Summary
The severe pneumonia known as Legionnaires' disease occurs following infection by the Gram‐negative bacterium Legionella pneumophila. Normally resident in fresh‐water sources, Legionella are ...subject to predation by eukaryotic phagocytes such as amoeba and ciliates. To counter this, L. pneumophila has evolved a complex system of effector proteins which allow the bacteria to hijack the phagocytic vacuole, hiding and replicating within their erstwhile killers. These same mechanisms allow L. pneumophila to hijack another phagocyte, lung‐based macrophages, which thus avoids a vital part of the immune system and leads to infection. The course of infection can be divided into five main categories: pathogen uptake, formation of the replication‐permissive vacuole, intracellular replication, host cell response, and bacterial exit. L. pneumophila effector proteins target every stage of this process, interacting with secretory, endosomal, lysosomal, retrograde and autophagy pathways, as well as with mitochondria. Each of these steps can be studied in protozoa or mammalian cells, and the knowledge gained can be readily applied to human pathogenicity. Here we describe the manner whereby L. pneumophila infects host protozoa, the various techniques which are available to analyse these processes and the implications of this model for Legionella virulence and the pathogenesis of Legionnaires' disease.
Challenges in protein-folding simulations Schulten, Klaus; Freddolino, Peter L; Harrison, Christopher B ...
Nature physics,
10/2010, Letnik:
6, Številka:
10
Journal Article
Recenzirano
Odprti dostop
A protein's shape is crucial for fulfilling its function within a cell. This Review discusses how molecular dynamics simulations have given us insight into the processes that turn a linear chain of ...amino acids into a unique three-dimensional protein. PUBLICATION ABSTRACT
To estimate the prevalence of common chronic conditions and multimorbidity among patients at GP encounters and among people in the Australian population. To assess the extent to which use of each ...individual patient's GP attendance over the previous year, instead of the average for their age-sex group, affects the precision of national population prevalence estimates of diagnosed chronic conditions.
A sub-study (between November 2012 and March 2016) of the Bettering the Evaluation and Care of Health program, a continuous national study of GP activity. Each of 1,449 GPs provided data for about 30 consecutive patients (total 43,501) indicating for each, number of GP attendances in previous year and all diagnosed chronic conditions, using their knowledge of the patient, patient self-report, and patient's health record.
Hypertension (26.5%) was the most prevalent diagnosed chronic condition among patients surveyed, followed by osteoarthritis (22.7%), hyperlipidaemia (16.6%), depression (16.3%), anxiety (11.9%), gastroesophageal reflux disease (GORD) (11.3%), chronic back pain (9.7%) and Type 2 diabetes (9.6%). After adjustment, we estimated population prevalence of hypertension as 12.4%, 9.5% osteoarthritis, 8.2% hyperlipidaemia, 8.0% depression, 5.8% anxiety and 5.2% asthma. Estimates were significantly lower than those derived using the previous method. About half (51.6%) the patients at GP encounters had two or more diagnosed chronic conditions and over one third (37.4%) had three or more. Population estimates were: 25.7% had two or more diagnosed chronic conditions and 15.8% had three or more.
Of the three approaches we have tested to date, this study provides the most accurate method for estimation of population prevalence of chronic conditions using the GP as an expert interviewer, by adjusting for each patient's reported attendance.
The bacteria causing Legionnaires’ disease, Legionella pneumophila, replicate intracellularly within unique Legionella-containing vacuoles (LCVs). LCV formation involves a type IV secretion system ...(T4SS) that translocates effector proteins into host cells. We show that the T4SS effector RidL localizes to LCVs, supports intracellular bacterial growth, and alters retrograde trafficking, in which selected proteins are transported from endosomes to the Golgi. The retromer complex that mediates retrograde trafficking localizes to LCVs independently of RidL and restricts intracellular bacterial growth. RidL binds the Vps29 retromer subunit and the lipid PtdIns(3)P, which localizes retromer components to membranes. Additionally, specific retromer cargo receptors and sorting nexins that mediate protein capture and membrane remodeling preferentially localize to LCVs in the absence of ridL. Ectopic RidL production inhibits retrograde trafficking, and L. pneumophila blocks retrograde transport at endosome exit sites in a ridL-dependent manner. Collectively, these findings suggest that RidL inhibits retromer function to promote intracellular bacterial replication.
