scholarly journals Oxidative ornithine metabolism supports non-inflammatory C. difficile colonization

2022 ◽  
Author(s):  
Kali M. Pruss ◽  
Fatima Enam ◽  
Eric Battaglioli ◽  
Mary DeFeo ◽  
Oscar R. Diaz ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
The United States ◽  
Wild Type ◽  
Targeted Metabolomics ◽  
Disease Symptoms ◽  
Increased Risk ◽  
Infection And Inflammation ◽  
Gnotobiotic Mice ◽  
Single Operon ◽  
Type Strains

AbstractThe enteric pathogen Clostridioides difficile (Cd) is responsible for a toxin-mediated infection that causes more than 200,000 recorded hospitalizations and 13,000 deaths in the United States every year1. However, Cd can colonize the gut in the absence of disease symptoms. Prevalence of asymptomatic colonization by toxigenic Cd in healthy populations is high; asymptomatic carriers are at increased risk of infection compared to noncolonized individuals and may be a reservoir for transmission of Cd infection2,3. Elucidating the molecular mechanisms by which Cd persists in the absence of disease is necessary for understanding pathogenesis and developing refined therapeutic strategies. Here, we show with gut microbiome metatranscriptomic analysis that mice recalcitrant to Cd infection and inflammation exhibit increased community-wide expression of arginine and ornithine metabolic pathways. To query Cd metabolism specifically, we leverage RNA sequencing in gnotobiotic mice infected with two wild-type strains (630 and R20291) and isogenic toxin-deficient mutants of these strains to differentiate inflammation-dependent versus -independent transcriptional states. A single operon encoding oxidative ornithine degradation is consistently upregulated across non-toxigenic Cd strains. Combining untargeted and targeted metabolomics with bacterial and host genetics, we demonstrate that both diet- and host-derived sources of ornithine provide a competitive advantage to Cd, suggesting a mechanism for Cd persistence within a non-inflammatory, healthy gut.

scholarly journals Effects of B.1.1.7 and B.1.351 on COVID-19 Dynamics: A Campus Reopening Study

2021 ◽  
Author(s):  
Kevin Linka ◽  
Mathias Peirlinck ◽  
Amelie Schäfer ◽  
Oguz Ziya Tikenogullari ◽  
Alain Goriely ◽  
...  
Keyword(s):  
Online Education ◽  
The United States ◽  
Wild Type ◽  
Seir Model ◽  
Population Mixing ◽  
Santa Clara County ◽  
Increased Risk ◽  
Controversial Topic ◽  
Almost All ◽  
Local Reproduction

AbstractThe timing and sequence of safe campus reopening has remained the most controversial topic in higher education since the outbreak of the COVID-19 pandemic. By the end of March 2020, almost all colleges and universities in the United States had transitioned to an all online education and many institutions have not yet fully reopened to date. For a residential campus like Stanford University, the major challenge of reopening is to estimate the number of incoming infectious students at the first day of class. Here we learn the number of incoming infectious students using Bayesian inference and perform a series of retrospective and projective simulations to quantify the risk of campus reopening. We create a physics-based probabilistic model to infer the local reproduction dynamics for each state and adopt a network SEIR model to simulate the return of all undergraduates, broken down by their year of enrollment and state of origin. From these returning student populations, we predict the outbreak dynamics throughout the spring, summer, fall, and winter quarters using the inferred reproduction dynamics of Santa Clara County. We compare three different scenarios: the true outbreak dynamics under the wild-type SARS-CoV-2, and the hypothetical outbreak dynamics under the new COVID-19 variants B.1.1.7 and B.1.351 with 56% and 50% increased transmissibility. Our study reveals that even small changes in transmissibility can have an enormous impact on the overall case numbers. With no additional countermeasures, during the most affected quarter, the fall of 2020, there would have been 203 cases under baseline reproduction, compared to 4727 and 4256 cases for the B.1.1.7 and B.1.351 variants. Our results suggest that population mixing presents an increased risk for local outbreaks, especially with new and more infectious variants emerging across the globe. Tight outbreak control through mandatory quarantine and test-trace-isolate strategies will be critical in successfully managing these local outbreak dynamics.

