Miracle-dz/UniFAR-FTUs huggingface dataset:
Effector-triggered immunity blocks pathogen degradation of an immunity-associated vesicle traffic regulator in Arabidopsis

Innate immunity in plants can be triggered by microbe- and pathogen-associated molecular patterns. The pathogen-associated molecular pattern-triggered immunity (PTI) is often suppressed by pathogen effectors delivered into the host cell. Plants can overcome pathogen suppression of PTI and reestablish pathogen resistance through effector-triggered immunity (ETI). An unanswered question is how plants might overcome pathogen-suppression of PTI during ETI. Findings described in this paper suggest a possible mechanism. During Pseudomonas syringae pathovar tomato (Pst) DC3000 infection of Arabidopsis, a host ADP ribosylation factor guanine nucleotide exchange factor, AtMIN7, is destabilized by the pathogen effector HopM1 through the host 26S proteasome. In this study, we discovered that AtMIN7 is required for not only PTI, consistent with the notion that Pst DC3000 degrades AtMIN7 to suppress PTI, but also ETI. The AtMIN7 level in healthy plants is low, but increases posttranscriptionally in response to activation of PTI. Whereas DC3000 infection led to degradation of AtMIN7, activation of ETI by three different effectors, AvrRpt2, AvrPphB, and HopA1, in Col-0 plants blocks the ability of Pst DC3000 to destabilize AtMIN7. Further analyses of bacterial translocation of HopM1 and AtMIN7 stability in HopM1 transgenic plants show that ETI prevents HopM1-mediated degradation of AtMIN7 inside the plant cell. Both AtMIN7 and HopM1 are localized to the trans-Golgi network/early endosome, a subcellular compartment that is not previously known to be associated with bacterial pathogenesis in plants. Thus, blocking pathogen degradation of trans-Golgi network/early endosome-associated AtMIN7 is a critical part of the ETI mechanism to counter bacterial suppression of PTI.
Control of a final gating charge transition by a hydrophobic residue in the S2 segment of a K+ channel voltage sensor

It is now well established that the voltage-sensor domains present in voltage-gated ion channels and some phosphatases operate by transferring several charged residues (gating charges), mainly arginines located in the S4 segment, across the electric field. The conserved phenylalanine F290 located in the S2 segment of the Shaker K channel is an aromatic residue thought to interact with all the four gating arginines carried by the S4 segment and control their transfer [Tao X, et al. (2010) Science 328:67–73]. In this paper we study the possible interaction of the gating charges with this residue by directly detecting their movement with gating current measurements in 12 F290 mutants. Most mutations do not significantly alter the first approximately 80–90% of the gating charge transfer nor the kinetics of the gating currents during activation. The effects of the F290 mutants are (i) the modification of a final activation transition accounting for approximately 10–20% of the total charge, similar to the effect of the ILT mutant [Ledwell JL, et al. (1999) J Gen Physiol 113:389–414] and (ii) the modification of the kinetics of the gating charge movement during deactivation. These effects are well correlated with the hydrophobicity of the substituted residue, showing that a hydrophobic residue at position 290 controls the energy barrier of the final gating transition. Our results suggest that F290 controls the transfer of R371, the fourth gating charge, during gating while not affecting the movement of the other three gating arginines.
Interaction of MC1R and PMEL alleles on solid coat colors in Highland cattle.

Six solid colors occur in Highland cattle: black, dun, silver dun and red, yellow, and white. These six coat colors are explained by a non-epistatic interaction of the genotypes at the MC1R and PMEL genes. A three base pair deletion in the PMEL gene leading to the deletion of a leucine from the signal peptide is observed in dilute-colored Highland cattle (c.50_52delTTC, p.Leu18del). The mutant PMEL allele acts in a semi-dominant manner. Dun Galloway cattle also have one copy of the deletion allele, and silver dun Galloway cattle have two copies. The presence of two adjacent leucine residues at the site of this deletion is highly conserved in human, horse, mouse and chicken as well as in cattle with undiluted coat colors. Highland and Galloway cattle thus exhibit a similar dose-dependent dilution effect based on the number of PMEL :c. 50_51delTTC alleles, as Charolais cattle with PMEL :c.64G>A alleles. The PMEL :c.64G>A allele was not found in Highland or Galloway cattle.
The Risks of Drunkenness (or, Ebrietas Resurrecta)

