Miracle-dz/UniFAR-FTUs huggingface dataset:
Stratified Communities of Active Archaea in Deep Marine Subsurface Sediments

ABSTRACT Archaeal 16S rRNA was extracted from samples of deep marine subsurface sediments from Peru Margin site 1227, Ocean Drilling Program leg 201. The amounts of archaeal 16S rRNA in each extract were quantified by serial dilution and reverse transcription (RT)-PCR. The results indicated a 1,000-fold variation in rRNA content with depth in the sediment, with the highest concentrations found near the sediment surface and in the sulfate-methane transition zone (SMTZ). The phylogenetic composition of the active archaeal population revealed by cloning and sequencing of RT-PCR products changed with depth. Several phylotypes affiliated with marine benthic group B (MBGB) dominated clone libraries from the upper part of the SMTZ and were detected only in this layer. Members of the miscellaneous crenarchaeotal group (MCG) dominated clone libraries from the other layers. These results demonstrate that archaeal communities change in activity and community composition over short distances in geochemically distinct zones of deep subseafloor sediments and that these changes are traceable in the rRNA pool. It was shown for the first time that members of both the MCG and MBGB Archaea are more active in the SMTZ than in layers above and below. This indicates that they benefit either directly or indirectly from the anaerobic oxidation of methane. They also appear to be ecophysiologically flexible, as they have been retrieved from a wide range of marine sediments of various geochemical properties.
Charcot-Marie-Tooth–Linked Mutant GARS Is Toxic to Peripheral Neurons Independent of Wild-Type GARS Levels

Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). In addition to GARS, mutations in three other tRNA synthetase genes cause similar neuropathies, although the underlying mechanisms are not fully understood. To address this, we generated transgenic mice that ubiquitously over-express wild-type GARS and crossed them to two dominant mouse models of CMT2D to distinguish loss-of-function and gain-of-function mechanisms. Over-expression of wild-type GARS does not improve the neuropathy phenotype in heterozygous Gars mutant mice, as determined by histological, functional, and behavioral tests. Transgenic GARS is able to rescue a pathological point mutation as a homozygote or in complementation tests with a Gars null allele, demonstrating the functionality of the transgene and revealing a recessive loss-of-function component of the point mutation. Missense mutations as transgene-rescued homozygotes or compound heterozygotes have a more severe neuropathy than heterozygotes, indicating that increased dosage of the disease-causing alleles results in a more severe neurological phenotype, even in the presence of a wild-type transgene. We conclude that, although missense mutations of Gars may cause some loss of function, the dominant neuropathy phenotype observed in mice is caused by a dose-dependent gain of function that is not mitigated by over-expression of functional wild-type protein.
Parkinson’s disease and pesticide exposure – a new assessment

Abstract Parkinson’s disease (PD) is an idiopathic disease and its pathological feature is a loss of pigmented neurons in the substantia nigra. Some commonly used pesticides possess neurotoxicity, and exposure to such compounds may trigger mechanisms similar to those in the development of idiopathic PD. We conducted a systematic review of epidemiological studies, aiming at a critical evaluation of the association between the development of PD and pesticide exposure. Reported effect sizes (ES) in the relevant studies were pooled into the meta-analysis to derive summary ES. The summary ES suggested a significantly positive association between PD and overall pesticide use (non-occupational and/or occupational pesticide use) [1.42; 95% confidence interval (CI) 1.32 to 1.52, the fixed-effects model], as well as between PD and occupational pesticide exposure (1.49 with a 95% CI of 1.34–1.66). Both occupational herbicide and occupational insecticide exposure showed a significant association with PD. The results of the meta-analysis reported in this study suggest the existence of a statistically positive association between PD and pesticide exposure. The majority of the studies that were pooled in the meta-analysis were case-control design with very few cohort studies and most with poor exposure characterization thus, any further case-control studies using similar methodologies are unlikely to have a significant impact or understanding on the currently-reported association between pesticide exposure and the development of idiopathic PD. Therefore, we believe that if further epidemiological studies are going to be conducted in the area, they should be prospective cohort studies that will include accurate exposure assessment.
Emergency nurse practitioner services in major accident and emergency departments: a United Kingdom postal survey.

