Miracle-dz/UniFAR-FTUs huggingface dataset:
In vitro 0N4R tau fibrils contain a monomorphic β-sheet core enclosed by dynamically heterogeneous fuzzy coat segments

Significance The microtubule-binding protein tau misfolds into filamentous aggregates in many neurodegenerative diseases. Understanding the structure and dynamics of tau fibrils is important for designing anti-tau inhibitors. Patient-brain-derived tau fibrils have been shown to adopt disease-specific molecular conformations, but in vitro heparin-fibrillized tau was recently proposed to exhibit significant structural polymorphism. Using solid-state NMR, we show that the β-sheet core of heparin-fibrillized 0N4R tau adopts a single molecular conformation that encompasses the second and third microtubule-binding repeats, and both cysteine residues in the protein are involved in side-chain packing with other β-sheet residues. Extensive characterization of the protein dynamics indicates that these tau fibrils are heterogeneously dynamic, and the first and fourth microtubule-binding repeats are semirigid while retaining β-sheet character. Misfolding of the microtubule-binding protein tau into filamentous aggregates is characteristic of many neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy. Determining the structures and dynamics of these tau fibrils is important for designing inhibitors against tau aggregation. Tau fibrils obtained from patient brains have been found by cryo-electron microscopy to adopt disease-specific molecular conformations. However, in vitro heparin-fibrillized 2N4R tau, which contains all four microtubule-binding repeats (4R), was recently found to adopt polymorphic structures. Here we use solid-state NMR spectroscopy to investigate the global fold and dynamics of heparin-fibrillized 0N4R tau. A single set of 13C and 15N chemical shifts was observed for residues in the four repeats, indicating a single β-sheet conformation for the fibril core. This rigid core spans the R2 and R3 repeats and adopts a hairpin-like fold that has similarities to but also clear differences from any of the polymorphic 2N4R folds. Obtaining a homogeneous fibril sample required careful purification of the protein and removal of any proteolytic fragments. A variety of experiments and polarization transfer from water and mobile side chains indicate that 0N4R tau fibrils exhibit heterogeneous dynamics: Outside the rigid R2–R3 core, the R1 and R4 repeats are semirigid even though they exhibit β-strand character and the proline-rich domains undergo large-amplitude anisotropic motions, whereas the two termini are nearly isotropically flexible. These results have significant implications for the structure and dynamics of 4R tau fibrils in vivo.
Phosphoproteomics reveals the biosynthesis of secondary metabolites in Catharanthus roseus under ultraviolet-B radiation.

Ultraviolet (UV)-B radiation acts as an elicitor to enhance the production of secondary metabolites in medicinal plants. To investigate the mechanisms, which lead to secondary metabolites in C. roseus under UVB radiation, a phosphoproteomic technique was used. ATP content increased in the leaves of C. roseus under UVB radiation. Phosphoproteins related to calcium such as calmodulin, calcium-dependent kinase, and heat shock proteins increased. Phosphoproteins related to protein synthesis/ modification/ degradation and signaling intensively changed. Metabolomic analysis indicated that the metabolites classified with pentoses, aromatic amino acids, and phenylpropanoids, accumulated under UVB radiation. Phosphoproteomic and immunoblot analyses indicated that proteins related to glycolysis and the reactive-oxygen species scavenging system was changed under UVB radiation. These results suggest that UVB radiation activates calcium related pathway and reactive-oxygen species scavenging system in C. roseus. These changes lead to the upregulation of proteins which are responsible for the redox reactions in secondary metabolism and are important for the accumulation of secondary metabolites in C. roseus under UVB radiation.
Gene flow across host-associated populations of the rice stem borer Chilo suppressalis Walker (Lepidoptera: Crambidae) - implications for Bt resistance management in rice.