Summary Data from nine population samples are combined in order to compare different population sub-groups as to prevalence of drinking problems among high “frequency of intoxication” drinkers. Various indicators of frequent intoxication and of drinking problems are presented and discussed. Suggestions are made as to fewer, simpler questions about drinking and as to better ways of studying problem risks.
Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion

Combination regimens that include artemisinin derivatives are recommended as first line antimalarials in most countries where malaria is endemic. However, the mechanism of action of artemisinin is not fully understood and the usefulness of this drug class is threatened by reports of decreased parasite sensitivity. We treated Plasmodium falciparum for periods of a few hours to mimic clinical exposure to the short half-life artemisinins. We found that drug treatment retards parasite growth and inhibits uptake of hemoglobin, even at sublethal concentrations. We show that potent artemisinin activity is dependent on hemoglobin digestion by the parasite. Inhibition of hemoglobinase activity with cysteine protease inhibitors, knockout of the cysteine protease falcipain-2 by gene deletion, or direct deprivation of host cell lysate, significantly decreases artemisinin sensitivity. Hemoglobin digestion is also required for artemisinin-induced exacerbation of oxidative stress in the parasite cytoplasm. Arrest of hemoglobin digestion by early stage parasites provides a mechanism for surviving short-term artemisinin exposure. These insights will help in the design of new drugs and new treatment strategies to circumvent drug resistance.
From normal aging to dementia: Risk factors & clinical findings in relation to vascular changes on brain MRI

Background By middle age brain pathology leading to cognitive impairment has already started. One indicator of pathology is a decline of total blood flow to the brain (tCBF). Midand late-life cardiovascular factors may contribute to the reduction in tCBF. We assess the association of midand late-life cardiovascular factors measured 30 and 5 yrs prior to the measure of tCBF. Methods tCBF was measured with two-dimensional phase-contrast MR angiography in 822 men and women (58% women, mean age 79 yrs) who participated in the Reykjavik Study (mid-life) and its follow on, the AGES-Reykjavik Study I (late-life) and II (measure of tCBF). We used linear regression analysis to study the association of tCBF to cardiovascular characteristics measured in midand late-life, adjusting for age, sex MRI detected infarcts, and brain volume. Results Mean(SD) tCBF was 578(108 ) mL/min, increased with age and did not differ by sex. There were statistically significant (p<0.05) inverse associations of tCBF to both midand late-life measures of hemoglobin, hematocrit and diastolic blood pressure, and to late-life indicators of major ECG detected coronary abnormalitites. Interpretation Hemotologic, hemodynamic and cardiac characteristics affecting cardiac output and amount of blood flow to the brain measured at mid-life and at late-life, were associated with lower tCBF in late-life.
Cervical Cancer Screening Disparities in an Ethnically Diverse Population of Women Residing in the United States in 1999: A Secondary Analysis of Data from the 1999 Behavioral Risk Factor Surveillance System

Black American women have the highest screening rates for cervical cancer among all the ethnic groups in the United States. Even though evidence from the literature suggests that the number of deaths from cervical cancer in the United States could be reduced by preventive screening, this particular minority population still suffers disproportionately higher mortality from the disease than the other minority and majority populations in the United States. This study was proposed to investigate cancer screening disparities among different subpopulations of women residing in the United States during 1999, and to recommend public health interventions that could potentially increase cervical cancer screening rates, thereby decreasing differential mortality rates for cervical cancer among these subpopulations.The Preventive Health Model in conjunction with data from the 1999 Behavioral Risk Factor Surveillance System was used to identify the covariates of cervical cancer screening behavior in an ethnically diverse population of American women residing in the United States during the specified timeframe. Univariate, bivariate and multivariable logistic regression procedures were used to evaluate the association between each one of the independent variables and the dependent variable (compliance with the 1999 cervical screening guidelines of the American Cancer Society).
Hubungan Kadar D dimer Pasien Pneumonia Komunitas Terhadap Derajat Skor CURB-65 Pada Saat Awal Masuk Rumah Sakit