OBJECTIVE: To establish the current and predicted distribution of formal emergency nurse practitioner services in major accident and emergency departments in the United Kingdom; to determine organisational variations in service provision, with specific reference to funding, role configuration, training, and scope of clinical activity. METHODS: Postal survey of senior nurses of all major accident and emergency departments in the United Kingdom (n = 293) in May/June 1996. RESULTS: There were 274 replies (94% response rate): 98 departments (36%) provided a formal service; a further 91 departments (33%) reported definite plans to introduce a service by the end of 1996; smaller departments, under 40000 new patient attendances annually, were less likely to provide a service than busier units (p < 0.001, chi2 for trend). Three different methods of making the role operational were identified: dedicated, integrated, and rotational. Only 16 (18%) were able to provide a 24 hour service; 91 departments (93%) employed emergency nurse practitioners who had received specific training, but wide variations in length, content, and academic level were noted; 82 departments (84%) authorised nurse practitioners to order x rays independently, but only 35 (36%) allowed them to interpret radiographs; 67 (68%) permitted "over the counter" drug supplying under local protocol, and 52 (54%), "prescription only" drug supplying from an agreed list. CONCLUSIONS: Formal emergency nurse practitioner services are provided in all parts of the United Kingdom, with predicted figures suggesting a rapidly accelerating upward trend. Wide variations in service organisation, training, and scope of activity are evident.
Hospital-Level Racial Disparities in Acute Myocardial Infarction Treatment and Outcomes

Background:Previous studies have documented racial disparities in treatment of acute myocardial infarction (AMI) among Medicare beneficiaries. However, the extent to which unobserved differences between hospitals explains some of these differences is unknown. Objective:The objective of this study was to determine whether the observed racial treatment disparities for AMI narrow when analyses account for differences in where blacks and whites are hospitalized. Research Design:Retrospective observational cohort study using Medicare claims and medical record review. Subjects:This study included 130,709 white and 8286 black Medicare patients treated in 4690 hospitals in 50 US states for confirmed AMI in 1994 and 1995. Measures:Measures in this study were receipt of reperfusion, aspirin, and smoking cessation counseling during hospitalization; prescription of aspirin, angiotensin-converting enzyme inhibitor, and beta-blocker at hospital discharge; receipt of cardiac catheterization, percutaneous coronary intervention (PCI), or bypass surgery (CABG) within 30 days of AMI; and 30-day and 1-year mortality. Results:Within-hospital analyses narrowed or erased black–white disparities for medical treatments received during the acute hospitalization, widened black–white disparities for follow-up surgical treatments, and augmented the survival advantage among blacks. These findings indicate that, on average, blacks went to hospitals that had lower rates of evidence-based medical treatments, higher rates of cardiac procedures, and worse risk-adjusted mortality after AMI. Conclusions:Incorporating the hospital effect altered the findings of racial disparity analyses in AMI and explained more of the disparities than race. A policy of targeted hospital-level interventions may be required for success of national efforts to reduce disparities.
Endothelial Dysfunction in Experimental Models of Arterial Hypertension: Cause or Consequence?

Hypertension is a risk factor for other cardiovascular diseases and endothelial dysfunction was found in humans as well as in various commonly employed animal experimental models of arterial hypertension. Data from the literature indicate that, in general, endothelial dysfunction would not be the cause of experimental hypertension and may rather be secondary, that is, resulting from high blood pressure (BP). The initial mechanism of endothelial dysfunction itself may be associated with a lack of endothelium-derived relaxing factors (mainly nitric oxide) and/or accentuation of various endothelium-derived constricting factors. The involvement and role of endothelium-derived factors in the development of endothelial dysfunction in individual experimental models of hypertension may vary, depending on the triggering stimulus, strain, age, and vascular bed investigated. This brief review was focused on the participation of endothelial dysfunction, individual endothelium-derived factors, and their mechanisms of action in the development of high BP in the most frequently used rodent experimental models of arterial hypertension, including nitric oxide deficient models, spontaneous (pre)hypertension, stress-induced hypertension, and selected pharmacological and diet-induced models.
How Skill Expertise Shapes the Brain Functional Architecture: An fMRI Study of Visuo-Spatial and Motor Processing in Professional Racing-Car and Naïve Drivers