BACKGROUND The rice stem borer, Chilo suppressalis, is a serious pest of rice, but also damages an aquatic vegetable, water oats (Zizania latifolia Turcz.). The time at which mating occurs is different between populations of rice stem borer associated with rice and those associated with water-oats, which suggests that undetected cryptic species may be associated with these plant hosts. If true, this would have significant management implications. This study is the first empirical test of this idea, using population genetic tools from two sampling cohorts. We genotyped 320 rice stem borer individuals from 2014, collected from rice and water-oats across five locations (where they exist in sympatry), using seven microsatellite loci. RESULTS We found no genetic structuring associated with host plant species. On water oats, some rice stem borers were found that had a similar mating time to the rice population, so in 2016, a second cohort of samples was screened by their timing of mating to get 'pure rice feeders' and 'pure water oats feeders'. These samples were genotyped with microsatellites, mitochondrial DNA (mtDNA - COI & COII), and a nuclear gene (EF1-α). Our mtDNA data suggest a relatively low amount of population subdivision associated with plant host, but the microsatellite data revealed no such genetic structure, and we were only able to identify one haplotype of EF1-α. CONCLUSIONS Our results indicate gene flow between rice and water oats populations of rice stem borer, indicating that water oats will likely provide a refuge for resistance management of Bt rice. This article is protected by copyright. All rights reserved.
Immunotherapeutic approaches in nasopharyngeal carcinoma

ABSTRACT Introduction: Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. Epstein-Barr virus (EBV) represents a unique etiological culprit in the poorly differentiated nonkeratinizing and undifferentiated subtypes. EBV antigens are expressed on tumor cells albeit in a restricted manner. Treatment options for recurrent or metastatic disease are limited. Nevertheless, emerging data from immunotherapy studies in NPC have shed light into their potential antitumor efficacy. Areas covered: This article reviews existing clinical evidence for different immunotherapeutic approaches for NPC, including adoptive cellular therapy, therapeutic cancer vaccines, and immune checkpoint inhibitors. Expert opinion: There is a growing understanding on EBV virology and the immune evasion mechanisms in NPC. Immunotherapeutic strategies leveraging these properties have shown encouraging efficacy and safety results in early-phase clinical studies. Moving forward, areas to be addressed include appropriate patient selection, optimal incorporation into standard treatment paradigms, biomarker identification, as well as the development of scalable and reproducible immune product generation processes.
A New Component of the Interstellar Matter: Small Grains and Large Aromatic Molecules

Deux modeles d'emission IR interstellaire sont developpes, l'un considerant les molecules aromatiques polycycliques (PAHs) comme une partie des grains de carbone amorphes, l'autre considerant les PAHs et les tres petits grains libres dans le milieu interstellaire. Les resultats de ces deux modeles sont compares aux observations et analyses
Characterization Of Secondary Metabolites From The Rhizome Of Cynara Scolymus And Their Antioxidant Properties

Abstract The aerial portions of Cynara scolymus commonly have been eaten as vegetables or functional foods by the people lived in Mediterranean region. In preliminary antioxidant screening, the rhizome portions (CSR) of this species showed better potential than leaves ones. However, neither phytochemical nor pharmacology studies of CSR have been reported to date. The purpose of this research was to identify the active components from CSR through bioassay-guided fractionation. The antioxidant properties of secondary metabolites 1–9 were evaluated in this investigation. Compounds 4–6, 8, and 9 showed antioxidant activities based on DPPH free radical scavenging activity with IC50 values of 22.91–147.21 μM. Besides, compound 8 significantly and dose-dependently reduced H2O2-induced ROS levels in keratinocyte HaCaT cells without cytotoxicity toward HaCaT. Overall, our studies demonstrated the rhizome of C. scolymus could be used as a new natural antioxidant like the edible aerial portions and phenolic compounds are the active components. Graphical Abstract
RSMLab : a web-based tool for recombinase-based state machine design and visualization

Biological state machines have the potential to enable a wide range of applications but until recently have been challenging to implement experimentally. To overcome this challenge, we described a scalable strategy for assembling biological state machines using recombinases. This platform enables the implementation of biological state machines with arbitrary behaviors, but the manual design of such state machines is increasingly challenging with increasing complexities. Here, we introduce RSMLab, an intuitive web-based application for creating circuits that implement state-dependent logic in living cells using our scalable state-machine framework. Through a graphical user interface, RSMLab users choose a desired state diagram, define arbitrary genes, and specify whether those genes are on or off in each state. RSMLab then returns a visualization of possible gene circuits that correspond to the user specifications. We use the RSMLab algorithm and demonstrate the circuit design process using examples of two-input, five-state and three-input, sixteen-state gene regulation programs. With the help of RSMLab, researchers can program state-dependent logic to study and program the way that cells respond to combinational and temporally distributed chemical events, without needing to be expert gene circuit engineers. We envision that biology-focused design software such as RSMLab will enable the faster, more reliable, and more accessible creation of DNA-encoded circuits for engineering complex cellular behaviors. Thesis Supervisor: Timothy K. Lu Title: Associate Professor
Reduced Capacity of Cognitive Control in Older Adults with Mild Cognitive Impairment.

