Miracle-dz/UniFAR-FTUs huggingface dataset:
Amyloid fibril formation and seeding by wild-type human lysozyme and its disease-related mutational variants.

Wild-type human lysozyme and its two stable amyloidogenic variants have been found to form partially folded states at low pH. These states are characterized by extensive disruption of tertiary interactions and partial loss of secondary structure. Incubation of the proteins at pH 2.0 and 37 degrees C (Ile56Thr and Asp67His variants) or 57 degrees C (wild-type) results in the formation of large numbers of fibrils over several days of incubation. Smaller numbers of fibrils could be observed under other conditions, including neutral pH. These fibrils were analyzed by electron microscopy, Congo red birefringence, thioflavine-T binding, and X-ray fiber diffraction, which unequivocally show their amyloid character. These data demonstrate that amyloidogenicity is an intrinsic property of human lysozyme and does not require the presence of specific mutations in its primary structure. The amyloid fibril formation is greatly facilitated, however, by the introduction of "seeds" of preformed fibrils to the solutions of the variant proteins, suggesting that seeding effects could be important in the development of systemic amyloidosis. Fibril formation by wild-type human lysozyme is greatly accelerated by fibrils of the variant proteins and vice versa, showing that seeding is not specific to a given protein. The fact that wild-type lysozyme has not been found in ex vivo deposits from patients suffering from this disease is likely to be related to the much lower population of incompletely folded states for the wild-type protein compared to its amyloidogenic variants under physiological conditions. These results support the concept that the ability to form amyloid is a generic property of proteins, but one that is mitigated against in a normally functioning organism.
Promotion and prevention orientations in the choice to attend lectures or watch them online

When presented with the option to use a new instructional technology, students often face an approach-avoidance conflict. This study explored promotion and prevention orientations, concepts linked to approach and avoidance in Higgins's regulatory focus theory, in the choice to attend lectures or watch them online. Openness, a core disposition in the Big Five Model of personality, and positive attitudes towards the utility of the Internet, reflect promotion orientations that are potentially related to the choice to watch lectures online. By contrast, neuroticism, another core disposition in the Big Five Model, and anxiety about the Internet as a computer technology, reflect a prevention orientation that is potentially related to the choice of attending lectures in class. The results illustrate that both promotion and prevention are at work in the choice to attend lectures or to watch them online. Neuroticism and anxiety about the Internet as a computer technology were related to the choice to attend lectures in class, whereas the perceived utility of the Internet was related to the choice to watch lectures online. Instructional mode choice was not related to examination performance, suggesting that the choice to attend lectures or watch them online has more to do with individual differences in promotion and prevention orientations than with pedagogical characteristics that impact learning.
Conceptualizing and scaling the developmental structure of behavior disorder: The Lifetime Alcohol Problems Score -as an example

We contrast the current, clinically based framework for behavior disorder against a life course framework, as an alternative structure upon which to map the variations in onset and stability of clinical symptomatology known to take place in adult life. This alternative developmental framework is used as a base around which to understand known variations in rates of alcohol abuse/dependence over the life course and to review existing schemes for the evaluation of developmental variation in “caseness. ” From this work, it was proposed that symptom structure be regarded as a mass of greater or lesser breadth, with properties of extensiveness in time and life course invasiveness, as a function of where in the life course the symptomatology first emerged, and the degree to which the mass sustained itself in developmental time. This framework guided the construction of a time-based measure of alcohol related symptomatology, called the Lifetime Alcohol Problems Score (LAPS). The LAPS discriminated among a variety of alcohol-specific and nonalcohol-specific measures of alcohol-related difficulty, including diagnosis of alcohol dependence, having been in treatment, level of other psychopathology, and measures of family disorganization. The measure has potential applicability for prospective studies, and in estimating clinical prognosis. The utility of the paradigm as a framework within which to conceptualize the emergence, ebb, and flow of other behavior disorders is also discussed.
Jagged1 regulates the activation of astrocytes via modulation of NFκB and JAK/STAT/SOCS pathways

