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Borrelia spirochetes are the causative agents of Lyme disease and relapsing fever, two of the most common tick-borne illnesses. A characteristic feature of these spirochetes is their highly segmented genomes which consists of a linear chromosome and a mixture of up to approximately 24 linear and circular extrachromosomal plasmids. The complexity of this genomic arrangement requires multiple strategies for efficient replication and partitioning during cell division, including the generation of hairpin ends found on linear replicons mediated by the essential enzyme ResT, a telomere resolvase. Using an integrative structural biology approach employing advanced modelling, circular dichroism, X-ray crystallography and small-angle X-ray scattering, we have generated high resolution structural data on ResT from B. garinii. Our data provides the first high-resolution structures of ResT from Borrelia spirochetes and revealed active site positioning in the catalytic domain. We also demonstrate that the C-terminal domain of ResT is required for both transesterification steps of telomere resolution, and is a requirement for DNA binding, distinguishing ResT from other telomere resolvases from phage and bacteria. These results advance our understanding of the molecular function of this essential enzyme involved in genome maintenance in Borrelia pathogens.
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Proteínas de Bactérias , Telômero , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Telômero/metabolismo , Cristalografia por Raios X , Modelos Moleculares , Grupo Borrelia Burgdorferi/genética , Grupo Borrelia Burgdorferi/enzimologia , Domínio Catalítico , Domínios Proteicos , Doença de Lyme/microbiologia , EndodesoxirribonucleasesRESUMO
BACKGROUND: Total hip arthroplasty (THA) has become a common intervention for human immunodeficiency virus (HIV)-positive patients who have osteonecrosis of the femoral head. This paper provides a systematic review to assess survivorships, patient-reported outcomes (PROMs), infection rates, other complications, and immune competence for patients who had THAs who did and did not have HIV. METHODS: A comprehensive and systematic review of published studies investigating the outcomes of THA in HIV-positive patients (osteonecrosis and non-osteonecrosis patients) was performed adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 10 studies with 9,534 HIV-positive patients fulfilled the inclusion and exclusion criteria. Manuscript quality was assessed on 2 scales: the Coleman Methodology Score and the level of evidence derived from Center for Evidence-Based Medicine criteria. Data were extracted from studies in the 5 key areas of interest: survivorships, PROMs, infection rates, complications, and clusters of differentiation-4 (CD4+) counts and viral loads. RESULTS: Implant survivorship was between 95% and 100%. Postoperative Harris Hip Scores were significantly improved from preoperative values in HIV-positive patients. Postoperative PROMs and infections did not appear to be different between HIV-positive and HIV-negative patients. Many of the cohort studies demonstrate comparable complication rates to matched controls. Where described (7 reports), mean CD4+ counts ranged from 425 to 646 cells/mm3, with low viral loads (3 reports) and variations not found to influence outcomes. CONCLUSIONS: THA is an effective treatment for HIV-positive patients, many of whom suffer from osteonecrosis of the femoral head. The results demonstrate excellent implant survivorship, improved quality of life, and a low risk of infections and complications.
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Artroplastia de Quadril , Necrose da Cabeça do Fêmur , Humanos , Necrose da Cabeça do Fêmur/cirurgia , Infecções por HIV/complicações , Medidas de Resultados Relatados pelo Paciente , Complicações Pós-Operatórias/epidemiologia , Resultado do TratamentoRESUMO
The chemistry and physics of macropolyhedral B18H22 clusters have attracted significant attention due to the interesting photophysical properties of anti-B18H22 (blue emission, laser properties) and related potential applications. We have focused our attention on the "forgotten" syn-B18H22 isomer, which has received very little attention since its discovery compared to its anti-B18H22 isomer, presumably because numerous studies have reported this isomer as nonluminescent. In our study, we show that in crystalline form, syn-B18H22 exhibits blue fluorescence and becomes phosphorescent when substituted at various positions on the cluster, associated with peculiar microstructural-dependent effects. This work is a combined theoretical and experimental investigation that includes the synthesis, separation, structural characterization, and first elucidation of the photophysical properties of three different monothiol-substituted cluster isomers, [1-HS-syn-B18H21] 1, [3-HS-syn-B18H21] 3, and [4-HS-syn-B18H21] 4, of which isomers 1 and 4 have been proved to exist in two different polymorphic forms. All of these newly substituted macropolyhedral cluster derivatives (1, 3, and 4) have been fully characterized by NMR spectroscopy, mass spectrometry, single-crystal X-ray diffraction, IR spectroscopy, and luminescence spectroscopy. This study also presents the first report on the mechanochromic shift in the luminescence of a borane cluster and generally enriches the area of rather rare boron-based luminescent materials. In addition, we present the first results proving that they are useful constituents of carbon-free self-assembled monolayers.
