Showing papers by "Tulane University published in 2019"
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TL;DR: It is determined that anti-spike IgG (S-IgG), in productively infected lungs, causes severe ALI by skewing inflammation-resolving response and providing a potential target for treatment of SARS-CoV or other virus-mediated lung injury.
Abstract: Newly emerging viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle Eastern respiratory syndrome CoVs (MERS-CoV), and H7N9, cause fatal acute lung injury (ALI) by driving hypercytokinemia and aggressive inflammation through mechanisms that remain elusive. In SARS-CoV/macaque models, we determined that anti-spike IgG (S-IgG), in productively infected lungs, causes severe ALI by skewing inflammation-resolving response. Alveolar macrophages underwent functional polarization in acutely infected macaques, demonstrating simultaneously both proinflammatory and wound-healing characteristics. The presence of S-IgG prior to viral clearance, however, abrogated wound-healing responses and promoted MCP1 and IL-8 production and proinflammatory monocyte/macrophage recruitment and accumulation. Critically, patients who eventually died of SARS (hereafter referred to as deceased patients) displayed similarly accumulated pulmonary proinflammatory, absence of wound-healing macrophages, and faster neutralizing antibody responses. Their sera enhanced SARS-CoV-induced MCP1 and IL-8 production by human monocyte-derived wound-healing macrophages, whereas blockade of FcγR reduced such effects. Our findings reveal a mechanism responsible for virus-mediated ALI, define a pathological consequence of viral specific antibody response, and provide a potential target for treatment of SARS-CoV or other virus-mediated lung injury.
751 citations
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Wake Forest University1, University of Mississippi Medical Center2, University of Pennsylvania3, University of Utah4, University of Alabama at Birmingham5, Veterans Health Administration6, National Institutes of Health7, University of Tennessee Health Science Center8, Stanford University9, Case Western Reserve University10, Tufts Medical Center11, Tulane University12
TL;DR: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of more than 140mm Hg did not result in a significant reduction in the risk of probable dementia.
Abstract: Importance There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. Objective To evaluate the effect of intensive blood pressure control on risk of dementia. Design, Setting, and Participants Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018. Interventions Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. Results Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97). Conclusions and Relevance Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point. Trial Registration ClinicalTrials.gov Identifier:NCT01206062
732 citations
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TL;DR: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community providing the theory and key practical aspects offlow cytometry enabling immunologists to avoid the common errors that often undermine immunological data.
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
698 citations
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Daniel Taliun1, Daniel N. Harris2, Michael D. Kessler2, Jedidiah Carlson3 +191 more•Institutions (61)
TL;DR: The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation as well as resources and early insights from the sequence data.
Abstract: Summary paragraph The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency
662 citations
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TL;DR: To open the clinical applications, it is necessary and important to develop the synthetic and long-lasting AMP analogs that overcome the disadvantages of their natural peptides and the potential problems for the drug candidates.
Abstract: Nowadays, the bacterial drug resistance leads to serious healthy problem worldwide due to the long-term use and the abuse of traditional antibiotics result in drug resistance of bacteria. Finding a new antibiotic is becoming more and more difficult. Antimicrobial peptides (AMPs) are the host defense peptides with most of them being the cationic (positively charged) and amphiphilic (hydrophilic and hydrophobic) α-helical peptide molecules. The membrane permeability is mostly recognized as the well-accepted mechanism to describe the action of cationic AMPs. These cationic AMPs can bind and interact with the negatively charged bacterial cell membranes, leading to the change of the electrochemical potential on bacterial cell membranes, inducing cell membrane damage and the permeation of larger molecules such as proteins, destroying cell morphology and membranes and eventually resulting in cell death. These AMPs have been demonstrated to have their own advantages over the traditional antibiotics with a broad-spectrum of antimicrobial activities including anti-bacteria, anti-fungi, anti-viruses, and anti-cancers, and even overcome bacterial drug-resistance. The natural AMPs exist in a variety of organisms and are not stable with a short half-life, more or less toxic side effects, and particularly may have severe hemolytic activity. To open the clinical applications, it is necessary and important to develop the synthetic and long-lasting AMP analogs that overcome the disadvantages of their natural peptides and the potential problems for the drug candidates.