Cognitive control for the coordination of mental operations is essential in normal cognitive functioning in daily life. Although the decline in cognitive control in older adults with mild cognitive impairment (MCI) has been demonstrated, whether this decline serves as a core deficit in MCI remains unclear. In this study, we employed a perceptual decision-making task to estimate the capacity of cognitive control (CCC) in older adults with MCI (n = 55) and the age-, sex-, and education-matched healthy controls (HC, n = 55) selected based on a commonly used battery of ten neuropsychological tests in five cognitive domains. We found that the CCC was significantly correlated to the neuropsychological measures of the battery. The mean CCC was significantly lower in the MCI group (3.06 bps) than in the HC group (3.59 bps) and significantly lower in the amnestic MCI subgroup (2.90 bps) than in the nonamnestic MCI subgroup (3.22 bps). In detecting and classifying MCI in machine learning, the classifier with the CCC as the input feature outperformed the overall classification with neuropsychological measures in a single cognitive domain. The classification performance was significantly increased when the CCC was included as a feature in addition to measures in a single domain, and the CCC served as a key feature in optimal classifiers with inputs from multiple domains. These results support the hypothesis that the decline in cognitive control is a core deficit in MCI and suggest that the CCC may serve as a key index in the diagnosis of MCI.
Biometrics in a data stream context

Biometric systems can provide safer authentication. However, biometric features may change over time, impacting the recognition performance due to outdated biometric references. It raises the need to automatically adapt the references over time, by using adaptive biometric systems. This thesis studied several aspects of adaptive biometric systems in a data stream context. Based on this investigation, it was observed that the best choice for each aspect can be user dependent. This motivated the proposal of a modular adaptive biometric system, which can select a different configuration for each user. It also generalizes several baselines and proposals into a single modular framework, while opening numerous opportunities for future work.
Computational investigation of retro‐isomer equilibrium structures: Intrinsically disordered, foldable, and cyclic peptides

We use all‐atom modeling and advanced‐sampling molecular dynamics simulations to investigate quantitatively the effect of peptide bond directionality on the equilibrium structures of four linear (two foldable, two disordered) and two cyclic peptides. We find that the retro forms of cyclic and foldable linear peptides adopt distinctively different conformations compared to their parents. While the retro form of a linear intrinsically disordered peptide with transient secondary structure fails to reproduce a secondary structure content similar to that of its parent, the retro form of a shorter disordered linear peptide shows only minor differences compared to its parent.
Vulnerable Plaque, Characteristics, Detection, and Potential Therapies

Plaque development and rupture are hallmarks of atherosclerotic vascular disease. Despite current therapeutic developments, there is an unmet necessity in the prevention of atherosclerotic vascular disease. It remains a challenge to determine at an early stage if atherosclerotic plaque will become unstable and vulnerable. The arrival of molecular imaging is receiving more attention, considering it allows for a better understanding of the biology of human plaque and vulnerabilities. Various plaque therapies with common goals have been tested in high-risk patients with cardiovascular disease. In this work, the process of plaque instability, along with current technologies for sensing and predicting high-risk plaques, is debated. Updates on potential novel therapeutic approaches are also summarized.
There’s an App for That: Using Geosocial Networking Apps to Access Young Black Gay, Bisexual, and other MSM at Risk for HIV

