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1.
Pediatr Res ; 87(2): 221-226, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31382269

RESUMO

Differences in preterm birth rates between black and white women are the largest contributor to racial disparities in infant mortality. In today's age of precision medicine, analysis of the genome, epigenome, metabolome, and microbiome has generated interest in determining whether these biomarkers can help explain racial disparities. We propose that there are pitfalls as well as opportunities when using precision medicine analyses to interrogate disparities in health. To conclude that racial disparities in complex conditions are genetic in origin ignores robust evidence that social and environmental factors that track with race are major contributors to disparities. Biomarkers measured in omic assays that may be more environmentally responsive than genomics, such as the epigenome or metabolome, may be on the causal pathway of race and preterm birth, but omic observational studies suffer from the same limitations as traditional cohort studies. Confounding can lead to false conclusions about the causal relationship between omics and preterm birth. Methodological strategies (including stratification and causal mediation analyses) may help to ensure that associations between biomarkers and exposures, as well as between biomarkers and outcomes, are valid signals. These epidemiologic strategies present opportunities to assess whether precision medicine biomarkers can uncover biology underlying perinatal health disparities.

2.
Food Microbiol ; 85: 103307, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31500711

RESUMO

Cold atmospheric-gaseous plasma (CAP) is an emerging non-thermal technology for decontamination of foodborne bacterial and viral pathogens. We obtained a >5 log10 reduction in the titer (TCID50) of feline calicivirus (FCV) on stainless steel discs and Romaine lettuce leaves after 3 min wet exposure to air plasma generated by a two-dimensional array of integrated coaxial-microhollow dielectric barrier discharge (2D-AICM-DBD). However, when human norovirus (HuNoV GII.4) was treated for 5 min under the same conditions, ~2.6 log10 (>99.5%) reduction in genome copy number was observed as measured by ethidium monoazide-coupled RT-qPCR (EMA-RT-qPCR). To assess this discrepancy, we studied CAP's effect on FCV by the cell culture method and by the EMA-coupled RT-qPCR method. It was found that the molecular titration method (EMA-RT-qPCR) underestimates the level of virus reduction by CAP. Additionally, the fecal matter present in HuNoV samples partially suppressed virucidal activity of CAP. Assuming that the lower virus reduction measured by EMA-RT-qPCR method compared to cell culture method for FCV is the same as for HuNoV, we can conclude that FCV may be used as a surrogate for HuNoV to assess the virucidal effect of CAP. CAP is able to inactivate 3.5 Log10 units of HuNoV at low titers after 2 min of exposure.


Assuntos
Fezes/virologia , Norovirus/efeitos dos fármacos , Gases em Plasma/farmacologia , Inativação de Vírus/efeitos dos fármacos , Azidas , Calicivirus Felino/efeitos dos fármacos , Calicivirus Felino/genética , Desinfecção/métodos , Humanos , Alface/virologia , Norovirus/genética , Reação em Cadeia da Polimerase em Tempo Real , Aço Inoxidável
4.
Nat Chem Biol ; 15(12): 1173-1182, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31686032

RESUMO

Efforts to construct synthetic biological circuits with more complex functions have often been hindered by the idiosyncratic behavior, limited dynamic range and crosstalk of commonly utilized parts. Here, we employ de novo RNA design to develop two high-performance translational repressors with sensing and logic capabilities. These synthetic riboregulators, termed toehold repressors and three-way junction (3WJ) repressors, detect transcripts with nearly arbitrary sequences, repress gene expression by up to 300-fold and yield orthogonal sets of up to 15 devices. Automated forward engineering is used to improve toehold repressor dynamic range and SHAPE-Seq is applied to confirm the designed switching mechanism of 3WJ repressors in living cells. We integrate the modular repressors into biological circuits that execute universal NAND and NOR logic and evaluate the four-input expression NOT ((A1 AND A2) OR (B1 AND B2)) in Escherichia coli. These capabilities make toehold and 3WJ repressors valuable new tools for biotechnological applications.

