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1.
Nat Commun ; 15(1): 4462, 2024 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-38796512

RESUMEN

Virulence and metabolism are often interlinked to control the expression of essential colonisation factors in response to host-associated signals. Here, we identified an uncharacterised transporter of the dietary monosaccharide ʟ-arabinose that is widely encoded by the zoonotic pathogen enterohaemorrhagic Escherichia coli (EHEC), required for full competitive fitness in the mouse gut and highly expressed during human infection. Discovery of this transporter suggested that EHEC strains have an enhanced ability to scavenge ʟ-arabinose and therefore prompted us to investigate the impact of this nutrient on pathogenesis. Accordingly, we discovered that ʟ-arabinose enhances expression of the EHEC type 3 secretion system, increasing its ability to colonise host cells, and that the underlying mechanism is dependent on products of its catabolism rather than the sensing of ʟ-arabinose as a signal. Furthermore, using the murine pathogen Citrobacter rodentium, we show that ʟ-arabinose metabolism provides a fitness benefit during infection via virulence factor regulation, as opposed to supporting pathogen growth. Finally, we show that this mechanism is not restricted to ʟ-arabinose and extends to other pentose sugars with a similar metabolic fate. This work highlights the importance integrating central metabolism with virulence regulation in order to maximise competitive fitness of enteric pathogens within the host-niche.


Asunto(s)
Arabinosa , Citrobacter rodentium , Escherichia coli Enterohemorrágica , Arabinosa/metabolismo , Animales , Ratones , Citrobacter rodentium/patogenicidad , Citrobacter rodentium/metabolismo , Citrobacter rodentium/genética , Humanos , Virulencia , Escherichia coli Enterohemorrágica/patogenicidad , Escherichia coli Enterohemorrágica/metabolismo , Escherichia coli Enterohemorrágica/genética , Regulación Bacteriana de la Expresión Génica , Factores de Virulencia/metabolismo , Factores de Virulencia/genética , Infecciones por Enterobacteriaceae/microbiología , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Sistemas de Secreción Tipo III/metabolismo , Sistemas de Secreción Tipo III/genética , Infecciones por Escherichia coli/microbiología , Femenino
2.
Sci Adv ; 10(12): eadj2770, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38507499

RESUMEN

Sulfur degassed at volcanic arcs calls for dissolved sulfate ions (S6+) released by subduction-zone fluids, oxidizing (in association with carbon) the subarc mantle, but sulfur speciation in subduction fluids at subarc depths remains unclear. We apply electrolytic fluid thermodynamics to model the dissolution behavior of pyrite in metacarbonate sediments as a function of P, T and rock redox state up to 4.3 gigapascals and 730°C. At subarc depth and the redox conditions of the fayalite-magnetite-quartz oxygen buffer, pyrite dissolution releases oxidized sulfur in fluids by disproportionation into sulfate, bisulfite, and sulfide species. These findings indicate that oxidized, sulfur-rich carbon-oxygen-hydrogen-sulfur (COHS) fluids form within subducting slabs at depths greater than 100 kilometers independent from slab redox state and that sulfur can be more effective than the concomitantly dissolved carbon at oxidizing the mantle wedge, especially when carbonates are stable.

3.
Nature ; 626(8001): 1125-1132, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38355796

RESUMEN

To conserve energy during starvation and stress, many organisms use hibernation factor proteins to inhibit protein synthesis and protect their ribosomes from damage1,2. In bacteria, two families of hibernation factors have been described, but the low conservation of these proteins and the huge diversity of species, habitats and environmental stressors have confounded their discovery3-6. Here, by combining cryogenic electron microscopy, genetics and biochemistry, we identify Balon, a new hibernation factor in the cold-adapted bacterium Psychrobacter urativorans. We show that Balon is a distant homologue of the archaeo-eukaryotic translation factor aeRF1 and is found in 20% of representative bacteria. During cold shock or stationary phase, Balon occupies the ribosomal A site in both vacant and actively translating ribosomes in complex with EF-Tu, highlighting an unexpected role for EF-Tu in the cellular stress response. Unlike typical A-site substrates, Balon binds to ribosomes in an mRNA-independent manner, initiating a new mode of ribosome hibernation that can commence while ribosomes are still engaged in protein synthesis. Our work suggests that Balon-EF-Tu-regulated ribosome hibernation is a ubiquitous bacterial stress-response mechanism, and we demonstrate that putative Balon homologues in Mycobacteria bind to ribosomes in a similar fashion. This finding calls for a revision of the current model of ribosome hibernation inferred from common model organisms and holds numerous implications for how we understand and study ribosome hibernation.