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ABSTRACT: COVID-19 infection and long COVID affect multiple organ systems, including the respiratory, cardiovascular, renal, digestive, neuroendocrine, musculoskeletal systems, and sensory organs. Exerkines, released during exercise, have a potent crosstalk effect between multiple body systems. This review describes the evidence of how exerkines can mitigate the effects of COVID-19 in each organ system that the virus affects. The evidence presented in the review suggests that exercise should be considered a first-line strategy in the prevention and treatment of COVID-19 infection and long COVID disease.
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COVID-19 , Humanos , Síndrome de COVID-19 Pós-Aguda , Exercício FísicoRESUMO
OBJECTIVE: To determine the association between directly measured physical activity and hospitalisation, intensive care unit (ICU) admission, ventilation and mortality rates in patients with a confirmed diagnosis of COVID-19. METHODS: Directly measured physical activity data from 65 361 adult patients with a COVID-19 diagnosis from 19 March 2020 to 30 June 2021, were grouped by activity level: low (<60 min/week), moderate (60-149 min/week) and high activity (≥150 min/week). The association of physical activity levels and the risk of adverse outcomes was analysed using modified Poisson regression. We accounted for demographics and comorbidities including conditions known to influence COVID-19 outcomes, as well as patient complexity as measured by the Johns Hopkins Adjusted Clinical Group system. The regression approach was further validated with a Bayesian network model built off a directed acyclic graph. RESULTS: High physical activity was associated with lower rates of hospitalisation (risk ratio, RR 0.66, 95% CI 0.63 to 0.70), ICU admission (RR 0.59, 95% CI 0.52 to 0.66), ventilation (RR 0.55, 95% CI 0.47 to 0.64) and death (RR 0.58, 95% CI 0.50 to 0.68) due to COVID-19 than those who engaged in low physical activity. Moderate physical activity also was associated with lower rates of hospitalisation (RR 0.87, 95% CI 0.82 to 0.91), admission to ICU (RR 0.80, 95% CI 0.71 to 0.89), ventilation (RR 0.73, 95% CI 0.62 to 0.84) and death (RR 0.79, 95% CI 0.69 to 0.91). CONCLUSIONS: Adults with high and moderate physical activity levels had significantly better outcomes than those with low activity when contracting COVID-19. The apparent protective effects of regular physical activity extended to those with concomitant chronic medical conditions.
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COVID-19 , Adulto , Teorema de Bayes , Teste para COVID-19 , Exercício Físico , Humanos , SARS-CoV-2RESUMO
Subcutaneous emphysema is commonly associated with infection caused by gas-producing organisms. In this case report, we describe a rare instance of traumatic subcutaneous emphysema of the hand and forearm caused by a puncture injury to the first web space of the hand. Our objective is to increase awareness of the potential for seemingly minor trauma to cause entrapment of significant air in subcutaneous tissues, thereby decreasing the likelihood that a clinically benign-appearing patient will be started down an unnecessarily aggressive treatment pathway. A 16-year-old, otherwise healthy white female, presented to the pediatric emergency room with an impressive amount of subcutaneous emphysema that developed over a 12-h period after sustaining an accidental laceration to the first web space of her right hand. She appeared nontoxic and had a clinically benign presentation. A comprehensive work-up was performed. She was splinted by the orthopedic surgery resident on call, and was admitted to the Pediatric Intensive Care Unit for overnight monitoring. She received tetanus vaccination and broad-spectrum antibiotics. The patient was discharged 2 days after admittance, with a splint applied to her right hand and forearm. She undertook home-based physical and occupational therapy. She had a pain-free range-of-motion in the right wrist, elbow and shoulder. The swelling in the right hand subsided completely. Although initially alarming, traumatic subcutaneous emphysema in an otherwise healthy patient from minor wounds (as featured in this case) does not necessarily mean one ought to proceed down an aggressive treatment algorithm. Careful evaluation of the patient's history, clinical examination findings, and determination of the Laboratory Risk Indicator for Necrotizing Fasciitis score can help guide physicians in the management of traumatic subcutaneous emphysema and potentially avoid unnecessary and costly interventions.