Purpose: Young black gay, bisexual, and other MSM (YBMSM) that carry a disproportionate HIV burden in the US Geosocial networking applications (GSN apps) are environments that may increase HIV risk among users. This study explored the acceptability and feasibility of using these apps for HIV/sexually transmitted infection (STI) public health outreach. Design: Semi-structured in-depth qualitative interviews. Setting: A frequently reported GSN app for meeting sex partners by newly diagnosed HIV-infected MSM in Baltimore. Participants: Seventeen YBMSM aged 18 to 24 (mean = 21.5/SD = 1.8) who were logged-on to the GSN app in venues or census tracts in high HIV transmission areas. Methods: Participants completed 60 to 90 minute semi-structured interviews, which were audio-recorded and transcribed. Interview data were analyzed in NVivo10 using categorical analysis and double-coded until consistency was achieved. Results: Participants described GSN apps as acceptable and feasible resources for public health practitioners seeking to access YBMSM to provide HIV/STI treatment and prevention services and resources. Three themes emerged: (1) the need to authenticate public health messages to distinguish from spam; (2) improved access to YBMSM including opportunities to identify and access virtual congregations of youth in non-gay-related spaces; and (3) the importance of avoiding stigmatizing YBMSM when targeting sexual health messages. Conclusion: GSN apps have great potential as tools for identifying and engaging at-risk YBMSM. Additional work is needed to understand limitations of this medium, to develop strategies to engage YBMSM without further stigmatizing them, and to maximize their outreach potential.
Mortality by cryptococcosis in Brazil from 2000 to 2012: A descriptive epidemiological study

Background Cryptococcosis is a neglected and predominantly opportunistic mycosis that, in Brazil, poses an important public health problem, due to its late diagnosis and high lethality. Methods The present study analysed cryptococcosis mortality in Brazil from January 2000 to December 2012, based on secondary data (Mortality Information System/SIM-DATASUS and IBGE). Results Out of 5,755 recorded deaths in which cryptococcosis was mentioned as one of the morbid states that contributed to death, two distinct groups emerged: 1,121 (19.5%) registered cryptococcosis as the basic cause of death, and 4,634 (80.5%) registered cryptococcosis associated with risk factors, mainly AIDS (75%), followed by other host risks (5.5%). The mortality rate by cryptococcosis as the basic cause was 6.19/million inhabitants, whereas the mortality rate by cryptococcosis as an associated cause was 25.19/million inhabitants. Meningitis was the predominant clinical form (80%), males were the more affected (69%), and 39.5 years old was the mean age. The highest mortality rate due to cryptococcosis as basic cause occurred in the state of Mato Grosso (10.96/million inhabitants). Mortality rates due to cryptococcosis as associated cause were highest in the states of Santa Catarina (70.41/million inhabitants) and Rio Grande do Sul (64.40/million inhabitants), both in the South Region. Southeast, Northeast and South showed significant time trends in mortality rates. Conclusions This study is relevant because it shows the magnitude of cryptococcosis mortality linked to AIDS and removes the invisibility of a particular non-AIDS-related disease, accounting for almost 20% of all cryptococcosis deaths. It can also contribute to control and surveillance programs, beyond highlighting the urgent prioritization of early diagnosis and proper treatment to reduce the unacceptable mortality rate of this neglected mycosis in Brazil.
Long-term and short-term duration of thienopyridine therapy after coronary stenting in patients with chronic kidney disease a meta-analysis of literature studies

Abstract The study aimed to compare the efficacy and safety outcome associated with a short and a prolonged duration of thienopyridine therapy in patients with chronic kidney disease (CKD) after coronary stenting. We systematically searched PubMed, EMBASE and the Cochrane Library from their inception to 1 January 2019 for studies comparing short and prolonged thienopyridine therapy in patients with CKD. Ischemic and bleeding events were considered as the clinical endpoints in this analysis. Odds Ratios (OR) with 95% confidence intervals (CIs) were used as estimates of effect size in random-effect models. Seven studies comprising a total of 17,628 CKD patients were included in the evaluation. Prolonged duration of thienopyridine use, when compared to short-term thienopyridine, was associated with reduced risk of all-cause mortality (odds ratio 0.75, 95% confidence interval: 0.70–0.81, P< .001) and stent thrombosis (OR: 0.54, 95% CI 0.32 to 0.89; P< .001), but the odds of myocardial infarction (OR: 0.91, 95% CI: 0.77–1.07; P = .23) and stroke (OR: 0.91, 95% CI 0.73 to 1.13; P = .38) did not differ according to different duration of thienopyridine. As for bleeding events, long-term thienopyridine therapy did not significantly increase the bleeding (OR: 0.95, 95% CI 0.79 to 1.14; P = .58). In these patients with CKD following PCI, prolonged thienopyridine therapy compared with short-term therapy, was associated with reduced all-cause mortality and stent thrombosis, without any significant difference in myocardial infarction, stroke, and bleeding. Thienopyridine prolongation decisions for CKD patients should be individualized after careful consideration of the benefit–risk balance.
Anti-inflammatory Effects of Persimmon (Diospyros kaki L.) in Experimental Rodent Rheumatoid Arthritis