5.
Angew Chem Int Ed Engl ; 58(52): 19000-19006, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31701606

RESUMO

This report details the development of a masked N-centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1-aminonorbornanes. This process employs the N-centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C-C bonds en route to the norbornane core. Achieving bond-forming reactivity as a function of the N-centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance. This methodology operates in continuous flow, enhancing the potential to translate beyond the academic sector. The operational simplicity of this photochemical process and the structural novelty of the (hetero)aryl-fused 1-aminonorbornane products are anticipated to provide a valuable addition to discovery efforts in pharmaceutical and agrochemical industries.

6.
Foodborne Pathog Dis ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31613646

RESUMO

We studied the efficacy of cold atmospheric-pressure plasma (CAP), generated by a two-dimensional array of integrated, coaxial, microhollow, dielectric barrier discharge plasma, against Salmonella enterica serovar Heidelberg (SH) on stainless steel, romaine lettuce, and chicken breast. Exposure of SH to CAP on a dry stainless steel surface had low bactericidal efficacy; only 2.5 log10 colony-forming units (CFUs) were inactivated after 10 min of exposure. On the other hand, the presence of moisture led to decontamination of ∼6.5 log10 CFUs after only 3 min. Although complete decontamination was not achieved on lettuce and chicken breast samples after 10 min of exposure, SH counts were reduced by ∼4.5 and 3.7 log10 CFUs, respectively. A partial suppression of bactericidal effects was observed on steel surfaces when it was coated with bovine serum albumin before spiking with bacteria and exposure to plasma, indicating that the proteinaceous nature of chicken meat may be partially responsible for lower efficacy of CAP on chicken muscles. The initial bacterial load was also found to affect the anti-SH efficacy; at high (∼6.5 log CFUs) and low (∼3.5 CFUs) initial counts, the time required for complete decontamination on stainless steel and lettuce decreased from 3 to 0.5 min and >10 to 1 min, respectively. However, the analysis of inactivation kinetics showed that effects of initial loads of contamination on the rate of bacterial inactivation were not statistically significant. This is consistent with other findings for conditions where both bacterial loads were under the multilayering threshold that might have affected the rate of killing.

7.
Front Genet ; 10: 826, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616465

RESUMO

Whole-genome sequencing is being rapidly applied to the study of helminth genomes, including de novo genome assembly, population genetics, and diagnostic applications. Although late-stage juvenile and adult parasites typically produce sufficient DNA for molecular analyses, these parasitic stages are almost always inaccessible in the live host; immature life stages found in the environment for which samples can be collected non-invasively offer a potential alternative; however, these samples typically yield very low quantities of DNA, can be environmentally resistant, and are susceptible to contamination, often from bacterial or host DNA. Here, we have tested five low-input DNA extraction protocols together with a low-input sequencing library protocol to assess the feasibility of whole-genome sequencing of individual immature helminth samples. These approaches do not use whole-genome amplification, a common but costly approach to increase the yield of low-input samples. We first tested individual parasites from two species spotted onto FTA cards-egg and L1 stages of Haemonchus contortus and miracidia of Schistosoma mansoni-before further testing on an additional five species-Ancylostoma caninum, Ascaridia dissimilis, Dirofilaria immitis, Strongyloides stercoralis, and Trichuris muris-with an optimal protocol. A sixth species-Dracunculus medinensis-was included for comparison. Whole-genome sequencing followed by analyses to determine the proportion of on- and off-target mapping revealed successful sample preparations for six of the eight species tested with variation both between species and between different life stages from some species described. These results demonstrate the feasibility of whole-genome sequencing of individual parasites, and highlight a new avenue toward generating sensitive, specific, and information-rich data for the diagnosis and surveillance of helminths.