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Enfisema Subcutâneo , Ferimentos Penetrantes , Humanos , Criança , Feminino , Adolescente , Antebraço , Enfisema Subcutâneo/etiologia , Enfisema Subcutâneo/terapia , Enfisema Subcutâneo/diagnóstico , Extremidade Superior , Antibacterianos/uso terapêutico , Ferimentos Penetrantes/cirurgiaRESUMO
Fractures of the radius and ulna are the most common fractures of the upper extremity, with distal fractures occurring more often than proximal fractures. A fall onto an outstretched hand is the most common mechanism of injury for fractures of the radius and ulna. Evaluation with radiography or ultrasonography usually can confirm the diagnosis. If initial imaging findings are negative and suspicion of fracture remains, splinting and repeat radiography in seven to 14 days should be performed. Incomplete compression fractures without cortical disruption, called buckle (torus) fractures, are common in children. Greenstick fractures, which have cortical disruption, are also common in children. Depending on the degree of angulation, buckle and greenstick fractures can be managed with immobilization. In adults, distal radius fractures are the most common forearm fractures and are typically caused by a fall onto an outstretched hand. A nondisplaced, or minimally displaced, distal radius fracture is initially treated with a sugar-tong splint, followed by a short-arm cast for a minimum of three weeks. It should be noted that these fractures may be complicated by a median nerve injury. Isolated midshaft ulna (nightstick) fractures are often caused by a direct blow to the forearm. These fractures are treated with immobilization or surgery, depending on the degree of displacement and angulation. Combined fractures involving both the ulna and radius generally require surgical correction. Radial head fractures may be difficult to visualize on initial imaging but should be suspected when there are limitations of elbow extension and supination following trauma. Treatment of radial head fractures depends on the specific characteristics of the fracture using the Mason classification.
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Fraturas do Rádio/terapia , Fraturas da Ulna/terapia , Adulto , Criança , Humanos , Imobilização/métodos , Exame Físico , Radiografia , Fraturas do Rádio/classificação , Fraturas do Rádio/diagnóstico , Fraturas da Ulna/classificação , Fraturas da Ulna/diagnóstico , UltrassonografiaRESUMO
BACKGROUND: The HealthyFood (HF) program offers members up to 25% cash back monthly on healthy food purchases. In this randomized controlled trial, we tested the efficacy of financial incentives combined with text messages in increasing healthy food purchases among HF members. METHODS: Members receiving the lowest (10%) cash back level were randomized to one of six arms: Arm 1 (Usual Care): 10% cash back, no weekly text, standard monthly text; Arm 2: 10% cash back, generic weekly text, standard monthly text; Arm 3: 10% cash back, personalized weekly text, standard monthly text; Arm 4: 25% cash back, personalized weekly text, standard monthly text; Arm 5: 10 + 15%NET cash back, personalized weekly text, standard monthly text; and, Arm 6: 10 + 15%NET cash back, personalized weekly text, unbundled monthly text. In the 10 + 15%NET cash back, the cash back amount was the baseline 10% plus 15% of the net difference between healthy and unhealthy spending. The generic text included information on HF and healthy eating, while the personalized text had individualized feedback on purchases. The standard monthly text contained the cash back amount. The unbundled monthly text included the amount lost due to unhealthy purchases. The primary outcome was the average monthly percent healthy food spending. Secondary outcomes were the percent unhealthy food spending, and the percent healthy and unhealthy food items. RESULTS: Of the members contacted, 20 opted out, and 2841 met all inclusion criteria. There were no between-arm differences in the examined outcomes. The largest mean (standard deviation) difference in percent healthy spending was between Arm 1 (24.8% [11%]) and Arm 2 (26.8% [13%]), and the largest mean difference in percent unhealthy spending was also between Arm 1 (24.4% [20%]) and Arm 2 (21.7% [17%]), but no differences were statistically significant after correction for multiple comparisons. CONCLUSIONS: None of the tested financial incentive structures or text strategies differentially affected food purchasing. Notably, more than doubling the cash back amount and introducing a financial disincentive for unhealthy purchases did not affect purchasing. These findings speak to the difficulty of changing shopping habits and to the need for innovative strategies to shift complex health behaviors. TRIAL REGISTRATION: NCT02486588 Increasing Engagement with a Healthy Food Benefit. The trial was prospectively registered on July 1, 2015.