538 citations
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TL;DR: Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide and can be targeted towards vulnerable populations if they are informed by variations in mortality rates.
Abstract: Objectives To use the estimates from the Global Burden of Disease Study 2016 to describe patterns of suicide mortality globally, regionally, and for 195 countries and territories by age, sex, and Socio-demographic index, and to describe temporal trends between 1990 and 2016. Design Systematic analysis. Main outcome measures Crude and age standardised rates from suicide mortality and years of life lost were compared across regions and countries, and by age, sex, and Socio-demographic index (a composite measure of fertility, income, and education). Results The total number of deaths from suicide increased by 6.7% (95% uncertainty interval 0.4% to 15.6%) globally over the 27 year study period to 817 000 (762 000 to 884 000) deaths in 2016. However, the age standardised mortality rate for suicide decreased by 32.7% (27.2% to 36.6%) worldwide between 1990 and 2016, similar to the decline in the global age standardised mortality rate of 30.6%. Suicide was the leading cause of age standardised years of life lost in the Global Burden of Disease region of high income Asia Pacific and was among the top 10 leading causes in eastern Europe, central Europe, western Europe, central Asia, Australasia, southern Latin America, and high income North America. Rates for men were higher than for women across regions, countries, and age groups, except for the 15 to 19 age group. There was variation in the female to male ratio, with higher ratios at lower levels of Socio-demographic index. Women experienced greater decreases in mortality rates (49.0%, 95% uncertainty interval 42.6% to 54.6%) than men (23.8%, 15.6% to 32.7%). Conclusions Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide. Suicide mortality was variable across locations, between sexes, and between age groups. Suicide prevention strategies can be targeted towards vulnerable populations if they are informed by variations in mortality rates.
472 citations
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Baylor College of Medicine1, Beth Israel Deaconess Medical Center2, Emory University3, Ochsner Medical Center4, Icahn School of Medicine at Mount Sinai5, Cedars-Sinai Medical Center6, University of Tennessee Health Science Center7, University of Texas Health Science Center at San Antonio8, Scripps Health9, Tulane University10, University of Alabama at Birmingham11, Oakland University12, University of Washington13, University of Miami14, Washington University in St. Louis15, University of California, Irvine16, Grady Memorial Hospital17
TL;DR: Looking AHEAD = Look Action for Health in Diabetes means taking action to control Cardiovascular Risk in Diabetes Blood pressure and looking at potential barriers to this action.
323 citations
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Mayo Clinic1, University of Poitiers2, Tulane University3, Imperial College Healthcare4, University Hospitals Birmingham NHS Foundation Trust5, Columbia University6, Monash University7, University College London8, LSU Health Sciences Center Shreveport9, National and Kapodistrian University of Athens10, Princess Margaret Cancer Centre11, University of Pavia12, University of Queensland13, Loyola University Medical Center14, Hôpital Maisonneuve-Rosemont15, University of Alabama at Birmingham16, University of Alberta17, University of Pennsylvania18
TL;DR: The IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy.
Abstract: The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.
299 citations
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Wageningen University and Research Centre1, University of Puerto Rico2, National Autonomous University of Mexico3, Colby College4, National Institute of Amazonian Research5, University of São Paulo6, Federal University of Pernambuco7, University of Alberta8, Paul Sabatier University9, International Institute of Minnesota10, University of Colorado Boulder11, University of Connecticut12, Smithsonian Tropical Research Institute13, Tulane University14, University of Stirling15, Clemson University16, Comisión Nacional para el Conocimiento y Uso de la Biodiversidad17, Universidade Federal de Minas Gerais18, Centro Agronómico Tropical de Investigación y Enseñanza19, Alexander von Humboldt Biological Resources Research Institute20, The Catholic University of America21, Colorado Mesa University22, State University of New York at Purchase23, University of Haifa24, University of Wisconsin-Madison25, Universidade Federal do Rio Grande do Sul26, Universidade Federal de Viçosa27, Costa Rica Institute of Technology28, University of Minnesota29, University of California, Santa Barbara30, Pedagogical and Technological University of Colombia31, Museu Paraense Emílio Goeldi32, University of California, Berkeley33, Columbia University34, New York Botanical Garden35, National University of Singapore36, Yale-NUS College37, Puerto Rico Department of Agriculture38, University of Amsterdam39, Louisiana State University40, University of Puerto Rico, Río Piedras41
TL;DR: This work assesses how tree species richness and composition recover during secondary succession across gradients in environmental conditions and anthropogenic disturbance in an unprecedented multisite analysis for the Neotropics.