8.
Matern Child Health J ; 23(12): 1621-1626, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31620951

RESUMO

OBJECTIVE: To ascertain the relation of men's lifelong class status (as measured by neighborhood income) to the rates of early (< 34 weeks) and late (34-36 weeks) preterm birth (PTB). METHODS: Stratified and multilevel, multivariable binomial regression analyses were computed on the Illinois transgenerational birth-file of infants (born 1989-1991) and their parents (born 1956-1976) with appended U.S. census income information. The median family income of men's census tract residence at two-time periods were utilized to assess lifelong class status (defined by residence in either the lower or upper half of neighborhood income distribution). RESULTS: In Cook County Illinois, the preterm rate for births (n = 8115) to men with a lifelong lower class status was twice that of births (n = 10,330) to men with a lifelong upper class status: 13% versus 6.0%, RR = 2.2 (2.0, 2.4). This differential was greatest in early PTB rates: 3.9% versus 1.4%, RR = 3.0 (2.5, 3.7). The relation of men's lifelong class status to both PTB components persisted among non-teens, married, college-educated, and non-Latina White women, respectively. The adjusted (controlling for maternal demographic characteristics) RR of early and late PTB for men with a lifelong lower (versus upper) class status were 1.4 (1.1, 1.9) and 1.2 (1.0, 1.4), respectively. The population attributable risk of early PTB for men's lifelong lower class status equaled 16%. CONCLUSIONS: Men's lifelong lower (versus upper) class status is a novel risk factor for early preterm birth regardless of maternal demographic characteristics. This intriguing finding has public health relevance.


Assuntos
Pai/psicologia , Nascimento Prematuro/epidemiologia , Características de Residência , Classe Social , Adulto , Escolaridade , Feminino , Humanos , Illinois/epidemiologia , Renda , Recém-Nascido , Masculino , Idade Materna , Gravidez , População Urbana
9.
PLoS Biol ; 17(10): e3000485, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31622335

RESUMO

Schistosomes are parasitic flatworms that infect over 200 million people, causing the neglected tropical disease, schistosomiasis. A single drug, praziquantel, is used to treat schistosome infection. Limitations in mass drug administration programs and the emergence of schistosomiasis in nontropical areas indicate the need for new strategies to prevent infection. It has been known for several decades that rotifers colonizing the schistosome's snail intermediate host produce a water-soluble factor that paralyzes cercariae, the life cycle stage infecting humans. In spite of its potential for preventing infection, the nature of this factor has remained obscure. Here, we report the purification and chemical characterization of Schistosome Paralysis Factor (SPF), a novel tetracyclic alkaloid produced by the rotifer Rotaria rotatoria. We show that this compound paralyzes schistosome cercariae and prevents infection and does so more effectively than analogous compounds. This molecule provides new directions for understanding cercariae motility and new strategies for preventing schistosome infection.

10.
Neurology ; 93(21): e1932-e1943, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31653707

RESUMO

OBJECTIVE: To identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs). METHODS: Over the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts. RESULTS: Total MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year (p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% (p < 0.05) and 2.55% (p < 0.01). Range-of-motion measurements decreased by 3.21° (p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° (p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% (p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed. CONCLUSION: Results of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs.

11.
J Nutr ; 149(12): 2085-2100, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504675

RESUMO

Research on the interplay between iron and copper metabolism in humans began to flourish in the mid-20th century, and diseases associated with dysregulated homeostasis of these essential trace minerals are common even today. Iron deficiency is the most frequent cause of anemia worldwide, leading to significant morbidity, particularly in developing countries. Iron overload is also quite common, usually being the result of genetic mutations which lead to inappropriate expression of the iron-regulatory hormone hepcidin. Perturbations of copper homeostasis in humans have also been described, including rare genetic conditions which lead to severe copper deficiency (Menkes disease) or copper overload (Wilson disease). Historically, the common laboratory rat (Rattus norvegicus) was the most frequently utilized species to model human physiology and pathophysiology. Recently, however, the development of genetic-engineering technology combined with the worldwide availability of numerous genetically homogenous (i.e., inbred) mouse strains shifted most research on iron and copper metabolism to laboratory mice. This created new opportunities to understand the function of individual genes in the context of a living animal, but thoughtful consideration of whether mice are the most appropriate models of human pathophysiology was not necessarily involved. Given this background, this review is intended to provide a guide for future research on iron- and copper-related disorders in humans. Generation of complementary experimental models in rats, swine, and other mammals is now facile given the advent of newer genetic technologies, thus providing the opportunity to accelerate the identification of pathogenic mechanisms and expedite the development of new treatments to mitigate these important human disorders.