STUDIES ON THE PARASITISM AND VARIATION OF ALTERNARIA RAPHANI

1950 ◽  
Vol 28c (3) ◽  
pp. 288-317 ◽  
Author(s):  
R. G. Atkinson
Keyword(s):  
Soil Moisture ◽  
Natural Infection ◽  
The United States ◽  
Nutritional Requirements ◽  
Diseased Plant ◽  
Cultural Variation ◽  
Wild Type ◽  
Rate Of Growth ◽  
Type Strains ◽  
Radish Seed

The natural infection of radish seed with A. Raphani may result in a lack of germination, a pre- or postemergence blight, a distinctive lesioning of cotyledons and hypocotyls, the presence of scablike lesions on table radish, and in the spotting and blighting of leaves, stalks, and siliques. The fungus was isolated from the internal tissues of all parts of dormant radish seed. Although the pathogen has been reported only on radish in Canada and the United States, the present investigation shows that Canadian isolates are capable of causing a severe leaf blight of stocks and wallflowers. Under field conditions at St. Catharines, Ont., most rapid progress of the disease occurred at temperatures within the optimum range for the fungus, i.e., 22° to 26 °C. Experimental evidence suggests that A. Raphani does not establish an overwintering inoculum in the soil by means of diseased plant debris. Increased soil moisture was associated with increased seedling disease. At a high soil moisture content, infection was lowest at 18 °C.; at medium soil moisture, it was lowest at 18 °C. and also at 23 °C., the next highest experimental temperature.Monosporous isolations showed the presence of numerous wild type strains of A. Raphani which were closely related culturally. Five of these studied intensively differed widely in virulence and sporulation, but had similar growth rates and nutritional requirements for maximum growth. Although most isolates of A. Raphani produced only a few spores in ordinary agar cultures, abundant sporulation was obtained by wounding plate cultures and removing the lids of the culture plates. In agar culture, the wild types readily produced mostly appressed variant strains also showing close cultural relations. These variants exhibited wide differences in pathogenicity, rate of growth, and nutritional requirements, but all showed practically complete loss of sporulation either in normal or wounded cultures. The effects of cultural variation of wild type strains on cultural habit, pathogenicity, rate of growth, sporulating capacity, and nutritional requirements were random and unrelated. These data, as well as the spontaneous origin and irreversibility of the variants, favored the view that they arose in culture by mutation in the naturally occurring strains.A. Raphani was shown to be capable of surviving at least 18 months in dry soil cultures with no loss of cultural habit, virulence, or sporulation.Appreciable increase in emergence and decrease in seedling infection was obtained by seed treatments with some of the common fungicidal dusts.

scholarly journals Genetic Tools for Select-Agent-Compliant Manipulation of Burkholderia pseudomallei

2007 ◽  
Vol 74 (4) ◽  
pp. 1064-1075 ◽  
Author(s):  
Kyoung-Hee Choi ◽  
Takehiko Mima ◽  
Yveth Casart ◽  
Drew Rholl ◽  
Ayush Kumar ◽  
...  
Keyword(s):  
Burkholderia Pseudomallei ◽  
Natural Transformation ◽  
The United States ◽  
Broad Host Range ◽  
Wild Type ◽  
Chromosomal Dna ◽  
Site Specific ◽  
Genetic Manipulations ◽  
Type Strains ◽  
Selection Markers