Abstract: Old-growth tropical forests harbor an immense diversity of tree species but are rapidly being cleared, while secondary forests that regrow on abandoned agricultural lands increase in extent. We assess how tree species richness and composition recover during secondary succession across gradients in environmental conditions and anthropogenic disturbance in an unprecedented multisite analysis for the Neotropics. Secondary forests recover remarkably fast in species richness but slowly in species composition. Secondary forests take a median time of five decades to recover the species richness of old-growth forest (80% recovery after 20 years) based on rarefaction analysis. Full recovery of species composition takes centuries (only 34% recovery after 20 years). A dual strategy that maintains both old-growth forests and species-rich secondary forests is therefore crucial for biodiversity conservation in human-modified tropical landscapes.
273 citations
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University of Pennsylvania1, Wake Forest University2, University of Mississippi Medical Center3, University of Utah4, University of Alabama at Birmingham5, Veterans Health Administration6, National Institutes of Health7, University of Tennessee Health Science Center8, Stanford University9, Case Western Reserve University10, Genentech11, Tufts Medical Center12, Tulane University13
TL;DR: Among hypertensive adults, targeting an SBP of less than 120 mm HG, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small.
Abstract: Importance The effect of intensive blood pressure lowering on brain health remains uncertain. Objective To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes. Design, Setting, and Participants A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016. Interventions Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315). Main Outcomes and Measures The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome. Results Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3(difference, 0.92 cm3[95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3(difference, 1.45 cm3[95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, −0.54 cm3[95% CI, −0.87 to −0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3(difference, −30.6 cm3[95% CI, −32.3 to −28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3(difference, −26.9 cm3[95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, −3.7 cm3[95% CI, −6.3 to −1.1]). Conclusions and Relevance Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small. Trial Registration ClinicalTrials.gov Identifier:NCT01206062
267 citations
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TL;DR: It is demonstrated that the 2D/2D Ti3C2/g-C3N4 composites are promising photocatalysts thanks to the ultrathin MXenes as efficient co-catalysts for photoc atalytic hydrogen production.
Abstract: Photocatalytic hydrogen evolution from water has received enormous attention due to its ability to address a number of global environmental and energy-related issues. Here, we synthesize 2D/2D Ti3C2/g-C3N4 composites by electrostatic self-assembly technique and demonstrate their use as photocatalysts for hydrogen evolution under visible light irradiation. The optimized Ti3C2/g-C3N4 composite exhibited a 10 times higher photocatalytic hydrogen evolution performance (72.3 μmol h-1 gcat-1) than that of pristine g-C3N4 (7.1 μmol h-1 gcat-1). Such enhanced photocatalytic performance was due to the formation of 2D/2D heterojunctions in the Ti3C2/g-C3N4 composites. The intimate contact between the monolayer Ti3C2 and g-C3N4 nanosheets promotes the separation of photogenerated charge carriers at the Ti3C2/g-C3N4 interface. Furthermore, the ultrahigh conductivity of Ti3C2 and the Schottky junction formed between g-C3N4/MXene interfaces facilitate the photoinduced electron transfer and suppress the recombination with photogenerated holes. This work demonstrates that the 2D/2D Ti3C2/g-C3N4 composites are promising photocatalysts thanks to the ultrathin MXenes as efficient co-catalysts for photocatalytic hydrogen production.