The assessment of level severity in patient with community acquired pneumonia (CAP) is very important to determine the next management of disease. D dimer (DD) is known as one of biomarker coagulation may be helpful in predicting the severity of CAP at the early admission in hospital. The application of DD is known to be used in diagnosis and to help clinician to make prognosis. To determine the correlation between D dimer and CURB-65 score in CAP patients at the early admission in hospital. This was an cross-sectional study. We had examined CAP subject with CURB-65(Confusion, Urea, Respiratory rate, Blood pressure, Age >65 years), DD, other laboratory assessment and sputum and blood culture at the early admission at emergency room (ER). We had correlate the DD levels with CURB-65 to determined prognostic utility of DD. Total of CAP subject was 57, there were 10 subjects (100%) with DD <500 μg/ L included in the mild-moderate CURB-65, 12 subjects (100%) with DD 500-999 μg/ L included in the mild-moderate CURB-65, 11 subjects (100%) with DD 500-999 μg/ L included in the mild-moderate CURB-65, and from 24 subjects with DDl > 2000 μg/ L consists of 2 subjects (8.3%) included in the mild-moderate CURB-65 and 22 subjects (91.7%) included severe CURB-65. D dimer is a biomarker of coagulation that has correlation with clinical scoring system CURB-65. D dimer can be use to determine the prognosis in CAP at early admission.
Preparation and Biofunctionalization of Multicolor Conjugated Polymer Nanoparticles for Imaging and Detection of Tumor Cells

Dr. L. Feng School of Chemistry and Chemical Engineering Shanxi University Taiyuan , 030006 , P. R. China Dr. L. Feng, Dr. L. Liu, Dr. F. Lv, Prof. S. Wang Beijing National Laboratory for Molecular Sciences Key Laboratory of Organic Solids Institute of Chemistry Chinese Academy of Sciences Beijing 100190 , P. R. China E-mail: wangshu@iccas.ac. cn Prof. G. C. Bazan Departments of Chemistry & Biochemistry and Materials, Center for Polymers and Organic Solids University of California Santa Barbara , CA 93106–9510 , USA E-mail: bazan@chem.ucsb. edu
Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance

A wealth of evidence supports the essential contributions of mast cells (MCs) to immune defense against bacteria and parasites; however, the role of MCs in viral infections has not been defined. We now report that rodent, monkey, and human MCs are able to detect dengue virus (DENV), a lymphotropic, enveloped, single-stranded, positive-sense RNA virus that results in MC activation and degranulation. We observe that the response of MCs to DENV also involves the activation of antiviral intracellular host response pathways, melanoma differentiation-associated gene 5 (MDA5) and retinoic acid inducible gene 1 (RIG-I), and the de novo transcription of cytokines, including TNF-α and IFN-α, and chemokines, such as CCL5, CXCL12, and CX3CL1. This multifaceted response of MCs to DENV is consequential to the containment of DENV in vivo because, after s.c. infection, MC-deficient mice show increased viral burden within draining lymph nodes, which are known to be targeted organs during DENV spread, compared with MC-sufficient mice. This containment of DENV is linked to the MC-driven recruitment of natural killer and natural killer T cells into the infected skin. These findings support expanding the defined role of immunosurveillance by MCs to include viral pathogens.
Different telomere-length dynamics at the inner cell mass versus established embryonic stem (ES) cells