ABSTRACT Because of Burkholderia pseudomallei's classification as a select agent in the United States, genetic manipulation of this bacterium is strictly regulated. Only a few antibiotic selection markers, including gentamicin, kanamycin, and zeocin, are currently approved for use with this bacterium, but wild-type strains are highly resistant to these antibiotics. To facilitate routine genetic manipulations of wild-type strains, several new tools were developed. A temperature-sensitive pRO1600 broad-host-range replicon was isolated and used to construct curable plasmids where the Flp and Cre recombinase genes are expressed from the rhamnose-regulated Escherichia coli PBAD promoter and kanamycin (nptI) and zeocin (ble) selection markers from the constitutive Burkholderia thailandensis ribosomal P S12 or synthetic bacterial P EM7 promoter. Flp and Cre site-specific recombination systems allow in vivo excision and recycling of nptII and ble selection markers contained on FRT or loxP cassettes. Finally, expression of Tn7 site-specific transposase from the constitutive P1 integron promoter allowed development of an efficient site-specific chromosomal integration system for B. pseudomallei. In conjunction with a natural transformation method, the utility of these new tools was demonstrated by isolating an unmarked Δ(amrRAB-oprA) efflux pump mutant. Exploiting natural transformation, chromosomal DNA fragments carrying this mutation marked with zeocin resistance were transferred between the genomes of two different B. pseudomallei strains. Lastly, the deletion mutation was complemented by a chromosomally integrated mini-Tn7 element carrying the amrAB-oprA operon. The new tools allow routine select-agent-compliant genetic manipulations of B. pseudomallei and other Burkholderia species.

scholarly journals Effects of B.1.1.7 and B.1.351 on COVID-19 dynamics. A campus reopening study

2021 ◽  
Author(s):  
Kevin Linka ◽  
Mathias Peirlinck ◽  
Amelie Schäfer ◽  
Oguz Ziya Tikenogullari ◽  
Alain Goriely ◽  
...  
Keyword(s):  
Online Education ◽  
The United States ◽  
Base Line ◽  
Wild Type ◽  
Population Mixing ◽  
Santa Clara County ◽  
Increased Risk ◽  
Controversial Topic ◽  
Almost All ◽  
Local Reproduction

AbstractThe timing and sequence of safe campus reopening has remained the most controversial topic in higher education since the outbreak of the COVID-19 pandemic. By the end of March 2020, almost all colleges and universities in the United States had transitioned to an all online education and many institutions have not yet fully reopened to date. For a residential campus like Stanford University, the major challenge of reopening is to estimate the number of incoming infectious students at the first day of class. Here we learn the number of incoming infectious students using Bayesian inference and perform a series of retrospective and projective simulations to quantify the risk of campus reopening. We create a physics-based probabilistic model to infer the local reproduction dynamics for each state and adopt a network SEIR model to simulate the return of all undergraduates, broken down by their year of enrollment and state of origin. From these returning student populations, we predict the outbreak dynamics throughout the spring, summer, fall, and winter quarters using the inferred reproduction dynamics of Santa Clara County. We compare three different scenarios: the true outbreak dynamics under the wild-type SARS-CoV-2, and the hypothetical outbreak dynamics under the new COVID-19 variants B.1.1.7 and B.1.351 with 56% and 50% increased transmissibility. Our study reveals that even small changes in transmissibility can have an enormous impact on the overall case numbers. With no additional countermeasures, during the most affected quarter, the fall of 2020, there would have been 203 cases under base-line reproduction, compared to 4727 and 4256 cases for the B.1.1.7 and B.1.351 variants. Our results suggest that population mixing presents an increased risk for local outbreaks, especially with new and more infectious variants emerging across the globe. Tight outbreak control through mandatory quarantine and test-trace-isolate strategies will be critical in successfully managing these local outbreak dynamics.

scholarly journals Current progress of fluoroquinolones-increased risk of aortic aneurysm and dissection

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Cui Jun ◽  
Bian Fang
Keyword(s):  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
False Lumen ◽  
The United States ◽  
Black Box ◽  
Research Progress ◽  
Major Life ◽  
Increased Risk ◽  
Aortic Aneurysm And Dissection ◽  
Black Box Warnings