The Notch pathway is implicated in many aspects of the central nervous system (CNS) development and functions. Recently, we and others identified the Notch pathway to be involved in inflammatory events of the CNS. To understand the implication of this pathway on astrocytes, we have studied the Jagged‐Notch‐Hes pathway under inflammatory conditions. LPS exposure induced an upregulation of Jagged1 expression on cultured astrocytes. To address the role of Jagged1 in the modulation of inflammation, we used a siRNA mediated silencing of Jagged1 (siRNA J1). Jagged1 inhibition induced important variations on the Notch pathway components like Hes1, Hes5, Notch3, and RBP‐Jκ. siRNA J1 repressed the mRNA expression of genes known as hallmarks of the gliosis like GFAP and endothelin(B) receptor. On activated astrocytes, the inhibition of Jagged1 had antiinflammatory effects and resulted in a decrease of LPS‐induced proinflammatory cytokines (IL1β, IL1α, and TNFα) as well as the iNOS expression. The inhibition of Jagged1 induced a modulation of the JAK/STAT/SOCS signaling pathway. Most interestingly, the siRNA J1 decreased the LPS‐induced translocation of NFκB p65 and this could be correlated to the phosphorylation of IκBα. These results suggest that during inflammatory and gliotic events of the CNS, Jagged1/Notch signaling sustains the inflammation mainly through NFκB and in part through JAK/STAT/SOCS signaling pathways. © 2009 Wiley‐Liss, Inc.
Factors Associated with Complete Adherence to HIV Combination Antiretroviral Therapy

Abstract Purpose: To assess factors associated with adherence, particularly pill burden, to combination antiretroviral therapy (cART) using multivariate models. Method: A cross-sectional survey of US adults with a self-reported diagnosis of HIV/AIDS was conducted between April and May 2007. Respondents on a cART regimen of at least 2 nucleoside reverse transcriptase inhibitors plus at least 1 protease inhibitor or non-nucleoside reverse transcriptase inhibitor (n = 461) were included in the analytic sample. Multiple logistic regression models determined independent predictors of complete adherence (defined as never missing or skipping an antiretroviral dose). Results: Fifty-four percent of respondents reported complete adherence to cART. Adherent respondents reported a lower percentage of hospitalizations (11% vs 28%; P < .0001) and emergency room visits (26% vs 34%; P < .09). Respondents taking the single tablet efavirenz/emtricitabine/tenofovir fixed-dose regimen were significantly more likely to have complete adherence than respondents taking other cART regimens (odds ratio [OR] 2.1, P < .05), and higher imputed daily HIV pill count was associated with lower likelihood of complete adherence (OR 0.93, P < .05). Conclusion: This study shows the negative impact of higher pill burden on medication adherence, an important factor associated with treatment outcomes in patients with HIV/AIDS.
CD38 Controls ADP-Ribosyltransferase-2-Catalyzed ADP-Ribosylation of T Cell Surface Proteins1

ADP-ribosyltransferase-2 (ART2), a GPI-anchored, toxin-related ADP-ribosylating ectoenzyme, is prominently expressed by murine T cells but not by B cells. Upon exposure of T cells to NAD, the substrate for ADP-ribosylation, ART2 catalyzes ADP-ribosylation of the P2X7 purinoceptor and other functionally important cell surface proteins. This in turn activates P2X7 and induces exposure of phosphatidylserine and shedding of CD62L. CD38, a potent ecto-NAD-glycohydrolase, is strongly expressed by most B cells but only weakly by T cells. Following incubation with NAD, CD38-deficient splenocytes exhibited lower NAD-glycohydrolase activity and stronger ADP-ribosylation of cell surface proteins than their wild-type counterparts. Depletion of CD38high cells from wild-type splenocytes resulted in stronger ADP-ribosylation on the remaining cells. Similarly, treatment of total splenocytes with the CD38 inhibitor nicotinamide 2′-deoxy-2′-fluoroarabinoside adenine dinucleotide increased the level of cell surface ADP-ribosylation. Furthermore, the majority of T cells isolated from CD38-deficient mice “spontaneously” exposed phosphatidylserine and lacked CD62L, most likely reflecting previous encounter with ecto-NAD. Our findings support the notion that ecto-NAD functions as a signaling molecule following its release from cells by lytic or nonlytic mechanisms. ART2 can sense and translate the local concentration of ecto-NAD into corresponding levels of ADP-ribosylated cell surface proteins, whereas CD38 controls the level of cell surface protein ADP-ribosylation by limiting the substrate availability for ART2.
Prolonged strenuous exercise alters the cardiovascular response to dobutamine stimulation in male athletes