The present study was designed to investigate the brain functional architecture that subserves visuo-spatial and motor processing in highly skilled individuals. By using functional magnetic resonance imaging (fMRI), we measured brain activity while eleven Formula racing-car drivers and eleven ‘naïve’ volunteers performed a motor reaction and a visuo-spatial task. Tasks were set at a relatively low level of difficulty such to ensure a similar performance in the two groups and thus avoid any potential confounding effects on brain activity due to discrepancies in task execution. The brain functional organization was analyzed in terms of regional brain response, inter-regional interactions and blood oxygen level dependent (BOLD) signal variability. While performance levels were equal in the two groups, as compared to naïve drivers, professional drivers showed a smaller volume recruitment of task-related regions, stronger connections among task-related areas, and an increased information integration as reflected by a higher signal temporal variability. In conclusion, our results demonstrate that, as compared to naïve subjects, the brain functional architecture sustaining visuo-motor processing in professional racing-car drivers, trained to perform at the highest levels under extremely demanding conditions, undergoes both ‘quantitative’ and ‘qualitative’ modifications that are evident even when the brain is engaged in relatively simple, non-demanding tasks. These results provide novel evidence in favor of an increased ‘neural efficiency’ in the brain of highly skilled individuals.
Hydration state of the Martian surface as seen by Mars Express OMEGA: 1. Analysis of the 3 μm hydration feature

[1] Global mapping by the visible/near-infrared OMEGA spectrometer gives the first opportunity to study in detail the characteristics of the 3 μm hydration absorption on the surface of Mars. This feature is caused by bending and stretching vibrations of adsorbed or structural H2O and/or OH- bound to minerals. A specific data reduction scheme has been developed to remove the contribution of thermally emitted radiance from OMEGA spectra. With the derived albedo spectra, variations in strength and shape of the 3 μm feature can be accurately assessed. Calibration issues are discussed and data only within the nominal calibration level of the instrument are analyzed, which corresponds to a surface coverage of ∼30%. All OMEGA spectra exhibit the presence of this absorption feature, which can be explained by the presence of adsorbed water as well as by alteration rinds or coatings resulting from weathering. Strong variations of the band strength are observed. Correlations between hydration, albedo, and elevation are examined. Terrains enriched in phyllosilicates, sulfates, or hydroxides exhibit an increased hydration signature as well as a weaker combination overtone H2O absorption at ∼1.9 μm. Careful analysis also reveals seasonal variations in surface hydration, with soils in the northern midlatitudes decreasing in hydration between northern spring and summer. This hydration change is best explained by the presence of winter frost followed by equilibration of frost-free soil with the atmosphere and by increased surface temperatures reducing the adsorptive capacity of the regolith.
Protein-ligand binding site recognition using complementary binding-specific substructure comparison and sequence profile alignment

MOTIVATION Identification of protein-ligand binding sites is critical to protein function annotation and drug discovery. However, there is no method that could generate optimal binding site prediction for different protein types. Combination of complementary predictions is probably the most reliable solution to the problem. RESULTS We develop two new methods, one based on binding-specific substructure comparison (TM-SITE) and another on sequence profile alignment (S-SITE), for complementary binding site predictions. The methods are tested on a set of 500 non-redundant proteins harboring 814 natural, drug-like and metal ion molecules. Starting from low-resolution protein structure predictions, the methods successfully recognize >51% of binding residues with average Matthews correlation coefficient (MCC) significantly higher (with P-value <10(-9) in student t-test) than other state-of-the-art methods, including COFACTOR, FINDSITE and ConCavity. When combining TM-SITE and S-SITE with other structure-based programs, a consensus approach (COACH) can increase MCC by 15% over the best individual predictions. COACH was examined in the recent community-wide COMEO experiment and consistently ranked as the best method in last 22 individual datasets with the Area Under the Curve score 22.5% higher than the second best method. These data demonstrate a new robust approach to protein-ligand binding site recognition, which is ready for genome-wide structure-based function annotations. AVAILABILITY http://zhanglab.ccmb. med.umich. edu/COACH/
The Hardness of the Closest Vector Problem With Preprocessing Over$ell_infty$Norm