AbstractAortic aneurysm (AA) and aortic dissection (AD) are major life-threatening diseases around the world. AA is a localized or diffuse dilation of the aorta, while AD is the separation of the layers creating a false lumen within the aortic wall. Fluoroquinolones (FQ) remain one of the most important kind of antibiotics and have a wider clinical use and broad antibacterial spectrum. FQ were also reported to treat infected AA. The most common adverse events (AEs) of FQ are mild and reversible, like headaches, diarrhea and nausea. Due to FQ-related serious AEs, such as tendonitis and tendon rupture, chondrotoxicity, or retinal detachment, QT-prolongation and dysglycemia, the United States Food and Drug Administration (FDA) issued a black box warning for FQ for systemic use in 2016 and updated warnings for FQ several times since then. Of note, in December 2018, FDA issued several “black box warnings” against FQ with the latest safety announcement warning about an increased risk of ruptures in the aorta blood vessel in certain patients. Recently, many studies have indicated an association between FQ and an increase risk of AA and AD. However, the exact mechanism of FQ-induced AA/AD remains unclear. This review aims to highlight the latest research progress of the alarming association between FQ and AA/AD. Moreover, molecular mechanisms of FQ in increasing risk of AA and AD are explored. Hopefully, this review can provide novel insights into FQ-increased the risk of AA/AD and a starting place for stewardship interventions.

scholarly journals International Evaluation of MIC Distributions and Epidemiological Cutoff Value (ECV) Definitions for Fusarium Species Identified by Molecular Methods for the CLSI Broth Microdilution Method

2015 ◽  
Vol 60 (2) ◽  
pp. 1079-1084 ◽  
Author(s):  
A. Espinel-Ingroff ◽  
A. L. Colombo ◽  
S. Cordoba ◽  
P. J. Dufresne ◽  
J. Fuller ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Fusarium Species ◽  
Gene Mutations ◽  
The United States ◽  
Wild Type ◽  
Content Type ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
The Relationship ◽  
Dna Pcr

ABSTRACTThe CLSI epidemiological cutoff values (ECVs) of antifungal agents are available for variousCandidaspp.,Aspergillusspp., and the Mucorales. However, those categorical endpoints have not been established forFusariumspp., mostly due to the difficulties associated with collecting sufficient CLSI MICs for clinical isolates identified according to the currently recommended molecular DNA-PCR-based identification methodologies. CLSI MIC distributions were established for 53Fusarium dimerumspecies complex (SC), 10F. fujikuroi, 82F. proliferatum, 20F. incarnatum-F. equisetiSC, 226F. oxysporumSC, 608F. solaniSC, and 151F. verticillioidesisolates originating in 17 laboratories (in Argentina, Australia, Brazil, Canada, Europe, Mexico, and the United States). According to the CLSI guidelines for ECV setting, ECVs encompassing ≥97.5% of pooled statistically modeled MIC distributions were as follows: for amphotericin B, 4 μg/ml (F. verticillioides) and 8 μg/ml (F. oxysporumSC andF. solaniSC); for posaconazole, 2 μg/ml (F. verticillioides), 8 μg/ml (F. oxysporumSC), and 32 μg/ml (F. solaniSC); for voriconazole, 4 μg/ml (F. verticillioides), 16 μg/ml (F. oxysporumSC), and 32 μg/ml (F. solaniSC); and for itraconazole, 32 μg/ml (F. oxysporumSC andF. solaniSC). Insufficient data precluded ECV definition for the other species. Although these ECVs could aid in detecting non-wild-type isolates with reduced susceptibility to the agents evaluated, the relationship between molecular mechanisms of resistance (gene mutations) and MICs still needs to be investigated forFusariumspp.

scholarly journals Molecular Mechanisms and Emerging Therapeutics for Osteoporosis

2020 ◽  
Vol 21 (20) ◽  
pp. 7623 ◽  
Author(s):  
Ji-Yoon Noh ◽  
Young Yang ◽  
Haiyoung Jung
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Risk Groups ◽  
The United States ◽  
Bone Architecture ◽  
Global Challenge ◽  
Emerging Therapies ◽  
Metabolic Bone ◽  
Increased Risk ◽  
Control Disease

Osteoporosis is the most common chronic metabolic bone disease. It has been estimated that more than 10 million people in the United States and 200 million men and women worldwide have osteoporosis. Given that the aging population is rapidly increasing in many countries, osteoporosis could become a global challenge with an impact on the quality of life of the affected individuals. Osteoporosis can be defined as a condition characterized by low bone density and increased risk of fractures due to the deterioration of the bone architecture. Thus, the major goal of treatment is to reduce the risk for fractures. There are several treatment options, mostly medications that can control disease progression in risk groups, such as postmenopausal women and elderly men. Recent studies on the basic molecular mechanisms and clinical implications of osteoporosis have identified novel therapeutic targets. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for osteoporosis management in the future. Here, we review the etiology of osteoporosis and the molecular mechanism of bone remodeling, present current pharmacological options, and discuss emerging therapies targeting novel mechanisms, investigational treatments, and new promising therapeutic approaches.