12.
Placenta ; 83: 37-42, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31477205

RESUMO

INTRODUCTION: African American women are at higher risk for preterm birth compared to white women, but no placental pathology has characterized this disparity. The objective of this study was to examine the association of race with placental pathology among very preterm births. METHODS: We conducted an eight-year retrospective cohort study of very preterm infants born at ≤32 weeks at Northwestern Prentice Women's Hospital in Chicago, Illinois. Archived placental slides underwent standardized masked histopathologic review. Logistic regression was performed for placental pathology, adjusting for available relevant covariates and stratified by infant sex and gestational age. RESULTS: Placentas were available for 296 white and 224 African American mother-infant pairs among births at ≤32 weeks gestation. Compared to placentas from white births, the adjusted OR (aOR) for acute inflammation in placentas from African American births was 1.95 (95% CI 0.87-4.37), the aOR for chronic inflammation was 3.35 (1.49-7.54), the aOR for fetal vascular pathology was 0.82 (0.29-2.32), and the aOR for maternal vascular pathology was 1.01 (0.51-1.99). Stratified analysis showed associations between all placental pathologies and race among male births. Across gestational age groups (<28 and ≥ 28 weeks), the association between race and placental pathology was present for chronic inflammation and fetal vascular pathology. DISCUSSION: Race is associated with placental pathology, and in particular, with chronic inflammation among very preterm births. The effect is modified by infant sex and gestational age. Placental histopathology may be useful markers for understanding the biological processes that shape disparities in pregnancy outcomes.

13.
Sci Data ; 6(1): 165, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477737

RESUMO

Rapid changes in ocean circulation and climate have been observed in marine-sediment and ice cores over the last glacial period and deglaciation, highlighting the non-linear character of the climate system and underlining the possibility of rapid climate shifts in response to anthropogenic greenhouse gas forcing. To date, these rapid changes in climate and ocean circulation are still not fully explained. One obstacle hindering progress in our understanding of the interactions between past ocean circulation and climate changes is the difficulty of accurately dating marine cores. Here, we present a set of 92 marine sediment cores from the Atlantic Ocean for which we have established age-depth models that are consistent with the Greenland GICC05 ice core chronology, and computed the associated dating uncertainties, using a new deposition modeling technique. This is the first set of consistently dated marine sediment cores enabling paleoclimate scientists to evaluate leads/lags between circulation and climate changes over vast regions of the Atlantic Ocean. Moreover, this data set is of direct use in paleoclimate modeling studies.

14.
Science ; 365(6457): 986-987, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31488676
15.
Health Place ; 59: 102193, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31450078

RESUMO

OBJECTIVE: To examine whether mortgage discrimination, or redlining, is a risk factor for preterm birth among African American women in Chicago, and how it is related to racial residential segregation. METHODS: This was a retrospective cross-sectional study in Chicago, Illinois, 1989-1991. African American mothers (n = 33,586) in the Illinois Transgenerational Birth File were linked to the 1990 census and the 1990-1995 Home Mortgage Disclosure Act database. Logistic regression models assessed the relationship between redlining and preterm birth rates. RESULTS: Preterm birth rates were higher among African American women in redlined areas (18.5%) vs. non-redlined areas (17.1%). Unadjusted and adjusted odds ratio for preterm birth among African American women in redlined neighborhoods, compared to non-redlined neighborhoods, were 1.08 (95% CI 1.03-1.14) and 1.12 (1.04-1.20), respectively. By level of racial residential segregation, preterm birth rate was elevated (18.2%) in redlined, high-proportion African American areas compared to non-redlined high-proportion African American areas (16.7%), redlined low- (16.2%) and mid-proportion (16.1%) African American areas. CONCLUSIONS: Mortgage discrimination may be an important measure of institutional racism to be used in understanding racial disparities in preterm birth.

