suitable for clinical use as denture base material.
Influence of TS (rs34743033) and RUNX1 (rs2014300) gene polymorphisms on survival outcomes of fluorouracil-based chemotherapy in Chinese advanced gastric cancer patients

Background This study aimed to explore the clinical correlation of single-nucleotide polymorphisms of thymidylate synthase (TS) and runt-related transcription factor 1 (RUNX1) in patients with postoperative stage II and III gastric cancer (GC). Patients and methods Samples were obtained from 661 patients with postoperative stage II and III GC. TS (rs34743033) and RUNX1 (rs2014300) were genotyped in 261 patients who received postoperative basic platinum and fluorouracil chemotherapy regimens and 400 patients who did not accept chemotherapy. Results TS (rs34743033) variant genotypes significantly prolonged the median overall survival (OS) time compared to the patients who only received adjuvant chemotherapy (HR 1.604, 95% CI 1.068–2.410, p=0.021). Moreover, 3R/3R variant genotypes were demonstrated to have a positive effect on the OS of patients who received chemotherapy based on cisplatin (HR 1.754, 95% CI 1.041–2.954, p=0.031) compared to oxaliplatin. A stratification analysis indicated that 2R/3R and 2R/2R variant genotypes were associated with inferior survival in GC patients with intestinal-type tumors, tumor less than 5 cm in size, and poorly differentiated tumors (p<0.05). However, RUNX1 (rs2014300) AA genotypes markedly increased the risk of death in GC patients compared with the GG/GA genotypes (p=0.007), but no significant difference was observed between chemotherapy based on platinum. The stratification analysis showed that the GA/AA genotype was significantly associated with inferior survival in well to moderately differentiated tumors (HR 2.001, 95% CI 1.082–3.703, p=0.023). Conclusion These preliminary results indicated that the two polymorphisms had a significant effect on postoperative adjuvant chemotherapy. TS (rs34743033) and RUNX1 (rs2014300) may be used as biomarkers to predict prognosis and select chemotherapy regimens in GC patients.
A US/Mexico Study of Joint Associations of Physical Activity and Sedentary Behavior on Anthropometric Indicators, Migration Status, Country of Birth and Country of Residence

Background: This study examined the influence of migration status, nativity and country of residence on joint associations of physical activity (PA) and sedentary behavior (SB) in anthropometric indicators of Mexicans and Mexican-Americans living in the US and in Mexico. Methods: We examined data from two large national surveys, the National Health and Nutrition Examination Survey from the US (NHANES, 2011–2012) and Mexico (ENSANUT, 2012). Using self-reported minutes of moderate to vigorous physical activity and SB, we calculated four categories for analyses. Anthropometric measures consisted of body mass index (BMI) and waist circumference (WC). We used data of migration status, nativity and country of residence. Linear regression models examined how joint categories of PA and SB were associated with BMI and WC according to migration status, nativity and country of residence, controlling for health risk behaviors. Results: Analyses showed that even among those in the category with the lowest risk behavior, “physically active and low sedentary”, there were differences in BMI and WC by migration status, nativity and country of residence. Within this lower risk category, Mexican immigrants living in the US had the greatest association with high BMI, while US-born Mexican-Americans living in the US had the highest WC values when compared with the group of Mexicans living in Mexico. Conclusions: Joint categories of PA and SB were associated with BMI and WC by migration status, nativity and country of residence among populations with Mexican ethnicity.
Diversity of Influenza A(H5N1) Viruses in Infected Humans, Northern Vietnam, 2004–2010

Influenza viruses exist in each host as a collection of genetically diverse variants, which might enhance their adaptive potential. To assess the genetic and functional diversity of highly pathogenic avian influenza A(H5N1) viruses within infected humans, we used deep-sequencing methods to characterize samples obtained from infected patients in northern Vietnam during 2004–2010 on different days after infection, from different anatomic sites, or both. We detected changes in virus genes that affected receptor binding, polymerase activity, or interferon antagonism, suggesting that these factors could play roles in influenza virus adaptation to humans. However, the frequency of most of these mutations remained low in the samples tested, implying that they were not efficiently selected within these hosts. Our data suggest that adaptation of influenza A(H5N1) viruses is probably stepwise and depends on accumulating combinations of mutations that alter function while maintaining fitness.
Unusual Sites of High-Grade Neuroendocrine Carcinomas: A Case Series and Review of the Literature