Abstract Persimmon (Diospyros kaki L.) fruits are used in traditional medicine largely due to their claimed beneficial effects on human health. The aim of this work was to evaluate the anti-inflammatory activity of a persimmon extract in rats with collagen-induced arthritis (CIA). CIA was induced in Wistar rats through an intradermal injection of an emulsion of bovine type II collagen (CII) in complete Freund’s adjuvant (FCA). Macroscopic evidence of CIA first appeared as periarticular erythema and edema in the hind paws. The incidence of CIA was 100% by day 27 in the CII-challenged rats, and the severity of CIA progressed for 35 days. Radiographs revealed focal resorption of bone, with osteophyte formation in the tibiotarsal joint and soft tissue swelling. The histopathologic features included erosion of the cartilage at the joint margins. The persimmon extract showed an anti-inflammatory effect given the significant reduction in both the edema volume and radiological alterations attributed to CIA in the bone. We demonstrate that the administration of persimmon extract attenuates the degree of chronic inflammation and tissue damage characteristic of CIA in rats, most probably by the potent antioxidant characteristics of the extract.
Variable selection in competing risks models based on quantile regression

The proportional subdistribution hazard regression model has been widely used by clinical researchers for analyzing competing risks data. It is well known that quantile regression provides a more comprehensive alternative to model how covariates influence not only the location but also the entire conditional distribution. In this paper, we develop variable selection procedures based on penalized estimating equations for competing risks quantile regression. Asymptotic properties of the proposed estimators including consistency and oracle properties are established. Monte Carlo simulation studies are conducted, confirming that the proposed methods are efficient. A bone marrow transplant data set is analyzed to demonstrate our methodologies.
Plasminogen activator inhibitor-1 activity and the 4G/5G polymorphism are prospectively associated with blood pressure and hypertension status.

OBJECTIVES Plasminogen activator inhibitor-1 (PAI-1) has consistently shown positive associations with blood pressure (BP). Whether elevations in PAI-1 levels precede or result from raised BP is still under debate and data on prospective studies are limited. Hence, we investigated the prospective associations of PAI-1 and the 4G/5G polymorphism with brachial and central BP and pulse pressure (PP) over a 10-year period. METHODS Black South Africans aged 30 years and older were included. Baseline data collection commenced in 2005 (n = 2010) with follow-up data collection in 2010 (n = 1288) and 2015 (n = 926). Plasma PAI-1 activity (PAI-1act), 4G/5G polymorphism genotyping, waist circumference and BP measurements were performed and analysed using sequential regression and mixed models. RESULTS In multivariable adjusted analyses, PAI-1act and the 4G/4G (vs. the 5G/5G) genotype increased the odds of developing hypertension in the total group [1.04 (1.01; 1.08) and 1.82 (1.07; 3.12) respectively]. Furthermore, PAI-1act was prospectively associated with brachial SBP (r = 0.0815) and PP (r = 0.0832) in the total group, and with central PP in women (r = 0.1125; all P < 0.05). Addition of waist circumference to the models either decreased or nullified the contribution of PAI-1act to BP and hypertension development. CONCLUSION PAI-1act and the 4G/4G (vs. the 5G/5G) genotype increased the odds of developing hypertension. Furthermore, PAI-1act associated prospectively with both brachial and central BP. These associations were mediated in part by central adiposity. The study supports the hypothesis that PAI-1 also contributes to hypertension development rather than solely being a consequence thereof.