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Capital Medical University1, Xi'an Jiaotong University2, Huazhong University of Science and Technology3, Fudan University4, China Medical University (PRC)5, Guangzhou Medical University6, Zhejiang University7, Sichuan University8, Peking University9, Peking Union Medical College10, China-Japan Friendship Hospital11, Clinical Trial Service Unit12, National Institutes of Health13, Tulane University14
TL;DR: The national prevalence of asthma in a representative sample of the Chinese population was 4·2% (95% CI 3·1-5·6), representing 45·7 million Chinese adults, and smoking, childhood pneumonia or bronchitis, parental history of respiratory disease, and low education attainment were associated with prevalent asthma.
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TL;DR: This review critically summarizes the recent advances made in the utility of fluorescent higher calixarenes for bioapplications, molecular sensors, in bioimaging, for drug and gene delivery, in self-assembly/aggregation, and as smart materials.
Abstract: Calix[n]arenes (n = 4, 5, 6, 8) are "chalicelike" phenol-based macrocycles that are among the most fascinating and highly studied scaffolds in supramolecular chemistry. This stems from the functional and tunable diversity at both their upper and lower rims, their preorganized nonpolar cavities and preorganized ion-binding sites, and their well-defined conformations. Conjugation of calixarene scaffolds with various fluorogenic groups has led to the development of smart fluorescent probes that have been utilized as molecular sensors, in bioimaging, for drug and gene delivery, in self-assembly/aggregation, and as smart materials. The fine-tuning and incorporation of different ligating sites in the calix[4]arene scaffold have produced numerous molecular sensors for cations, anions, and biomolecules. Moreover, the aqueous solubility of p-sulfonatocalix[4]arenes has engendered their potential use in drug/gene delivery and enzymatic assays. In addition, because of their strong optical properties, fluorescent calix[4]arenes have been used to develop smart materials, including gels as well as nonlinear optical, organic light-emitting diode, and multiphoton materials. Finally, significant developments in the utility of fluorescent higher calixarenes have been made for bioapplications. This review critically summarizes the recent advances made in all of these different areas.
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TL;DR: Current NCCN guidelines and Gleason scores cannot reliably stratify patients with prostate cancer for the presence or absence of pathogenic germline variants, which underscores the need to revisit current guidelines.
Abstract: Importance Prostate cancer is the third leading cause of cancer-related death in men in the United States. Although serious, most of these diagnoses are not terminal. Inherited risk for prostate cancer is associated with aggressive disease and poorer outcomes, indicating a critical need for increased genetic screening to identify disease-causing variants that can pinpoint individuals at increased risk for metastatic castration-resistant prostate cancer. Objective To identify positive (pathogenic, likely pathogenic, and increased risk) germline variants in a large prostate cancer cohort and to evaluate the usefulness of current practice guidelines in recognizing individuals at increased risk for prostate cancer who would benefit from diagnostic genetic testing. Design, Setting, and Participants Cross-sectional study of data from 3607 men with a personal history of prostate cancer who underwent germline genetic testing between 2013 and 2018 and were unselected for family history, stage of disease, or age at diagnosis. Referral-based testing was performed at a Clinical Laboratory Improvement Amendments/College of American Pathologists–certified diagnostic laboratory. All analysis took place between February 2017 and August 2018. Main Outcomes and Measures The frequency and distribution of positive germline variants, and the percentage of individuals with prostate cancer who met National Comprehensive Cancer Network (NCCN) guidelines for germline genetic testing. Results Of 3607 men (mean [SD] age at testing, 67 [9.51] years; mean age at diagnosis, 60 [9.05] years) with a personal diagnosis of prostate cancer who were referred for genetic testing, 620 (17.2%) had positive germline variants, of which only 30.7% were variants inBRCA1/2. Positive variants inHOXB13, a gene associated only with prostate cancer risk, were identified in 30 patients (4.5%). DNA mismatch repair variants with substantial known therapeutic implications were detected in 1.74% of variants in the total population tested. Examination of self-reported family histories indicated that 229 individuals (37%) with positive variants in this cohort would not have been approved for genetic testing using the NCCN genetic/familial breast and ovarian guidelines for patients with prostate cancer. Conclusions and Relevance Current NCCN guidelines and Gleason scores cannot reliably stratify patients with prostate cancer for the presence or absence of pathogenic germline variants. Most positive genetic test results identified in this study have important management implications for patients and their families, which underscores the need to revisit current guidelines.