Prolonged strenuous exercise has been associated with transient impairment in left ventricular (LV) systolic and diastolic function that has been termed ‘cardiac fatigue’. It has been postulated that cardiac β‐adrenoreceptor desensitization may play a central role; however, data are limited. Accordingly, we assessed the cardiovascular response to progressive dobutamine stimulation after prolonged strenuous exercise (2 km swim, 90 km bike, 21 km run). Nine experienced male athletes were studied: PRE (2–3 days before), POST (after) and REC (1–2 days later). The cardiovascular response to progressive continuous dobutamine stimulation (0, 5, 20, and 40 μg kg−1 min−1) was assessed, including heart rate (HR), systolic blood pressure (SBP), LV cavity areas (two‐dimensional echocardiography) and contractility (end‐systolic elastance, SBP/end‐systolic cavity area (ESCA)). POST there was limited evidence of myocardial necrosis (measured by troponin I), while catecholamines were elevated. HR was higher POST (mean ±s.d.; PRE, 58 ± 9; POST, 79 ± 9; REC, 57 ± 7 beats min−1; P < 0.05), while SBP was lower (PRE, 127 ± 15; POST, 116 ± 9; REC, 121 ± 12 mmHg; P < 0.05). A blunted HR, SBP and LV contractility (SBP/ESCA; PRE 29 ± 6 versus POST 20 ± 6 mmHg cm−2; P < 0.05) response to dobutamine was demonstrated POST, with values returning towards baseline in REC. Following prolonged strenuous exercise, the chronotropic and inotropic response to dobutamine stimulation is blunted. This study supports the hypothesis that beta‐receptor downregulation and/or desensitization may play a major role in prolonged‐strenuous‐exercise‐mediated cardiac fatigue.
Genetic relatedness does not retain spatial pattern across multiple spatial scales: dispersal and colonization in the coral, Pocillopora damicornis

Patterns of isolation by distance are uncommon in coral populations. Here, we depart from historical trends of large‐scale, geographical genetic analyses by scaling down to a single patch reef in Kāne‘ohe Bay, Hawai‘i, USA, and map and genotype all colonies of the coral, Pocillopora damicornis. Six polymorphic microsatellite loci were used to assess population genetic and clonal structure and to calculate individual colony pairwise relatedness values. Our results point to an inbred, highly clonal reef (between 53 and 116 clonal lineages of 2352 genotyped colonies) with a much skewed genet frequency distribution (over 70% of the reef was composed of just seven genotypes). Spatial autocorrelation analyses revealed that corals found close together on the reef were more genetically related than corals further apart. Spatial genetic structure disappears, however, as spatial scale increases and then becomes negative at the largest distances. Stratified, random sampling of three neighbouring reefs confirms that reefs are demographically open and inter‐reef genetic structuring was not detected. Attributing process to pattern in corals is complicated by their mixed reproductive strategies. Separate autocorrelation analyses, however, show that the spatial distribution of both clones and nonclones contributes to spatial genetic structure. Overall, we demonstrate genetic structure on an intrareef scale and genetic panmixia on an inter‐reef scale indicating that, for P. damicornis, the effect of small‐ and large‐scale dispersal processes on genetic diversity are not the same. By starting from an interindividual, intrareef level before scaling up to an inter‐reef level, this study demonstrates that isolation‐by‐distance patterns for the coral P. damicornis are limited to small scales and highlights the importance of investigating genetic patterns and ecological processes at multiple scales.
Cell wall-related proteins of unknown function: missing links in plant cell wall development.