•The host retromer complex restricts Legionella replication and localizes to LCVs•The Legionella effector RidL targets the eukaryotic retromer Vps29 subunit•Ectopic production of RidL inhibits retrograde transport in eukaryotic cells•Deletion of ridL abrogates the inhibition of retrograde trafficking by Legionella
The causative agent of Legionnaires' disease, Legionella pneumophila, uses the Icm/Dot type IV secretion system (T4SS) to form in phagocytes a distinct "Legionella-containing vacuole" (LCV), which ...intercepts endosomal and secretory vesicle trafficking. Proteomics revealed the presence of the small GTPase Ran and its effector RanBP1 on purified LCVs. Here we validate that Ran and RanBP1 localize to LCVs and promote intracellular growth of L. pneumophila. Moreover, the L. pneumophila protein LegG1, which contains putative RCC1 Ran guanine nucleotide exchange factor (GEF) domains, accumulates on LCVs in an Icm/Dot-dependent manner. L. pneumophila wild-type bacteria, but not strains lacking LegG1 or a functional Icm/Dot T4SS, activate Ran on LCVs, while purified LegG1 produces active Ran(GTP) in cell lysates. L. pneumophila lacking legG1 is compromised for intracellular growth in macrophages and amoebae, yet is as cytotoxic as the wild-type strain. A downstream effect of LegG1 is to stabilize microtubules, as revealed by conventional and stimulated emission depletion (STED) fluorescence microscopy, subcellular fractionation and Western blot, or by microbial microinjection through the T3SS of a Yersinia strain lacking endogenous effectors. Real-time fluorescence imaging indicates that LCVs harboring wild-type L. pneumophila rapidly move along microtubules, while LCVs harboring ΔlegG1 mutant bacteria are stalled. Together, our results demonstrate that Ran activation and RanBP1 promote LCV formation, and the Icm/Dot substrate LegG1 functions as a bacterial Ran activator, which localizes to LCVs and promotes microtubule stabilization, LCV motility as well as intracellular replication of L. pneumophila.
To estimate prevalence of chronic conditions among patients seeing a general practitioner (GP), patients attending general practice at least once in a year, and the Australian population.
A sub-study ...of the BEACH (Bettering the Evaluation and Care of Health) program, a continuous national study of general practice activity conducted between July 2008 and May 2009. Each of 290 GPs provided data for about 30 consecutive patients (total 8,707) indicating diagnosed chronic conditions, using their knowledge of the patient, patient self-report, and patient's health record.
Estimates of prevalence of chronic conditions among patients surveyed, adjusted prevalence in patients who attended general practice at least once that year, and national population prevalence.
Two-thirds (66.3%) of patients surveyed had at least one chronic condition: most prevalent being hypertension (26.6%), hyperlipidaemia (18.5%), osteoarthritis (17.8%), depression (13.7%), gastro-oesophageal reflux disease (11.6%), asthma (9.5%) and Type 2 diabetes (8.3%). For patients who attended general practice at least once, we estimated 58.8% had at least one chronic condition. After further adjustment we estimated 50.8% of the Australian population had at least one chronic condition: hypertension (17.4%), hyperlipidaemia (12.7%), osteoarthritis (11.1%), depression (10.5%) and asthma (8.0%) being most prevalent.
This study used GPs to gather information from their knowledge, the patient, and health records, to provide prevalence estimates that overcome weaknesses of studies using patient self-report or health record audit alone. Our results facilitate examination of primary care resource use in management of chronic conditions and measurement of prevalence of multimorbidity in Australia.