16.
Nat Microbiol ; 4(12): 2109-2117, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31451773

RESUMO

Growth rate and metabolic state of bacteria have been separately shown to affect antibiotic efficacy1-3. However, the two are interrelated as bacterial growth inherently imposes a metabolic burden4; thus, determining individual contributions from each is challenging5,6. Indeed, faster growth is often correlated with increased antibiotic efficacy7,8; however, the concurrent role of metabolism in that relationship has not been well characterized. As a result, a clear understanding of the interdependence between growth and metabolism, and their implications for antibiotic efficacy, are lacking9. Here, we measured growth and metabolism in parallel across a broad range of coupled and uncoupled conditions to determine their relative contribution to antibiotic lethality. We show that when growth and metabolism are uncoupled, antibiotic lethality uniformly depends on the bacterial metabolic state at the time of treatment, rather than growth rate. We further reveal a critical metabolic threshold below which antibiotic lethality is negligible. These findings were general for a wide range of conditions, including nine representative bactericidal drugs and a diverse range of Gram-positive and Gram-negative species (Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus). This study provides a cohesive metabolic-dependent basis for antibiotic-mediated cell death, with implications for current treatment strategies and future drug development.

17.
Science ; 365(6455): 780-785, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31439791

RESUMO

Stimuli-responsive materials activated by biological signals play an increasingly important role in biotechnology applications. We exploit the programmability of CRISPR-associated nucleases to actuate hydrogels containing DNA as a structural element or as an anchor for pendant groups. After activation by guide RNA-defined inputs, Cas12a cleaves DNA in the gels, thereby converting biological information into changes in material properties. We report four applications: (i) branched poly(ethylene glycol) hydrogels releasing DNA-anchored compounds, (ii) degradable polyacrylamide-DNA hydrogels encapsulating nanoparticles and live cells, (iii) conductive carbon-black-DNA hydrogels acting as degradable electrical fuses, and (iv) a polyacrylamide-DNA hydrogel operating as a fluidic valve with an electrical readout for remote signaling. These materials allow for a range of in vitro applications in tissue engineering, bioelectronics, and diagnostics.

18.
Ambio ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31441018

RESUMO

Highly pathogenic avian influenza (HPAI) H5N1 has led to the death or destruction of millions of domesticated and wild birds and caused hundreds of human deaths worldwide. As with other HPAIs, H5N1 outbreaks among poultry have generally been caused by contact with infected migratory waterfowl at the interface of wildlands and human-dominated landscapes. Using a case-control epidemiological approach, we analyzed the relation between habitat protection and H5N1 outbreaks in China from 2004 to 2017. We found that while proximity to unprotected waterfowl habitats and rice paddy generally increased outbreak risk, proximity to the most highly protected habitats (e.g., Ramsar-designated lakes and wetlands) had the opposite effect. Protection likely involves two mechanisms: the separation of wild waterfowl and poultry populations and the diversion of wild waterfowl from human-dominated landscapes toward protected natural habitats. Wetland protection could therefore be an effective means to control avian influenza while also contributing to avian conservation.

19.
Biometals ; 32(5): 745-755, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31368012

RESUMO

Hinokitiol, a natural lipophilic chelator, appears capable of replacing several iron transporters after they have been genetically ablated. Divalent metal-ion transporter (DMT1) is the major iron importer in enterocytes and erythroblasts. We have compared DMT1 and hinokitiol in multiple fashions to learn if the smaller molecule is a suitable substitute using two HEK293 cell lines engineered to overexpress different isoforms of DMT1. Both the macromolecule and the lipophilic chelator enable import of ferrous ions into HEK293 cells. Hinokitiol also mediates ferric ion import but DMT1 cannot do so. While DMT1 can also import Mn2+ ions, hinokitiol lacks this ability. The Michaelis-Menten analysis for kinetics of macromolecular catalysis is also suitable for hinokitiol-supported iron import. To compare hinokitiol to DMT1 relative to other metal ions that DMT1 can transport, we employed an organic extraction procedure with which we initially matched the results obtained for Fe2+, Fe3+ and Mn2+, and then showed that multiple other cations were unlikely to enter via hinokitiol. The small chelator thus shares some functional properties with DMT1, but distinct difference were also noted.

20.
Nat Biotechnol ; 37(8): 962, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31312048

RESUMO

In the version of this article initially published, the second NIH grant "R24-DK49216" to author George Q. Daley contained an error. The grant number should have read U54DK110805. The error has been corrected in the HTML and PDF versions of the article.

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