Asunto(s)
Proteínas Bacterianas , Respuesta al Choque por Frío , Factores de Terminación de Péptidos , Biosíntesis de Proteínas , Psychrobacter , Proteínas Ribosómicas , Ribosomas , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/ultraestructura , Factor Tu de Elongación Peptídica/química , Factor Tu de Elongación Peptídica/metabolismo , Factor Tu de Elongación Peptídica/ultraestructura , Proteínas Ribosómicas/química , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/ultraestructura , Ribosomas/química , Ribosomas/metabolismo , Ribosomas/ultraestructura , Psychrobacter/química , Psychrobacter/genética , Psychrobacter/metabolismo , Psychrobacter/ultraestructura , Microscopía por Crioelectrón , Factores de Terminación de Péptidos/química , Factores de Terminación de Péptidos/genética , Factores de Terminación de Péptidos/metabolismo , Factores de Terminación de Péptidos/ultraestructura
5.
Dig Dis Sci ; 69(2): 360-369, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38041763

RESUMEN

BACKGROUND: Fecal immunochemical test (FIT) is less effective in detecting advanced adenomas (AA) than colonoscopy. Increase in FIT for colorectal cancer (CRC) screening may lead to an increased number of undetected AAs which may develop into future CRCs. AIM: We determined the potential impact of FIT expansion on missed AAs and future CRC diagnoses in an urban, tertiary-care, safety-net hospital. METHODS: CRC and AA diagnoses were identified in patients undergoing colonoscopy for average-risk CRC screening or positive FIT between 2017 and 2019 at Boston Medical Center. Poisson regression modeling was used to estimate the frequency of AAs per year by age group using data from 2017 to 2019, assuming average outpatient volume and proportion of screening colonoscopies. Total number of patients who received FIT was extrapolated from those who underwent colonoscopy for positive FIT. We estimated AAs per year if 'one-time' FIT was used for screening in 75% and 100% of the population and subtracted this from the estimated AAs per year under the Poisson model to determine missed AAs. We used previously described, age and gender specific estimates of the annual progression of AA to CRC. RESULTS: The estimated number of CRCs detected per year is 4.6/1785 males and 4.6/2086 females screened. With 75% FIT expansion, we estimate an additional 3.5 (95% CI 1.3, 9.5) and 2.2 (95% CI 0.64, 7.6) CRCs; with 100% FIT expansion, we estimate an additional 7.4 (95% CI 3.7, 14.9) and 4.2 (95% CI 1.7, 10.5) CRCs, in 5 years, in males and females, respectively. CONCLUSION: Expansion of FIT may substantially increase CRC incidence.


Asunto(s)
Colonoscopía , Neoplasias Colorrectales , Masculino , Femenino , Humanos , Tamizaje Masivo , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Sangre Oculta , Detección Precoz del Cáncer , Heces
6.
Nutrients ; 15(24)2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38140360

RESUMEN

This narrative review explores the impact of sleep and nutrition on injury risk in adolescent athletes. Sleep is viewed as essential to the recuperation process and is distinguished as an active participant in recovery through its involvement in growth, repair, regeneration, and immunity. Furthermore, the literature has shown that the sleep of athletes impacts elements of athletic performance including both physical and cognitive performance, recovery, injury risk, and mental well-being. For sleep to have a restorative effect on the body, it must meet an individual's sleep needs whilst also lasting for an adequate duration and being of adequate quality, which is age-dependent. The literature has suggested that athletes have increased sleep needs compared to those of the general population and thus the standard recommendations may not be sufficient for athletic populations. Therefore, a more individualised approach accounting for overall sleep health may be more appropriate for addressing sleep needs in individuals including athletes. The literature has demonstrated that adolescent athletes achieve, on average, ~6.3 h of sleep, demonstrating a discrepancy between sleep recommendations (8-10 h) and actual sleep achieved. Sleep-wake cycles undergo development during adolescence whereby adaptation occurs in sleep regulation during this phase. These adaptations increase sleep pressure tolerance and are driven by the maturation of physiological, psychological, and cognitive functioning along with delays in circadian rhythmicity, thus creating an environment for inadequate sleep during adolescence. As such, the adolescent period is a phase of rapid growth and maturation that presents multiple challenges to both sleep and nutrition; consequently, this places a significant burden on an adolescent athletes' ability to recover, thus increasing the likelihood of injury. Therefore, this article aims to provide a comprehensive review of the available literature on the importance of sleep and nutrition interactions in injury risk in adolescent athletes. Furthermore, it provides foundations for informing further investigations exploring the relation of sleep and nutrition interactions to recovery during adolescence.