Case series Patient: Female, 29 • Female, 69 • Female, 52 • Female, 71 • Male, 62 • Female, 67 Final Diagnosis: Neuroendocrine carcinoma Symptoms: Abdominal pain Medication: — Clinical Procedure: — Specialty: Oncology Objective: Unusual clinical course Background: Neuroendocrine tumors (NETs) encompass a diverse group of varying clinicopathological entities arising from cells of the endocrine and nervous systems. The presentation of these unique tumors can range from occult disease discovered incidentally to hyperactive, metastatic secretory tumors. NETs most commonly originate in the gastrointestinal and respiratory tract, although they may occur at any site in the body due to the wide distribution of neuroendocrine cells. Their classification system is complex and continues to evolve, and the current system uses histological grade in defining these subtypes. Neuroendocrine carcinomas (NECs), or high-grade, poorly-differentiated NETs, are the most aggressive subtype. Surgical resection remains the primary treatment modality and may be curative, thus early diagnosis is paramount. Management of advanced NETs remains both a diagnostic and therapeutic challenge; however, advances in our understanding of these unique neoplasms as well as an evolving classification system has led to the development of adjunctive therapeutic approaches aimed to minimize morbidity and improve patient outcomes. Case Report: We present 6 cases of unusual sites of high-grade neuroendocrine carcinomas involving the cervix, gallbladder, oesophagus, ovary, prostate, and urinary bladder. Conclusions: Our case series highlights the heterogenous and aggressive nature of this subtype of NETs as well as their diagnostic and therapeutic difficulties. We also review the evolution of the NET classification system and its impact on the management of these malignancies.
Opposing roles of endosomal innate immunity proteins IFITM3 and TLR7 in human metapneumovirus infection

Human metapneumovirus (hMPV) utilizes a bifurcated cellular entry strategy, fusing either with the plasma membrane or, after endocytosis, with the endosome membrane. Whether cellular factors restrict or enhance either entry pathway is largely unknown. We found that the interferon-induced transmembrane protein 3 (IFITM3) inhibits hMPV infection to an extent similar to endocytosis-inhibiting drugs, and an IFITM3 variant that accumulates at the plasma membrane in addition to its endosome localization provided increased virus restriction. Mechanistically, IFITM3 blocks hMPV F protein-mediated membrane fusion, and inhibition of infection was reversed by the membrane destabilizing drug amphotericin B. Conversely, we unexpectedly found that infection by some hMPV strains is enhanced by Toll-like receptor 7 (TLR7), an endosomal protein, suggesting that cellular entry via endocytosis may be particularly advantageous for hMPV despite eventual restriction of this pathway upon induction of IFITM3. Overall, our results identify IFITM3 and TLR7 as endosomal factors differentially regulating hMPV infection.
C and P in aquatic food chain: a review on C:P stoichiometry and PUFA regulation.

Key-words: aquatic ecosystem, grazing food chain, microbial loop, PUFA, stoichiometry, homeostasis Carbon (C) and phosphorous (P) regulation in aquatic food chains are transferred from lower to upper trophic levels primarily as polyunsaturated fatty acids (PUFAs) and C:P stoichiometry. The majority of C is transferred through algal based pathway. Microbial loop, though optionally contributes to C transfer, highly constrained by P limitation and bacterial predator type. Lack of essential PUFAs in bacteria is also responsible for its low trophic transfer of C. The seston size and algal taxonomic variations directly affect herbivore through P-dependent food quality and de novo synthesis of PUFAs. Change in algal community over a gradient could therefore determine C transfer. Feeding nature (herbivorous or carnivorous) and predator sizes also regulate transfer efficiency of C and P to upper trophic levels. As trophic levels move up, P-limitation becomes higher compared to autotrophs. For Daphnia, as mostly studied aquatic herbivore member, P limitation becomes critical at C:P > 300 indicating excess C is not always invited under P-deficient situations. However, as a part of homeostasis mechanism for trophic upgrading, conversion of algal-zooplankton interface from qualitative to quantitative could minimize such critical C:P regulation at higher trophic levels. Protists, in turn, with high clearance rate by zooplankton predator could also compensate qualitative effect.
Crowdsourced Software Development and Maintenance

As modern software systems are becoming increasingly complex, developers often need to rely on online sources to address problems encountered during software development and maintenance. These resources provide developers with access to peers' expertise, covering knowledge of different software lifecycle phases, including design, implementation, and maintenance. However, exploiting such knowledge and converting it into actionable items is far from trivial, due to the vastness of the information available online as well as to its unstructured nature. In this research, we aim at (partially) crowdsourcing the software design, implementation and maintenance process by exploiting the knowledge embedded in various sources available on the Web (e.g., Stack Overflow discussions, presentations on SlideShare, open source code, etc.). For example, we want to support software design decisions (e.g., whether to use a specific library for the implementation of a feature) by performing opinion mining on the vast amount of information available on the Web, and we want to recommend refactoring operations by learning from the code written in open source systems. The final goal is to improve developers' productivity and code quality.
Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