Murine embryonic stem (ES) cells have unusually long telomeres, much longer than those in embryonic tissues. Here we address whether hyper-long telomeres are a natural property of pluripotent stem cells, such as those present at the blastocyst inner cell mass (ICM), or whether it is a characteristic acquired by the in vitro expansion of ES cells. We find that ICM cells undergo telomere elongation during the in vitro derivation of ES-cell lines. In vivo analysis shows that the hyper-long telomeres of morula-injected ES cells remain hyper-long at the blastocyst stage and longer than telomeres of the blastocyst ICM. Telomere lengthening during derivation of ES-cell lines is concomitant with a decrease in heterochromatic marks at telomeres. We also found increased levels of the telomere repeat binding factor 1 (TRF1) telomere-capping protein in cultured ICM cells before telomere elongation occurs, coinciding with expression of pluripotency markers. These results suggest that high TRF1 levels are present in pluripotent cells, most likely to ensure proficient capping of the newly synthesized telomeres. These results highlight a previously unnoticed difference between ICM cells at the blastocyst and ES cells, and suggest that abnormally long telomeres in ES cells are likely to result from continuous telomere lengthening of proliferating ICM cells locked at an epigenetic state associated to pluripotency.
Antigen-specific induced Foxp3+ regulatory T cells are generated following CD40/CD154 blockade

Blockade of the CD40/CD154 pathway potently attenuates T-cell responses in models of autoimmunity, inflammation, and transplantation. Indeed, CD40 pathway blockade remains one of the most powerful methods of prolonging graft survival in models of transplantation. But despite this effectiveness, the cellular and molecular mechanisms underlying the protective effects of CD40 pathway blockade are incompletely understood. Furthermore, the relative contributions of deletion, anergy, and regulation have not been measured in a model in which donor-reactive CD4+ and CD8+ T-cell responses can be assessed simultaneously. To investigate the impact of CD40/CD154 pathway blockade on graft-specific T-cell responses, a transgenic mouse model was used in which recipients containing ovalbumin-specific CD4+ and CD8+ TCR transgenic T cells were grafted with skin expressing ovalbumin in the presence or absence of anti-CD154 and donor-specific transfusion. The results indicated that CD154 blockade altered the kinetics of donor-reactive CD8+ T-cell expansion, delaying differentiation into IFN-γ+ TNF+ multifunctional cytokine producers. The eventual differentiation of cytokine-producing effectors in tolerant animals coincided with the emergence of an antigen-specific CD4+ CD25hi Foxp3+ T-cell population, which did not arise from endogenous natural Treg but rather were peripherally generated from naïve Foxp3− precursors.
Dual and opposing roles of the unfolded protein response regulated by IRE1α and XBP1 in proinsulin processing and insulin secretion

As a key regulator of the unfolded protein response, the transcription factor XBP1 activates genes in protein secretory pathways and is required for the development of certain secretory cells. To elucidate the function of XBP1 in pancreatic β-cells, we generated β-cell-specific XBP1 mutant mice. Xbp1f/f;RIP-cre mice displayed modest hyperglycemia and glucose intolerance resulting from decreased insulin secretion from β-cells. Ablation of XBP1 markedly decreased the number of insulin granules in β-cells, impaired proinsulin processing, increased the serum proinsulin:insulin ratio, blunted glucose-stimulated insulin secretion, and inhibited cell proliferation. Notably, XBP1 deficiency not only compromised the endoplasmic reticulum stress response in β-cells but also caused constitutive hyperactivation of its upstream activator, IRE1α, which could degrade a subset of mRNAs encoding proinsulin-processing enzymes. Hence, the combined effects of XBP1 deficiency on the canonical unfolded protein response and its negative feedback activation of IRE1α caused β-cell dysfunction in XBP1 mutant mice. These results demonstrate that IRE1α has dual and opposing roles in β-cells, and that a precisely regulated feedback circuit involving IRE1α and its product XBP1s is required to achieve optimal insulin secretion and glucose control.
Paleozoic origin of insect large dsDNA viruses