The demand for green hydrogen as an energy carrier is projected to exceed 350 million tons per year by 2050, driven by the need for sustainable distribution and storage of energy generated from ...sources. Despite its potential, hydrogen production currently faces challenges related to cost efficiency, compliance, monitoring, and safety. This work proposes Hydrogen 4.0, a cyber-physical approach that leverages Industry 4.0 technologies-including smart sensing, analytics, and the Internet of Things (IoT)-to address these issues in hydrogen energy plants. Such an approach has the potential to enhance efficiency, safety, and compliance through real-time data analysis, predictive maintenance, and optimised resource allocation, ultimately facilitating the adoption of renewable green hydrogen. The following sections break down conventional hydrogen plants into functional blocks and discusses how Industry 4.0 technologies can be applied to each segment. The components, benefits, and application scenarios of Hydrogen 4.0 are discussed while how digitalisation technologies can contribute to the successful integration of sustainable energy solutions in the global energy sector is also addressed.
Picornaviruses, including
species A to D (EV) and
species A (PeV-A), are the leading reported causes of pediatric central nervous system infections in the United States. We investigated the molecular ...epidemiology of EV and PeV-A over 10 years in cerebrospinal fluid (CSF) collected from children seen at Children's Mercy-Kansas City (CMKC) from 2007 through 2016. The overall prevalence for EV was 16% (862/5,362) and 7% (271/4,016) for PeV. Among all picornavirus CSF detections, EV was 76%, and PeV-A was 24%. Multiple EV types cocirculated each year, with a total of 31 EV types detected in the 10-year period; the majority belonged to EV-B species (96%). Two PeV-A types were detected; PeV-A3 was the dominant PeV-A type (95%). The top five picornaviruses (PeV-A3, 26%; E30, 11%; E6, 10%; E18, 9%; E9, 7%) in the CSF of infants accounted for two-thirds of all detections, and PeV-A3 was the leading picornavirus detected. Routine testing and reporting of PeV-A in addition to EV, especially in children under 6 months old with acute febrile illnesses, could reduce hospital stays and antibiotic usage.
To describe general practitioner's (GP's) current management of rotator cuff related shoulder pain (RCRP) in Australia and identify if this is consistent with recommended care and best available ...evidence. The secondary aim was to determine if GP management of RCRP changed over time.
Data about management of RCRP by Australian GPs was extracted from the Bettering the Evaluation of Care of Health program database over its final five years (April 2011-March 2016). Patient and GP characteristics and encounter management data were extracted. Results are reported using descriptive statistics with point estimates and 95% confidence intervals. A secondary analysis over a 16 year period (2000-2016) examined management data for RCRP in four year periods.
RCRP was the most common shoulder condition managed by GPs at 5.12 per 1,000 encounters; and at an estimated 732,000 times nationally in 2015-2016. Management rate was higher among male patients (5.5 per 1000 encounters c.f. 4.8 for female patients) and was highest in the 45-64 year old age group (8.6 per 1000). RCRP was most frequently managed with medications (54.7%), steroid injection (19.5%) followed by non-steroidal anti-inflammatory drugs (NSAIDs) (19.1%). Imaging was ordered for 43.4% (ultrasound 41.2% and x-ray 11.6%) of all RCRP presentations (new and returning). Over half (53.0%) of new RCRP presentations were referred for ultrasound imaging. In the 16 year period 2000-16 ultrasound imaging more than doubled from 19.1% to 41.9% of management occasions. In parallel, prescribed steroid injection increased from 9.8% to 19.7%.
The usual care provided by GPs for RCRP relies on the use of ultrasound and steroid injection. This is not consistent with recommended care and clinical guidelines that recommend these are delayed until after 6-12 weeks of NSAID medication, exercise and activity modification. There has been a significant increase in the rate of steroid injection and ultrasound imaging, which may be due in part to policy change.
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