Asunto(s)
Rendimiento Atlético , Sueño , Humanos , Adolescente , Sueño/fisiología , Ritmo Circadiano/fisiología , Atletas/psicología , Estado Nutricional , Rendimiento Atlético/fisiología
7.
Nature ; 622(7984): 712-717, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37880437

RESUMEN

The detection of deep reflected S waves on Mars inferred a core size of 1,830 ± 40 km (ref. 1), requiring light-element contents that are incompatible with experimental petrological constraints. This estimate assumes a compositionally homogeneous Martian mantle, at odds with recent measurements of anomalously slow propagating P waves diffracted along the core-mantle boundary2. An alternative hypothesis is that Mars's mantle is heterogeneous as a consequence of an early magma ocean that solidified to form a basal layer enriched in iron and heat-producing elements. Such enrichment results in the formation of a molten silicate layer above the core, overlain by a partially molten layer3. Here we show that this structure is compatible with all geophysical data, notably (1) deep reflected and diffracted mantle seismic phases, (2) weak shear attenuation at seismic frequency and (3) Mars's dissipative nature at Phobos tides. The core size in this scenario is 1,650 ± 20 km, implying a density of 6.5 g cm-3, 5-8% larger than previous seismic estimates, and can be explained by fewer, and less abundant, alloying light elements than previously required, in amounts compatible with experimental and cosmochemical constraints. Finally, the layered mantle structure requires external sources to generate the magnetic signatures recorded in Mars's crust.

8.
Mol Pharm ; 20(8): 4086-4099, 2023 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-37466053

RESUMEN

The effects of atomic layer (ALC) coating on physical properties and storage stability were examined in solid powders containing myoglobin, a model protein. Powders containing myoglobin and mannitol (1:1 w/w) were prepared by lyophilization or spray drying and subjected to aluminum oxide or silicon oxide ALC coating. Uncoated samples of these powders as well as coated and uncoated samples of myoglobin as received served as controls. After preparation (t0), samples were analyzed for moisture content, reconstitution time, myoglobin secondary structure, crystallinity, and protein aggregate content. Samples were stored for 3 months (t3) under controlled conditions (53% RH, 40 °C) in both open and closed vials and then analyzed as above. At t3, the recovery of soluble native (i.e., monomeric) protein depended on formulation, coating type, and drying method and was up to 2-fold greater in coated samples than in uncoated controls. Promisingly, some samples with high recovery also showed low soluble aggregate content (<10%) at t3 and low total monomer loss; the latter was correlated to sample moisture content. Overall, the results demonstrate that ALC coatings can stabilize solid protein formulations during storage, providing benefits over uncoated controls.


Asunto(s)
Mioglobina , Mioglobina/química , Polvos/química , Liofilización , Estructura Secundaria de Proteína , Estabilidad de Medicamentos
9.
Beilstein J Nanotechnol ; 14: 725-737, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37346784

RESUMEN

Multilayer III-V-based solar cells are complex devices consisting of many layers and interfaces. The study and the comprehension of the mechanisms that take place at the interfaces is crucial for efficiency improvement. In this work, we apply frequency-modulated Kelvin probe force microscopy under ambient conditions to investigate the capability of this technique for the analysis of an InP/GaInAs(P) multilayer stack. KPFM reveals a strong dependence on the local doping concentration, allowing for the detection of the surface potential of layers with a resolution as low as 20 nm. The analysis of the surface potential allowed for the identification of space charge regions and, thus, the presence of several junctions along the stack. Furthermore, a contrast enhancement in the surface potential image was observed when KPFM was performed under illumination, which is analysed in terms of the reduction of surface band bending induced by surface defects by photogenerated carrier distributions. The analysis of the KPFM data was assisted by means of theoretical modelling simulating the energy bands profile and KPFM measurements.