Lignocellulosic biomass is an important feedstock for the pulp and paper industry as well as emerging biofuel and biomaterial industries. However, the recalcitrance of the secondary cell wall to chemical or enzymatic degradation remains a major hurdle for efficient extraction of economically important biopolymers such as cellulose. It has been estimated that approximately 10-15% of about 27,000 protein-coding genes in the Arabidopsis genome are dedicated to cell wall development; however, only about 130 Arabidopsis genes thus far have experimental evidence validating cell wall function. While many genes have been implicated through co-expression analysis with known genes, a large number are broadly classified as proteins of unknown function (PUFs). Recently the functionality of some of these unknown proteins in cell wall development has been revealed using reverse genetic approaches. Given the large number of cell wall-related PUFs, how do we approach and subsequently prioritize the investigation of such unknown genes that may be essential to or influence plant cell wall development and structure? Here, we address the aforementioned question in two parts; we first identify the different kinds of PUFs based on known and predicted features such as protein domains. Knowledge of inherent features of PUFs may allow for functional inference and a concomitant link to biological context. Secondly, we discuss omics-based technologies and approaches that are helping identify and prioritize cell wall-related PUFs by functional association. In this way, hypothesis-driven experiments can be designed for functional elucidation of many proteins that remain missing links in our understanding of plant cell wall biosynthesis.
Goat milk epithelial cells are highly permissive to CAEV infection in vitro.

The main route of small ruminant lentivirus dissemination is the ingestion of infected cells present in colostrum and milk from infected animals. However, whether only macrophages or other cell subtypes are involved in this transmission is unknown. We derived epithelial cell cultures, 100% cytokeratin positive, from milk of naturally infected and noninfected goats. One such culture, derived from a naturally infected goat, constitutively produced a high titer of virus in the absence of any cytopathic effect. The other cultures, negative for natural lentivirus infection, were tested for their susceptibility to infection with the CAEV-CO strain and a French field isolate CAEV-3112. We showed that milk epithelial cells are easily infected by either virus and produce viruses at titers as high as those obtained in permissive goat synovial membrane cells. The CAEV-CO strain replicated in milk epithelial cells in absence of any cytopathic effect, whereas the CAEV-3112 field isolate induced both cell fusion and cell lysis. Our results suggest that CAEV-infected milk epithelial cells of small ruminants may play an important role in virus transmission and pathogenesis.
Protein interactions with the platelet integrin αIIb regulatory motif

Integrins are transmembrane proteins regulating cellular shape, mobility and the cell cycle. A highly conserved signature motif in the cytoplasmic tail of the integrin α‐subunit, KXGFFKR, plays a critical role in regulating integrin function. To date, six proteins have been identified that target this motif of the platelet‐specific integrin αIIbβ3. We employ peptide‐affinity chromatography followed‐up with LC‐MS/MS analysis as well as protein chips to identify new potential regulators of integrin function in platelets and put them into their biological context using information from protein:protein interaction (PPI) databases. Totally, 44 platelet proteins bind with high affinity to an immobilized LAMWKVGFFKR‐peptide. Of these, seven have been reported in the PPI literature as interactors with integrin α‐subunits. 68 recombinant human proteins expressed on the protein chip specifically bind with high affinity to biotin‐tagged α‐integrin cytoplasmic peptides. Two of these proteins are also identified in the peptide‐affinity experiments, one is also found in the PPI databases and a further one is present in the data to all three approaches. Finally, novel short linear interaction motifs are common to a number of proteins identified.
A prospective study of 2 major age-related macular degeneration susceptibility alleles and interactions with modifiable risk factors.