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19 Aug 2019
TL;DR: In this article, a spin fluctuation-driven spin scattering and a metastable canted antiferromagnetic phase in MnBi{}_{2}$Te${}_{4}$
Abstract: This paper shows a spin fluctuation-driven spin scattering and a metastable canted antiferromagnetic phase in MnBi${}_{2}$Te${}_{4}$. These are signatures of an intrinsic anomalous Quantum Hall effect and open up new avenues to realize a quantum anomalous Hall insulator at high temperatures
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TL;DR: Disease-linked DNA hypermethylation can help drive oncogenesis partly by its effects on cancer stem cells and by the CpG island methylator phenotype (CIMP); atherosclerosis by disease-related cell transdifferentiation; autoimmune and neurological diseases through abnormal perturbations of cell memory; and diverse age-related accumulation of epigenetic alterations.
Abstract: Increasing numbers of studies implicate abnormal DNA methylation in cancer and many non-malignant diseases. This is consistent with numerous findings about differentiation-associated changes in DNA methylation at promoters, enhancers, gene bodies, and sites that control higher-order chromatin structure. Abnormal increases or decreases in DNA methylation contribute to or are markers for cancer formation and tumour progression. Aberrant DNA methylation is also associated with neurological diseases, immunological diseases, atherosclerosis, and osteoporosis. In this review, I discuss DNA hypermethylation in disease and its interrelationships with normal development as well as proposed mechanisms for the origin of and pathogenic consequences of disease-associated hypermethylation. Disease-linked DNA hypermethylation can help drive oncogenesis partly by its effects on cancer stem cells and by the CpG island methylator phenotype (CIMP); atherosclerosis by disease-related cell transdifferentiation; autoimmune and neurological diseases through abnormal perturbations of cell memory; and diverse age-associated diseases by age-related accumulation of epigenetic alterations.
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TL;DR: In this article, the authors review and assess what we have learned about what motivates individuals to pay or not pay their legally due tax liabilities, focusing on three specific questions: what does theory say about what motivate tax compliance? Second, what does the evidence show? Third, how can government use these insights to improve compliance?
Abstract: In this paper, I review and assess what we have learned about what motivates individuals to pay – or to not pay – their legally due tax liabilities. I focus on three specific questions. First, what does theory say about what motivates tax compliance? Second, what does the evidence show? Third, how can government use these insights to improve compliance? I conclude with some suggestions – and some predictions – for future research.
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University of North Carolina at Chapel Hill1, Harvard University2, University of Washington3, University of Illinois at Chicago4, University of Kentucky5, University of Colorado Denver6, Johns Hopkins University7, Fred Hutchinson Cancer Research Center8, University of Texas at Austin9, University of Texas Health Science Center at Houston10, Wake Forest University11, Rutgers University12, Brigham and Women's Hospital13, Broad Institute14, Kaiser Permanente15, Boston University16, University of Vermont17, University of Michigan18, Tulane University19, University of Alabama at Birmingham20, Albert Einstein College of Medicine21, Icahn School of Medicine at Mount Sinai22, Oklahoma Medical Research Foundation23, University of Minnesota24, University of Virginia25, Los Angeles Biomedical Research Institute26, United States Department of Veterans Affairs27, University of Mississippi Medical Center28, University of Wisconsin–Milwaukee29
TL;DR: It is demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data, which subsequently enhanced gene-mapping power for complex traits.
Abstract: Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.
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TL;DR: It is reported that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid–binding protein 4 (FABP4).