We show that the closest vector problem with preprocessing (CVPP) over lscr <sub>infin</sub> norm (CVPP<sub>infin</sub>) is NP-hard. The result is obtained by the reduction from the subset sum problem with preprocessing to CVPP<sub>infin</sub>. The reduction also shows the NP-hardness of CVP<sub>infin</sub>, which is much simpler than all previously known proofs. In addition, we also give a direct reduction from exact 3-sets cover problem to CVPP<sub>infin</sub>
Immunization with a Live Attenuated H7N9 Influenza Vaccine Protects Mice against Lethal Challenge

The emergence of severe cases of human influenza A (H7N9) viral infection in China in the spring of 2003 resulted in a global effort to rapidly develop an effective candidate vaccine. In this study, a cold-adapted (ca), live attenuated monovalent reassortant influenza H7N9 virus (Ah01/AA ca) was generated using reverse genetics that contained hemagglutinin (HA) and neuraminidase (NA) genes from a 2013 pandemic A H7N9 isolate, A/Anhui/01/2013 virus (Ah01/H7N9); the remaining six backbone genes derived from the cold-adapted influenza H2N2 A/Ann Arbor/6/60 virus (AA virus). Ah01/AA ca virus exhibited temperature sensitivity (ts), ca, and attenuation (att) phenotypes. Intranasal immunization of female BALB/c mice with Ah01/AA ca twice at a 2-week interval induced robust humoral, mucosal, and cell-mediated immune responses in a dose-dependent manner. Furthermore, the candidate Ah01/AA ca virus was immunogenic and offered partial or complete protection of mice against a lethal challenge by the live 2013 influenza A H7N9 (A/Anhui/01/2013). Protection was demonstrated by the inhibition of viral replication and the attenuation of histopathological changes in the challenged mouse lung. Taken together, these data support the further evaluation of this Ah01/AA ca candidate vaccine in primates.
Impact of Type 2 Diabetes on Impaired Kidney Function in Sub-Saharan African Populations

Background Diabetes is a leading risk factor for impaired kidney function, an indicator of chronic kidney disease. The aim of this study was to examine the association between type 2 diabetes (T2D) and impaired kidney function among adults in sub-Saharan Africa (SSA). Methods Participants were enrolled from Ghana, Kenya, and Nigeria. Impaired kidney function was based on an estimated glomerular filtration rate <60 ml/min/1.73 m2. Using logistic regression models, we conducted case–control analyses to estimate the multivariate-adjusted association of T2D and kidney function. Results We used data from 4815 participants for whom the mean (SD) age was 48 (15) years, 41% were male and 46% had T2D. Those with T2D were more likely to have impaired kidney function [13.4% (95% CI: 11.9–14.7)] compared to those without T2D [4.8% (95% CI: 4.0–5.6)], p-value <0.001. The multivariate odds ratio of impaired kidney function among those with type 2 diabetes was 1.50 (95% CI: 1.17–1.91) p-value = 0.001, compared to those without T2D. Also, individuals with T2D who were at least 60 years old, obese, hypertensive or dyslipidemic were more likely to have impaired kidney function compared to those without T2D. Conclusion T2D was associated with 50% increased risk of impaired kidney function in this sample of adults from SSA. Interventions targeted at prevention, early diagnosis, and management of T2D are likely to reduce the burden of kidney disease in SSA.
Adenovirus Induction of IRF3 Occurs through a Binary Trigger Targeting Jun N-Terminal Kinase and TBK1 Kinase Cascades and Type I Interferon Autocrine Signaling