10.
PLoS Genet ; 19(6): e1010784, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37276233

RESUMEN

Competitive bacteria-bacteriophage interactions have resulted in the evolution of a plethora of bacterial defense systems preventing phage propagation. In recent years, computational and bioinformatic approaches have underpinned the discovery of numerous novel bacterial defense systems. Anti-phage systems are frequently encoded together in genomic loci termed defense islands. Here we report the identification and characterisation of a novel anti-phage system, that we have termed Shield, which forms part of the Pseudomonas defensive arsenal. The Shield system comprises the core component ShdA, a membrane-bound protein harboring an RmuC domain. Heterologous production of ShdA alone is sufficient to mediate bacterial immunity against several phages. We demonstrate that Shield and ShdA confer population-level immunity and that they can also decrease transformation efficiency. We further show that ShdA homologues can degrade DNA in vitro and, when expressed in a heterologous host, can alter the organisation of the host chromosomal DNA. Use of comparative genomic approaches identified how Shield can be divided into four subtypes, three of which contain additional components that in some cases can negatively affect the activity of ShdA and/or provide additional lines of phage defense. Collectively, our results identify a new player within the Pseudomonas bacterial immunity arsenal that displays a novel mechanism of protection, and reveals a role for RmuC domains in phage defense.


Asunto(s)
Bacteriófagos , Bacteriófagos/genética , Pseudomonas/genética , Bacterias/genética , Genoma
11.
Hist Human Sci ; 36(2): 105-127, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37153716

RESUMEN

The disruptions to everyday life wrought by the COVID-19 pandemic include distortions in the experience of time, as reported widely by ordinary citizens and observed by journalists and social scientists. But how does this temporal disruption play out in different time scales-in the individual day as opposed to the medium- and long-term futures? And how might place influence how individuals experience and understand the pandemic's temporal transformations? This essay examines a range of temporal disruptions reported in day diaries and surveys submitted to the Everyday Life in Middletown project, an online archive that has been documenting ordinary life in Muncie, Indiana, USA since 2016. Viewing these materials as instances of life writing, the essay probes the interactions between temporal disruptions and the local setting as they inflect the autobiographical selves our writers construct in their pandemic writings. It shows how living in Muncie-a postindustrial city with its particular combination of historical, demographic, economic, social, and political dynamics-structures the autobiographical stories available to our writers, and how the disruption of time produces new variations and problems for life writing. In the midst of a global crisis, we glimpse the pandemic's reshaping of a local structure of feeling in which a pervasive, local narrative of civic decline frames individual self-fashioning.

12.
Cancer Cell ; 41(5): 970-985.e3, 2023 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-37084736

RESUMEN

We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients who develop metastasis are younger and male, with primary tumors enriched in micropapillary or solid histological subtypes and with a higher mutational burden, chromosomal instability, and fraction of genome doublings. Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions. Analyses of matched specimens show that oncogenic and actionable alterations are frequently shared between primary tumors and metastases, whereas copy number alterations of unknown significance are more often private to metastases. Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries. Key clinicopathological and genomic alterations in our cohort were externally validated. In summary, our analysis highlights the complexity of clinicopathological features and tumor genomics in LUAD organotropism.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Masculino , Adenocarcinoma del Pulmón/genética , Mutación , Variaciones en el Número de Copia de ADN , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Genómica , ADN Helicasas/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética
13.
J Appl Clin Med Phys ; 24(6): e13932, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36794436