scholarly journals Epidemiological Cutoffs and Cross-Resistance to Azole Drugs in Aspergillus fumigatus

2008 ◽  
Vol 52 (7) ◽  
pp. 2468-2472 ◽  
Author(s):  
Juan Luis Rodriguez-Tudela ◽  
Laura Alcazar-Fuoli ◽  
Emilia Mellado ◽  
Ana Alastruey-Izquierdo ◽  
Araceli Monzon ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Molecular Mechanisms ◽  
Susceptibility Testing ◽  
Antifungal Susceptibility ◽  
The United States ◽  
Cross Resistance ◽  
Wild Type ◽  
Mechanisms Of Resistance ◽  
Clinical Breakpoints ◽  
Resistant Strains

ABSTRACT Antifungal susceptibility testing of molds has been standardized in Europe and in the United States. Aspergillus fumigatus strains with resistance to azole drugs have recently been detected and the underlying molecular mechanisms of resistance characterized. Three hundred and ninety-three isolates, including 32 itraconazole-resistant strains, were used to define wild-type populations, epidemiological cutoffs, and cross-resistance between azole drugs. The epidemiological cutoff for itraconazole, voriconazole, and ravuconazole for the wild-type populations of A. fumigatus was ≤1 mg/liter. For posaconazole, the epidemiological cutoff was ≤0.25 mg/liter. Up till now, isolates susceptible to itraconazole have not yet displayed resistance to other azole drugs. Cross-resistance between azole drugs depends on specific mutations in cyp51A. Thus, a substitution of glycine in position 54 of Cyp51A confers cross-resistance between itraconazole and posaconazole. A substitution of methionine at position 220 or a duplication in tandem of a 34-bp fragment in the cyp51A promoter combined with a substitution of leucine at position 98 for histidine confers cross-resistance to all azole drugs tested. The results obtained in this study will help to develop clinical breakpoints for azole drugs and A. fumigatus.

In vitro and in vivo activities of AM-1155, a new fluoroquinolone, against Chlamydia spp.

1997 ◽  
Vol 41 (6) ◽  
pp. 1331-1334 ◽  
Author(s):  
N Miyashita ◽  
Y Niki ◽  
T Kishimoto ◽  
M Nakajima ◽  
T Matsushima
Keyword(s):  
United States ◽  
Body Weight ◽  
Survival Rate ◽  
Chlamydia Pneumoniae ◽  
The United States ◽  
Chlamydia Psittaci ◽  
Wild Type ◽  
Type Strains

The in vitro and in vivo activities of AM-1155, a new quinolone, against Chlamydia spp. were investigated. The MIC of AM-1155 for 10 standard strains of different Chlamydia spp. and 25 wild-type strains of Chlamydia pneumoniae isolated in Japan, which were morphologically different from clinical isolates from the United States, ranged from 0.063 to 0.125 microg/ml. Its activity was almost the same as those of sparfloxacin and tosufloxacin and was 4 and 16 times superior to those of levofloxacin and ciprofloxacin, respectively, but lower than those of clarithromycin and minocycline (range for each, 0.016 to 0.031 microg/ml). The minimal chlamydiacidal concentration of AM-1155 ranged from 0.063 to 0.125 microg/ml, while those of clarithromycin and minocycline ranged from 0.016 to 0.031 microg/ml and 0.016 to 0.063 microg/ml, respectively. The therapeutic effect of a 7-day course of AM-1155 at doses of 5 and 10 mg/kg of body weight administered orally twice daily to mice with experimental Chlamydia psittaci pneumonia was excellent, with a 100% survival rate at 21 days after infection. The efficacy was equal to those of clarithromycin and minocycline and higher than those of ciprofloxacin and ofloxacin.

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