ABSTRACT Pathogen recognition is a critical function of immune sentinel cells. Naïve macrophages or dendritic cells (DCs) undergo pathogen-directed activation and maturation, and as mature antigen-presenting cells (APCs), they contribute essential functions to both innate and adaptive immunity. Using recombinant adenovirus (rAdV) as a model for murine APC activation by DNA viruses, we demonstrate a critical role for stress kinase activation in cell intrinsic and extrinsic antiviral signaling cascades. We propose two viral triggers, viral capsid and viral DNA, are required for APC activation. Endosomal escape and presentation of cytosolic rAdV DNA induces phosphorylation of TANK-binding kinase 1 (TBK1) at serine 172 but does not induce IκB kinase ε activity as determined by in vitro kinase assays. However, induction of TBK1 alone is not sufficient for interferon regulatory factor 3 (IRF3) phosphorylation. We show that capsid-dependent activation of Jun N-terminal kinase (JNK) stress kinase is a necessary step, licensing TBK1 phosphorylation of IRF3 at Ser 396. A second later phase of JNK activity is required to coordinate phosphorylation of JNK-dependent transcription factors (c-Jun/ATF2) with activated IRF3 in the induction of primary IRF3-responsive transcripts. Finally, we demonstrate that maximal JNK/TBK1/IRF3 stimulation by rAdV depends on an intact type I interferon (IFN) signaling cascade. By requiring multiple viral triggers and type I IFN autocrine regulation, APCs have an inherent fail-safe mechanism against inappropriate activation and maturation.
Repetitive Pertussis Toxin Promotes Development of Regulatory T Cells and Prevents Central Nervous System Autoimmune Disease

Bacterial and viral infections have long been implicated in pathogenesis and progression of multiple sclerosis (MS). Incidence and severity of its animal model experimental autoimmune encephalomyelitis (EAE) can be enhanced by concomitant administration of pertussis toxin (PTx), the major virulence factor of Bordetella pertussis. Its adjuvant effect at the time of immunization with myelin antigen is attributed to an unspecific activation and facilitated migration of immune cells across the blood brain barrier into the central nervous system (CNS). In order to evaluate whether recurring exposure to bacterial antigen may have a differential effect on development of CNS autoimmunity, we repetitively administered PTx prior to immunization. Mice weekly injected with PTx were largely protected from subsequent EAE induction which was reflected by a decreased proliferation and pro-inflammatory differentiation of myelin-reactive T cells. Splenocytes isolated from EAE-resistant mice predominantly produced IL-10 upon re-stimulation with PTx, while non-specific immune responses were unchanged. Longitudinal analyses revealed that repetitive exposure of mice to PTx gradually elevated serum levels for TGF-β and IL-10 which was associated with an expansion of peripheral CD4+CD25+FoxP3+ regulatory T cells (Treg). Increased frequency of Treg persisted upon immunization and thereafter. Collectively, these data suggest a scenario in which repetitive PTx treatment protects mice from development of CNS autoimmune disease through upregulation of regulatory cytokines and expansion of CD4+CD25+FoxP3+ Treg. Besides its therapeutic implication, this finding suggests that encounter of the immune system with microbial products may not only be part of CNS autoimmune disease pathogenesis but also of its regulation.
LIPID CLASS, CAROTENOID, AND TOXIN DYNAMICS OF KARENIA BREVIS (DINOPHYCEAE) DURING DIEL VERTICAL MIGRATION 1

The internal lipid, carotenoid, and toxin concentrations of Karenia brevis (C. C. Davis) Gert Hansen and Moestrup are influenced by its ability to use ambient light and nutrients for growth and reproduction. This study investigated changes in K. brevis toxicity, lipid class, and carotenoid concentrations in low‐light, nitrate‐replete (250 μmol quanta · m−2 · s−1, 80 μM NO3); high‐light, nitrate‐replete (960 μmol quanta · m−2 · s−1, 80 μM NO3); and high‐light, nitrate‐reduced (960 μmol quanta · m−2 · s−1, <5 μM NO3) mesocosms. Reverse‐phase HPLC quantified the epoxidation state (EPS) of the xanthophyll‐cycle pigments diadinoxanthin and diatoxanthin, and a Chromarod Iatroscan thin layer chromatography/flame ionization detection (TLC/FID) system quantified changes in lipid class concentrations. EPS did not exceed 0.20 in the low‐light mesocosm, but increased to 0.65 in the high‐light mesocosms. Triacylglycerol and monogalactosyldiacylglycerol (MGDG) were the largest lipid classes consisting of 9.3% to 48.7% and 37.3% to 69.7% of total lipid, respectively. Both lipid classes also experienced the greatest concentration changes in high‐light experiments. K. brevis increased EPS and toxin concentrations while decreasing its lipid concentrations under high light. K. brevis may mobilize its toxins into the surrounding environment by reducing lipid concentrations, such as sterols, limiting competition, or toxins are released because lipids are decreased in high light, reducing any protective mechanism against their own toxins.