RESUMEN

ICRU 91, published in 2017, is an international standard for prescribing, recording, and reporting stereotactic treatments. Since its release, there has been limited research published on the implementation and impact of ICRU 91 on clinical practice. This work provides an assessment of the recommended ICRU 91 dose reporting metrics for their use in clinical treatment planning. A set of 180 intracranial stereotactic treatment plans for patients treated by the CyberKnife (CK) system were analyzed retrospectively using the ICRU 91 reporting metrics. The 180 plans comprised 60 trigeminal neuralgia (TGN), 60 meningioma (MEN), and 60 acoustic neuroma (AN) cases. The reporting metrics included the planning target volume (PTV) near-minimum dose ( D near - min ${D}_{{\rm{near}} - {\rm{min}}}$ ), near-maximum dose ( D near - max ${D}_{{\rm{near}} - {\rm{max}}}$ ), and median dose ( D 50 % ${D}_{50{\rm{\% }}}$ ), as well as the gradient index (GI) and conformity index (CI). The metrics were assessed for statistical correlation with several treatment plan parameters. In the TGN plan group, owing to the small targets, D near - min ${D}_{{\rm{near}} - {\rm{min}}}$ was greater than D near - max ${D}_{{\rm{near}} - {\rm{max}}}$ in 42 plans, whereas both metrics were not applicable in 17 plans. The D 50 % ${D}_{50{\rm{\% }}}$ metric was predominantly influenced by the prescription isodose line (PIDL). The GI was significantly dependent on target volume in all analyses performed, where the variables were inversely related. The CI was only dependent on target volume in treatment plans for small targets. The ICRU 91 D near - min ${D}_{{\rm{near}} - {\rm{min}}}$ and D near - max ${D}_{{\rm{near}} - {\rm{max}}}$ metrics breakdown in plans for small target volumes below 1 cm3 ; the Min and Max pixel should be reported in such cases. The D 50 % ${D}_{50{\rm{\% }}}$ metric is of limited use for treatment planning. Given their volume dependence, the GI and CI metrics could potentially serve as plan evaluation tools in the planning of the sites analyzed in this study, which would ultimately improve treatment plan quality.


Asunto(s)
Neuroma Acústico , Radiocirugia , Humanos , Estudios Retrospectivos , Neuroma Acústico/radioterapia , Neuroma Acústico/cirugía , Benchmarking , Planificación de la Radioterapia Asistida por Computador , Dosificación Radioterapéutica
14.
Rural Remote Health ; 23(1): 8140, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36802673

RESUMEN

Introduction (including aim): Axial spondyloarthritis (axSpA) is a chronic inflammatory and rheumatic disease that causes inflammation and structural changes to the skeleton. Patients with axSpA suffer from neck pain and stiffness and have severe and permanent restrictions in movement. Patients are advised to carry out prescribed exercises to maintain mobility, but most do not comply with this advice due to the unnatural nature of head and neck stretching exercises. Clinicians currently only test cervical rotation of patients with axSpA a few times per year. Pain and stiffness can fluctuate between appointments, and there is a need to accurately measure the patient's spinal mobility at home. METHODS: Virtual Reality (VR) headsets have been proven to be accurate and reliable when measuring neck movement. We are using VR to aid relaxation and promote mindfulness, whilst moving the participant's head to visual and auditory cues to enable completion of exercises. In this ongoing study, we are testing whether a smartphone-enabled VR system could be feasible for the measurement of cervical movement at home. RESULTS: The ongoing research will have a positive impact on the lives of patients suffering from axSpA. Regular measurement and assessment of spinal mobility at home will be beneficial to patients and clinicians for objective mobility measurement. DISCUSSION: Implementing VR as both a distractive and rehabilitation encouragement technique could improve patient engagement whilst simultaneously collecting granular mobility data. Additionally, implementing VR rehabilitation using smartphone technology will offer an inexpensive method of exercise and effective rehabilitation.


Asunto(s)
Espondiloartritis Axial , Medicina , Realidad Virtual , Humanos , Dolor , Ejercicio Físico
15.
J Thorac Cardiovasc Surg ; 166(1): 231-240.e2, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36621452