Abstract: The short-chain fatty acid propionate is a potent inhibitor of molds that is widely used as a food preservative and endogenously produced by gut microbiota. Although generally recognized as safe by the U.S. Food and Drug Administration, the metabolic effects of propionate consumption in humans are unclear. Here, we report that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid-binding protein 4 (FABP4). Fabp4-deficient mice and mice lacking liver glucagon receptor were protected from the effects of propionate. Although propionate did not directly promote glucagon or FABP4 secretion in ex vivo rodent pancreatic islets and adipose tissue models, respectively, it activated the sympathetic nervous system in mice, leading to secretion of these hormones in vivo. This effect could be blocked by the pharmacological inhibition of norepinephrine, which prevented propionate-induced hyperglycemia in mice. In a randomized, double-blind, placebo-controlled study in humans, consumption of a propionate-containing mixed meal resulted in a postprandial increase in plasma glucagon, FABP4, and norepinephrine, leading to insulin resistance and compensatory hyperinsulinemia. Chronic exposure of mice to a propionate dose equivalent to that used for food preservation resulted in gradual weight gain. In humans, plasma propionate decreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionate may activate a catecholamine-mediated increase in insulin counter-regulatory signals, leading to insulin resistance and hyperinsulinemia, which, over time, may promote adiposity and metabolic abnormalities. Further evaluation of the metabolic consequences of propionate consumption is warranted.
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TL;DR: It is discussed how it may be more useful to think of membrane permeabilizing peptides mechanisms as broad regions of a mechanistic landscape rather than discrete molecular processes.
Abstract: Membrane permeabilizing peptides (MPPs) are as ubiquitous as the lipid bilayer membranes they act upon. Produced by all forms of life, most membrane permeabilizing peptides are used offensively or defensively against the membranes of other organisms. Just as nature has found many uses for them, translational scientists have worked for decades to design or optimize membrane permeabilizing peptides for applications in the laboratory and in the clinic ranging from antibacterial and antiviral therapy and prophylaxis to anticancer therapeutics and drug delivery. Here, we review the field of membrane permeabilizing peptides. We discuss the diversity of their sources and structures, the systems and methods used to measure their activities, and the behaviors that are observed. We discuss the fact that “mechanism” is not a discrete or a static entity for an MPP but rather the result of a heterogeneous and dynamic ensemble of structural states that vary in response to many different experimental conditions. This ha...
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10 May 2019
TL;DR: In this article, the authors proposed to use Titanium dioxide (TiO2) as a promising candidate for hydrogen production via photocatalysis, but its large bandgap and fast charge recombination limits its efficiency.
Abstract: Titanium dioxide (TiO2) represents a promising candidate for hydrogen production via photocatalysis. However, its large bandgap and fast charge recombination limits its efficiency. To overcome this...
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University of California, Los Angeles1, University of Edinburgh2, King's College London3, Chang Gung University4, Memorial Hospital of South Bend5, Peking University6, Tulane University7, Fred Hutchinson Cancer Research Center8, National Institutes of Health9, Northwestern University10, Columbia University11, University of North Carolina at Chapel Hill12, VA Palo Alto Healthcare System13, Stanford University14, Children's Hospitals and Clinics of Minnesota15, University of Mississippi Medical Center16, Rutgers University17, Public Health England18
TL;DR: Leukocyte DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it and is more strongly associated with age than measured leukocyte TL (LTL).
Abstract: Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.
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TL;DR: Some recent progresses in better understanding of the role of Mutant p53 GOF in chemoresistance and the underlying mechanisms are reviewed, and the pros and cons of targeting mutant p53 for the development of anti-cancer therapies are discussed.
Abstract: Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers. Approximately 80% of p53 mutations are single point mutations with several hotspot mutations. Besides loss of function and dominant-negative effect on the wild-type p53 activity, the hotspot p53 mutants also acquire new oncogenic functions, so-called 'gain-of-functions' (GOF). Because the GOF of mutant p53 is highly associated with late-stage malignance and drug resistance, these p53 mutants have become hot targets for developing novel cancer therapies. In this essay, we review some recent progresses in better understanding of the role of mutant p53 GOF in chemoresistance and the underlying mechanisms, and discuss the pros and cons of targeting mutant p53 for the development of anti-cancer therapies.
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TL;DR: Women in this CKD cohort had lower risk of CKD progression and death compared with men, and in multivariable regression models, women had significantly lowerrisk of ESRD, 50% eGFR decline, progression to CKD stage 5, and death.