BACKGROUND Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years. OBJECTIVE To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years. METHODS 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. RESULTS DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. CONCLUSION DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.
The path to surgery in carcinoid heart disease: a retrospective study and a multidisciplinary proposal of a new algorithm

Abstract Background: Development of carcinoid heart disease (CHD) is the major negative prognostic factor in patients with the carcinoid syndrome. The only effective treatment is valve replacement. However, the selection of candidates and determination of optimal timing remain unclear. Considerable variability in local screening and treatment strategies exist. Methods: In this single-centre study, we retrospectively analysed the diagnostic process and outcome of all CHD patients who underwent valve surgery between 2000 and 2016. We propose a new CHD screening and management algorithm. Results: All patients (n = 15), mean age 64 ± 7, underwent tricuspid valve surgery. In 14 of them (93%) an additional valve was replaced. In only a minority of patients (27%) CHD diagnosis was established by screening. Survival after 1, 3, 12 and 24 months was 93%, 80%, 53% and 33%, respectively. Causes of death included infections and critical illness immediately postoperatively, and tumour progression and right heart failure in the longer term. There was a trend (p = .099) towards better preoperative right ventricular function in the patients who survived more than 12 months postoperatively (TAPSE 20 mm ± 4) compared to those who died between 3 to 12 months after surgery (TAPSE 16 mm ± 1). The former group had a shorter mean interval from diagnosis of the carcinoid syndrome to cardiac diagnosis than the latter (13 vs. 105 months, p = .014). Conclusion: Mortality after valve replacement for CHD remains high. A probably underestimated cause is late referral for cardiac surgery. We propose a systematic, multidisciplinary approach to all carcinoid syndrome patients.
Reported changes in oral health-related quality of life in children and adolescents before, during, and after orthodontic treatment: a longitudinal study

OBJECTIVES To investigate the changes in oral health-related quality of life (OHRQoL) before, during, and after orthodontic treatment, determine the relationship with the original treatment need and evaluate the influence of self-esteem (SE). MATERIALS AND METHODS OHRQoL questionnaires were used in an ongoing observational prospective cohort study at baseline (T0), 1 year after start (T1), and 1 month after the end of active orthodontic treatment (T2). Participants were 11-16-year-old at baseline and 215 complete cases were obtained from a total of 498. OHRQoL was scored by using the Child Perception Questionnaire (CPQ11-14), SE was assessed by the Dutch adaptation of the Harter's Self-Perception Profile for Adolescents and treatment need was defined by the Index of Orthodontic Treatment Need (IOTN). The Oral Aesthetic Subjective Impact Scale (OASIS) was included to score perceived treatment need. Data were analyzed with Spearman correlation, Mann-Whitney U-test and linear models for longitudinal data. RESULTS A significant decrease in IOTN and in OASIS was noted from T0-T1-T2 (P < 0.0001). CPQ results show a decrease from T0 to T2, from T1 to T2 and an increase from T0 to T1 (P < 0.0001). This was valid for the overall CPQ scores and its subdomains except for emotional well-being (EW), which decreases from T0-T1-T2. A correlation was found between baseline SE and the change of total CPQ scores between T0 and T2, also for EW (r = 0.325 and r = 0.354). CONCLUSIONS OHRQoL ameliorates after orthodontic treatment. High baseline SE works as a protective factor for OHRQoL.
A Development of a Prediction Model for Ungauged Catchment in the North of Thailand

Flow data are essential for hydrological study, planning, and management to prevent drought and flood in a region. In catchments where flow data are not recorded or of poor quality, hydrological indices could be an alternative for predicting flow in ungauged catchments. This study demonstrates the methodology for predicting flow in ungauged catchments through the case study of 37 sub-catchments of the upper Ping catchment in northwest Thailand from 2006-2014. The regression method was applied to investigate the relationship between three flow indices including runoff coefficient, base flow index, and 95th percentile of flow, and catchment properties. The prediction interval of the regression relationship was used to condition rainfall-runoff model parameters. The model performance was tested by NSE* and reliability. The 95th percentile of flow was found to be the most informative index to regionalize flow followed by RC. The BFI had least contribution to the prediction of flow with poor NSE* and large uncertainty. The 95th percentile of flow and RC generally worked well for small sub-catchments.