RESUMEN

OBJECTIVE: Molecular diagnostic assays require samples with high nucleic acid content to generate reliable data. Similarly, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) requires samples with adequate tumor content. We investigated whether shape-sensing robotic-assisted bronchoscopy (ssRAB) provides adequate samples for molecular and predictive testing. METHODS: We retrospectively identified diagnostic samples from a prospectively collected database. Pathologic reports were reviewed to assess adequacy of samples for molecular testing and feasibility of PD-L1 IHC. Tumor cellularity was quantified by an independent pathologist using paraffin-embedded sections. Univariable and multivariable linear regression models were constructed to assess associations between lesion- and procedure-related variables and tumor cellularity. RESULTS: In total, 128 samples were analyzed: 104 primary lung cancers and 24 metastatic lesions. On initial pathologic assessment, ssRAB samples were deemed to be adequate for molecular testing in 84% of cases; on independent review of cellular blocks, median tumor cellularity was 60% (interquartile range, 25%-80%). Hybrid capture-based next-generation sequencing was successful for 25 of 26 samples (96%), polymerase chain reaction-based molecular testing (Idylla; Biocartis) was successful for 49 of 52 samples (94%), and PD-L1 IHC was successful for 61 of 67 samples (91%). Carcinoid and small cell carcinoma histologic subtype and adequacy on rapid on-site evaluation were associated with higher tumor cellularity. CONCLUSIONS: The ssRAB platform provided adequate tissue for next-generation sequencing, polymerase chain reaction-based molecular testing, and PD-L1 IHC in >80% of cases. Tumor histology and adequacy on intraoperative cytologic assessment might be associated with sample quality and suitability for downstream assays.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Procedimientos Quirúrgicos Robotizados , Neoplasias Torácicas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/química , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/química , Antígeno B7-H1 , Broncoscopía , Estudios Retrospectivos , Estudios de Factibilidad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis
16.
Proc Natl Acad Sci U S A ; 120(1): e2212175120, 2023 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-36574699

RESUMEN

The ability of bacterial pathogens to adapt to host niches is driven by the carriage and regulation of genes that benefit pathogenic lifestyles. Genes that encode virulence or fitness-enhancing factors must be regulated in response to changing host environments to allow rapid response to challenges presented by the host. Furthermore, this process can be controlled by preexisting transcription factors (TFs) that acquire new roles in tailoring regulatory networks, specifically in pathogens. However, the mechanisms underlying this process are poorly understood. The highly conserved Escherichia coli TF YhaJ exhibits distinct genome-binding dynamics and transcriptome control in pathotypes that occupy different host niches, such as uropathogenic E. coli (UPEC). Here, we report that this important regulator is required for UPEC systemic survival during murine bloodstream infection (BSI). This advantage is gained through the coordinated regulation of a small regulon comprised of both virulence and metabolic genes. YhaJ coordinates activation of both Type 1 and F1C fimbriae, as well as biosynthesis of the amino acid tryptophan, by both direct and indirect mechanisms. Deletion of yhaJ or the individual genes under its control leads to attenuated survival during BSI. Furthermore, all three systems are up-regulated in response to signals derived from serum or systemic host tissue, but not urine, suggesting a niche-specific regulatory trigger that enhances UPEC fitness via pleiotropic mechanisms. Collectively, our results identify YhaJ as a pathotype-specific regulatory aide, enhancing the expression of key genes that are collectively required for UPEC bloodstream pathogenesis.


Asunto(s)
Infecciones por Escherichia coli , Proteínas de Escherichia coli , Sepsis , Infecciones Urinarias , Escherichia coli Uropatógena , Animales , Ratones , Escherichia coli/genética , Escherichia coli/metabolismo , Infecciones Urinarias/microbiología , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Infecciones por Escherichia coli/genética , Infecciones por Escherichia coli/microbiología , Factores de Virulencia/genética , Escherichia coli Uropatógena/genética , Regulación Bacteriana de la Expresión Génica
17.
Ultraschall Med ; 44(1): 36-49, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36228630

RESUMEN

OBJECTIVE: To evaluate the evidence and produce a summary and recommendations for the most common heart and lung point-of-care ultrasound (PoCUS). METHODS: We reviewed 10 clinical domains/questions related to common heart and lung applications of PoCUS. Following review of the evidence, a summary and recommendations were produced, including assigning levels of evidence (LoE) and grading of recommendation, assessment, development, and evaluation (GRADE). 38 international experts, the expert review group (ERG), were invited to review the evidence presented for each question. A level of agreement of over 75 % was required to progress to the next section. The ERG then reviewed and indicated their level of agreement of the summary and recommendation for each question (using a 5-point Likert scale), which was approved in the case of a level of agreement of greater than 75 %. A level of agreement was defined as a summary of "strongly agree" and "agree" on the Likert scale responses. FINDINGS AND RECOMMENDATIONS: One question achieved a strong consensus for an assigned LoE of 3 and a weak GRADE recommendation (question 1), the remaining 9 questions achieved broad agreement with an assigned LoE of 4 and a weak GRADE recommendation (question 2), three achieved an LoE of 3 with a weak GRADE recommendation (questions 3-5), three achieved an LoE of 3 with a strong GRADE recommendation (questions 6-8) and the remaining two were assigned an LoE of 2 with a strong GRADE recommendation (questions 9 and 10). CONCLUSION: These consensus-derived recommendations should aid clinical practice and highlight areas of further research for PoCUS in acute settings.