Abstract: Background In the United States, incidence of ESRD is 1.5 times higher in men than in women, despite men’s lower prevalence of CKD. Prior studies, limited by inclusion of small percentages of minorities and other factors, suggested that men have more rapid CKD progression, but this finding has been inconsistent. Methods In our prospective investigation of sex differences in CKD progression, we used data from 3939 adults (1778 women and 2161 men) enrolled in the Chronic Renal Insufficiency Cohort Study, a large, diverse CKD cohort. We evaluated associations between sex (women versus men) and outcomes, specifically incident ESRD (defined as undergoing dialysis or a kidney transplant), 50% eGFR decline from baseline, incident CKD stage 5 (eGFR 2 ), eGFR slope, and all-cause death. Results Participants’ mean age was 58 years at study entry; 42% were non-Hispanic black, and 13% were Hispanic. During median follow-up of 6.9 years, 844 individuals developed ESRD, and 853 died. In multivariable regression models, compared with men, women had significantly lower risk of ESRD, 50% eGFR decline, progression to CKD stage 5, and death. The mean unadjusted eGFR slope was −1.09 ml/min per 1.73 m 2 per year in women and −1.43 ml/min per 1.73 m 2 per year in men, but this difference was not significant after multivariable adjustment. Conclusions In this CKD cohort, women had lower risk of CKD progression and death compared with men. Additional investigation is needed to identify biologic and psychosocial factors underlying these sex-related differences.
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TL;DR: This work proposes a decentralized variant of Monte Carlo tree search (MCTS) that is suitable for a variety of tasks in multi-robot active perception and extends the theoretical analysis of standard MCTS to provide guarantees for convergence rates to the optimal payoff sequence.
Abstract: We propose a decentralized variant of Monte Carlo tree search (MCTS) that is suitable for a variety of tasks in multi-robot active perception. Our algorithm allows each robot to optimize its own ac...
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TL;DR: This work develops and applies a novel sub-epidemic modeling framework that supports a diversity of epidemic trajectories including stable incidence patterns with sustained or damped oscillations to better understand and forecast epidemic outbreaks.
Abstract: Simple phenomenological growth models can be useful for estimating transmission parameters and forecasting epidemic trajectories. However, most existing phenomenological growth models only support single-peak outbreak dynamics whereas real epidemics often display more complex transmission trajectories. We develop and apply a novel sub-epidemic modeling framework that supports a diversity of epidemic trajectories including stable incidence patterns with sustained or damped oscillations to better understand and forecast epidemic outbreaks. We describe how to forecast an epidemic based on the premise that the observed coarse-scale incidence can be decomposed into overlapping sub-epidemics at finer scales. We evaluate our modeling framework using three outbreak datasets: Severe Acute Respiratory Syndrome (SARS) in Singapore, plague in Madagascar, and the ongoing Ebola outbreak in the Democratic Republic of Congo (DRC) and four performance metrics. The sub-epidemic wave model outperforms simpler growth models in short-term forecasts based on performance metrics that account for the uncertainty of the predictions namely the mean interval score (MIS) and the coverage of the 95% prediction interval. For example, we demonstrate how the sub-epidemic wave model successfully captures the 2-peak pattern of the SARS outbreak in Singapore. Moreover, in short-term sequential forecasts, the sub-epidemic model was able to forecast the second surge in case incidence for this outbreak, which was not possible using the simple growth models. Furthermore, our findings support the view that the national incidence curve of the Ebola epidemic in DRC follows a stable incidence pattern with periodic behavior that can be decomposed into overlapping sub-epidemics. Our findings highlight how overlapping sub-epidemics can capture complex epidemic dynamics, including oscillatory behavior in the trajectory of the epidemic wave. This observation has significant implications for interpreting apparent noise in incidence data where the oscillations could be dismissed as a result of overdispersion, rather than an intrinsic part of the epidemic dynamics. Unless the oscillations are appropriately modeled, they could also give a false positive, or negative, impression of the impact from public health interventions. These preliminary results using sub-epidemic models can help guide future efforts to better understand the heterogenous spatial and social factors shaping sub-epidemic patterns for other infectious diseases.
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TL;DR: This paper evaluates the performance of several state-of-the-art convolutional neural networks in dermoscopic images of skin lesions in order to enhance the quality of images and apply data augmentation methodology to address the class skewness problem.