To understand how extant viruses interact with their hosts, we need a historical framework of their evolutionary association. Akin to retrovirus or hepadnavirus viral fossils present in eukaryotic genomes, bracoviruses are integrated in braconid wasp genomes and are transmitted by Mendelian inheritance. However, unlike viral genomic fossils, they have retained functional machineries homologous to those of large dsDNA viruses pathogenic to arthropods. Using a phylogenomic approach, we resolved the relationships between bracoviruses and their closest free relatives: baculoviruses and nudiviruses. The phylogeny showed that bracoviruses are nested within the nudivirus clade. Bracoviruses establish a bridge between the virus and animal worlds. Their inclusion in a virus phylogeny allowed us to relate free viruses to fossils. The ages of the wasps were used to calibrate the virus phylogeny. Bayesian analyses revealed that insect dsDNA viruses first evolved at ∼310 Mya in the Paleozoic Era during the Carboniferous Period with the first insects. Furthermore the virus diversification time frame during the Mesozoic Era appears linked to the diversification of insect orders; baculoviruses that infect larvae evolved at the same period as holometabolous insects. These results imply ancient coevolution by resource tracking between several insect dsDNA virus families and their hosts, dating back to 310 Mya.
Causal effect of education on mortality in a quasi-experiment on 1.2 million Swedes

In 1949–1962, Sweden implemented a 1-y increase in compulsory schooling as a quasi-experiment. Each year, children in a number of municipalities were exposed to the reform and others were kept as controls, allowing us to test the hypothesis that education is causally related to mortality. We studied all children born between 1943 and 1955, in 900 Swedish municipalities, with control for birth-cohort and area differences. Primary outcome measures are all-cause and cause-specific mortality until the end of 2007. The analyses include 1,247,867 individuals, of whom 92,351 died. We found lower all-cause mortality risk in the experimental group after age 40 [hazard ratio (HR) = 0.96, 95% confidence interval (CI) 0.93–0.99] but not before (HR = 1.03, 95% CI 0.98–1.07) or during the whole follow-up (HR = 0.98, 95% CI 0.95–1.01). After age 40, the experimental group had lower mortality from overall cancer, lung cancer, and accidents. In addition, exposed women had lower mortality from ischemic heart disease, and exposed men lower mortality from overall external causes. In analyses stratified for final educational level, we found lower mortality in the experimental group within the strata that settled for compulsory schooling only (HR = 0.94, 95% CI 0.89–0.99) and compulsory schooling plus vocational training (HR = 0.92, 95% CI 0.88–0.97). Thus, the experimental group had lower mortality from causes known to be related to education. Lower mortality in the experimental group was also found among the least educated, a group that clearly benefited from the reform in terms of educational length. However, all estimates are small and there was no evident impact of the reform on all-cause mortality in all ages.
The signature motif of the Saccharomyces cerevisiae Pif1 DNA helicase is essential in vivo for mitochondrial and nuclear functions and in vitro for ATPase activity

Abstract Pif1 family DNA helicases are conserved from bacteria to humans and have critical and diverse functions in vivo that promote genome integrity. Pif1 family helicases share a 23 amino acid region, called the Pif1 signature motif (SM) that is unique to this family. To determine the importance of the SM, we did mutational and functional analysis of the SM from the Saccharomyces cerevisiae Pif1 (ScPif1). The mutations deleted portions of the SM, made one or multiple single amino acid changes in the SM, replaced the SM with its counterpart from a bacterial Pif1 family helicase and substituted an α-helical domain from another helicase for the part of the SM that forms an α helix. Mutants were tested for maintenance of mitochondrial DNA, inhibition of telomerase at telomeres and double strand breaks, and promotion of Okazaki fragment maturation. Although certain single amino acid changes in the SM can be tolerated, the presence and sequence of the ScPif1 SM were essential for all tested in vivo functions. Consistent with the in vivo analyses, in vitro studies showed that the presence and sequence of the ScPif1 SM were critical for ATPase activity but not substrate binding.