Asunto(s)
Sistemas de Atención de Punto , Pruebas en el Punto de Atención , Humanos , Pulmón , Ultrasonografía
18.
Ultraschall Med ; 44(1): e1-e24, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36228631

RESUMEN

AIMS: To evaluate the evidence and produce a summary and recommendations for the most common heart and lung applications of point-of-care ultrasound (PoCUS). METHODS: We reviewed 10 clinical domains/questions related to common heart and lung applications of PoCUS. Following review of the evidence, a summary and recommendation were produced, including assignment of levels of evidence (LoE) and grading of the recommendation, assessment, development, and evaluation (GRADE). 38 international experts, the expert review group (ERG), were invited to review the evidence presented for each question. A level of agreement of over 75 % was required to progress to the next section. The ERG then reviewed and indicated their level of agreement regarding the summary and recommendation for each question (using a 5-point Likert scale), which was approved if a level of agreement of greater than 75 % was reached. A level of agreement was defined as a summary of "strongly agree" and "agree" on the Likert scale responses. FINDINGS AND RECOMMENDATIONS: One question achieved a strong consensus for an assigned LoE of 3 and a weak GRADE recommendation (question 1). The remaining 9 questions achieved broad agreement with one assigned an LoE of 4 and weak GRADE recommendation (question 2), three achieving an LoE of 3 with a weak GRADE recommendation (questions 3-5), three achieved an LoE of 3 with a strong GRADE recommendation (questions 6-8), and the remaining two were assigned an LoE of 2 with a strong GRADE recommendation (questions 9 and 10). CONCLUSION: These consensus-derived recommendations should aid clinical practice and highlight areas of further research for PoCUS in acute settings.


Asunto(s)
Sistemas de Atención de Punto , Pruebas en el Punto de Atención , Humanos , Pulmón , Ultrasonografía
20.
Proc Natl Acad Sci U S A ; 119(45): e2210299119, 2022 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-36322762

RESUMEN

Ecologically beneficial traits in bacteria are encoded by intrinsic and horizontally acquired genes. However, such traits are not universal, and the highly mosaic nature of bacterial genomes requires control at the transcriptional level to drive these processes. It has emerged that regulatory flexibility is widespread in the Escherichia coli species, whereby preexisting transcription factors can acquire new and unrelated roles in regulating beneficial traits. DsdC is the regulator of D-serine tolerance in E. coli, is essential for D-serine catabolism, and is often encoded by two copies in neonatal meningitis-associated E. coli (NMEC). Here, we reveal that DsdC is a global regulator of transcription in NMEC and does not require D-serine for the control of novel beneficial traits. We show that DsdC binds the chromosome in an unusual manner, with many binding sites arranged in clusters spanning entire operons and within gene coding sequences, such as neuO. Importantly, we identify neuO as the most significantly down-regulated gene in a strain deleted for both dsdC copies, in both the presence and absence of D-serine. NeuO is prophage encoded in several NMEC K1 isolates and mediates capsule O-acetylation but has no effect on attachment to or invasion of human brain endothelial cells. Instead, we demonstrate that NeuO provides resistance against K1 bacteriophage attack and that this critical function is regulated by DsdC. This work highlights how a horizontally acquired enzyme that functions in cell-surface modulation can be controlled by an intrinsic regulator to provide a key ecological benefit to an E. coli pathotype.


Asunto(s)
Bacteriófagos , Proteínas de Escherichia coli , Recién Nacido , Humanos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Bacteriófagos/metabolismo , Células Endoteliales/metabolismo , Serina/metabolismo
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