Abstract: Melanoma is the most aggressive type of skin cancer, which significantly reduces the life expectancy. Early detection of melanoma can reduce the morbidity and mortality associated with skin cancer. Dermoscopic images acquired by dermoscopic instruments are used in computational analysis for skin cancer detection. However, some image quality limitations such as noises, shadows, artefacts exist that could compromise the robustness of the skin image analysis. Hence, developing an automatic intelligent system for skin cancer diagnosis with accurate detection rate is crucial. In this paper, we evaluate the performance of several state-of-the-art convolutional neural networks in dermoscopic images of skin lesions. Our experiment is conducted on a graphics processing unit (GPU) to speed up the training and deployment process. To enhance the quality of images, we employ different pre-processing steps. We also apply data augmentation methodology such as horizontal and vertical flipping techniques to address the class skewness problem. Both pre-processing and data augmentation could help to improve the final accuracy.
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Vita-Salute San Raffaele University1, University of Florence2, University of Bedfordshire3, Harvard University4, University of Turku5, Imperial College London6, National Scientific and Technical Research Council7, Tulane University8, University of Toronto9, Erasmus University Rotterdam10, Baylor College of Medicine11, Boston Children's Hospital12
TL;DR: This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypog onadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development.
Abstract: The hypothalamic–pituitary–gonadal axis is of relevance in many processes related to the development, maturation and ageing of the male. Through this axis, a cascade of coordinated activities is carried out leading to sustained testicular endocrine function, with gonadal testosterone production, as well as exocrine function, with spermatogenesis. Conditions impairing the hypothalamic–pituitary–gonadal axis during paediatric or pubertal life may result in delayed puberty. Late-onset hypogonadism is a clinical condition in the ageing male combining low concentrations of circulating testosterone and specific symptoms associated with impaired hormone production. Testosterone therapy for congenital forms of hypogonadism must be lifelong, whereas testosterone treatment of late-onset hypogonadism remains a matter of debate because of unclear indications for replacement, uncertain efficacy and potential risks. This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypogonadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development. Male hypogonadism is a disorder associated with low testosterone levels and impaired spermatogenesis. The condition can arise from inherent defects in the testes or abnormalities in the regulation of testosterone secretion at the hypothalamic or pituitary level. This Primer summarizes the conditions that can lead to hypogonadism in boys and men.
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TL;DR: Despite the value of DBS, future developments should be aimed at developing less invasive techniques and attaining not just symptom improvement but curative disease modification.
Abstract: Deep brain stimulation (DBS) has evolved considerably over the past 4 decades. Although it has primarily been used to treat movement disorders such as Parkinson's disease, essential tremor, and dystonia, recently it has been approved to treat obsessive-compulsive disorder and epilepsy. Novel potential indications in both neurological and psychiatric disorders are undergoing active study. There have been significant advances in DBS technology, including preoperative and intraoperative imaging, surgical approaches and techniques, and device improvements. In addition to providing significant clinical benefits and improving quality of life, DBS has also increased the understanding of human electrophysiology and network interactions. Despite the value of DBS, future developments should be aimed at developing less invasive techniques and attaining not just symptom improvement but curative disease modification.
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Paris Descartes University1, Ghent University Hospital2, University of Florence3, Rambam Health Care Campus4, University of Bari5, I.M. Sechenov First Moscow State Medical University6, Seconda Università degli Studi di Napoli7, Katholieke Universiteit Leuven8, university of lille9, Dresden University of Technology10, Russian Academy11, Hospital General Universitario Gregorio Marañón12, University of Erlangen-Nuremberg13, University of Cologne14, Sapienza University of Rome15, Rutgers University16, Carol Davila University of Medicine and Pharmacy17, Nippon Medical School18, Tulane University19, Lund University20, University of Verona21
TL;DR: Rituximab use was associated with a good safety profile in this large SSc-cohort and significant change was observed on skin fibrosis, but not on lung, but the limitation is the observational design.
Abstract: Objective To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. Methods We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. Results 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p Conclusion Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.