OBJECTIVES To delineate the magnitude of susceptibility to age-related macular degeneration (AMD) due to common variants in the gene for complement factor H (CFH) and the predicted gene LOC387715 and to determine whether these variants interact with modifiable risk factors. METHODS We compared cases who developed AMD (n = 457) with 1071 age- and sex-matched control subjects in a prospective nested case-control study within the Nurses' Health Study and the Health Professionals Follow-up Study. We determined the incidence rate ratios and 95% confidence intervals (CIs) for AMD for each genotype and examined the interactions with modifiable risk factors. RESULTS Participants with 1 or 2 copies of the Y402H variant of CFH were, respectively, 1.98 (95% CI, 1.64-2.40) and 3.92 (95% CI, 2.69-5.76) times more likely to develop AMD, whereas the incident rate ratios (95% CIs) for 1 and 2 copies of LOC387715 A69S were 2.38 (1.92-2.96) and 5.66 (3.69-8.76), respectively. The fraction of AMD cases attributable to these 2 variants was 63% (95% CI, 58%-68%). Subjects homozygous for both risk alleles had a 50-fold increased risk of AMD (95% CI, 10.8-237), and cigarette smoking and obesity multiplied the risks associated with these variants. CONCLUSION Age-related macular degeneration has emerged as a paradigmatic example of a common disease caused by the interplay of genetic predisposition and exposure to modifiable risk factors.
Long-term Outcome of Biliary and Duodenal Stents in Palliative Treatment of Patients with Unresectable Adenocarcinoma of the Head of Pancreas

BACKGROUND:Life expectancy in patients with unresectable pancreatic cancer has improved by using new chemotherapeutic regimens. Biliary and digestive stenoses can be endoscopically treated in most cases. However, long-term efficacy of these stenting procedures remains unknown.AIM:To evaluate the incidence of biliary and duodenal stenoses as well as technical success and short- and long-term patency of endoscopically deployed stents in patients with unresectable pancreatic cancer.PATIENTS AND METHODS:All consecutive patients with unresectable cancer of the pancreatic head seen between January 1999 and September 2003 in our center were retrospectively studied. Patients with biliary and/or duodenal stenoses underwent endoscopic stent insertion as first intention therapy. Outcomes included technical and clinical success, stent patency, and survival.RESULTS:One hundred patients, median age 65 yr (32–85), with locally advanced (62%) or metastatic (38%) pancreatic cancer were studied. Eighty-three percent received at least one line of chemotherapy. The actuarial median survival was 11 months (0.7–29.3). Biliary and duodenal stenoses occurred in 81 and 25 patients, respectively. A biliary stent was successfully placed in 74 patients (91%). When a self-expandable metallic stent was first introduced (N = 59), a single stent was sufficient in 41 patients (69%) (median duration of stent patency 7 months (0.4–21.1)). Duodenal stenting was successful in 24 patients (96%); among them, 96% required a single stent (median duration of stent patency 6 months [0.5–15.7]). In the 23 patients who developed both biliary and duodenal stenoses, combined stenting was successful in 91% of cases. No major complication or death occurred related to endoscopic treatment.CONCLUSION:Endoscopic palliative treatment of both biliary and duodenal stenoses is safe and effective in the long term, including in patients with combined obstructions. Use of such palliative management is justified as repeat procedures are rarely required even in patients who have a long survival.
Brisk walking and serum lipid and lipoprotein variables in previously sedentary women--effect of 12 weeks of regular brisk walking followed by 12 weeks of detraining.

The purpose of this study was to examine the effectiveness of brisk walking as a means of improving endurance fitness and influencing serum lipid and lipoprotein variables in previously sedentary women. Walkers (n = 10, mean (s.e.m.) age 47.3(2.0) years) followed a programme of brisk walking (mean(s.e.m.) speed 1.76(0.03) m s-1) for 12 weeks, after which the training stimulus was withdrawn. Controls (n = 10, mean(s.e.m.) age 41.6(1.2) years) maintained their habitual sedentary lifestyle throughout. Endurance fitness was determined using laboratory measures of responses to treadmill walking. Serum lipid and lipoprotein variables were determined in venous blood (12-h fasted). Body fatness was assessed by anthropometry and dietary practice using the 7-day weighed food intake technique. Measurements were repeated after 12 and 24 weeks. Brisk walking resulted in a decrease in heart rate and blood lactate concentration during exercise, while detraining was accompanied by a reversal of these changes. Changes in body mass and the ratio of circumferences at the waist and hip did not differ between groups but the sum of four skinfolds decreased with brisk walking and increased with detraining. High density lipoprotein (HDL) and HDL2 cholesterol increased with walking and decreased with detraining but no between group changes (analysis of variance, P < 0.05) were found in other lipid and lipoprotein variables. These findings suggest that regular brisk walking can improve endurance fitness and increase HDL cholesterol concentration in sedentary women.