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Comportamento do Consumidor/economia , Dieta Saudável/economia , Retroalimentação , Motivação , Envio de Mensagens de Texto , Adulto , Comportamento do Consumidor/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Programas e Projetos de SaúdeRESUMO
This paper is concerned with predicting the progressive damage and failure of multi-layered hybrid textile composites subjected to uniaxial tensile loading, using a novel two-scale computational mechanics framework. These composites include three-dimensional woven textile composites (3DWTCs) with glass, carbon and Kevlar fibre tows. Progressive damage and failure of 3DWTCs at different length scales are captured in the present model by using a macroscale finite-element (FE) analysis at the representative unit cell (RUC) level, while a closed-form micromechanics analysis is implemented simultaneously at the subscale level using material properties of the constituents (fibre and matrix) as input. The N-layers concentric cylinder (NCYL) model (Zhang and Waas 2014 Acta Mech. 225, 1391-1417; Patel et al. submitted Acta Mech.) to compute local stress, srain and displacement fields in the fibre and matrix is used at the subscale. The 2-CYL fibre-matrix concentric cylinder model is extended to fibre and (N-1) matrix layers, keeping the volume fraction constant, and hence is called the NCYL model where the matrix damage can be captured locally within each discrete layer of the matrix volume. The influence of matrix microdamage at the subscale causes progressive degradation of fibre tow stiffness and matrix stiffness at the macroscale. The global RUC stiffness matrix remains positive definite, until the strain softening response resulting from different failure modes (such as fibre tow breakage, tow splitting in the transverse direction due to matrix cracking inside tow and surrounding matrix tensile failure outside of fibre tows) are initiated. At this stage, the macroscopic post-peak softening response is modelled using the mesh objective smeared crack approach (Rots et al. 1985 HERON 30, 1-48; Heinrich and Waas 2012 53rd AIAA/ASME/ASCE/AHS/ASC Structures, Structural Dynamics and Materials Conference, Honolulu, HI, 23-26 April 2012 AIAA 2012-1537). Manufacturing-induced geometric imperfections are included in the simulation, where the FE mesh of the unit cell is generated directly from micro-computed tomography (MCT) real data using a code Simpleware Results from multi-scale analysis for both an idealized perfect geometry and one that includes geometric imperfections are compared with experimental results (Pankow et al. 2012 53rd AIAA/ASME/ASCE/AHS/ASC Structures, Structural Dynamics and Materials Conference, Honolulu, HI, 23-26 April 2012 AIAA 2012-1572). This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'.
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OBJECTIVE: Improving diet quality is a key factor for promoting population health. Social norms can support or undermine these efforts. The present study aimed to investigate the relationship between seasonal variation in food purchases and BMI. DESIGN: The study population comprises members of a South African health promotion programme. Data come from scanner data of food purchases by 400 000 enrolled households at supermarkets and repeated individual surveys (about 500 000 participants) between 2009 and 2013. RESULTS: Members in the health promotion programme spent 16·7 % of total food expenditure on nutritionally undesirable foods (sugar-sweetened beverages, candy, ice cream, etc.) and 24·7 % on healthy foods (fruit/vegetables, whole grains, non-fat dairy, etc.). Fruits and vegetables accounted for 13·5 % of purchases (half of all healthy food spending). Yet there were pronounced seasonal variations, with December being the peak month for unhealthy food purchases, which were 40 % higher than in January. This holiday peak was associated with short-term weight gain, but average body mass did not revert to pre-holiday levels. From 2009 to 2013, respondents gained about 0·13 BMI units per year (0·43 kg for men, 0·30 for women). From November to January alone, the increase was 0·1 BMI units for men (0·35 kg) and 0·8 BMI units for women (0·20 kg). CONCLUSIONS: Purchases of nutritionally undesirable foods peak in December and are accompanied by weight gain from November to January. Despite weight loss after January, the November to January weight gain accounts for 60-70 % of the annual gain.
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Índice de Massa Corporal , Comportamento do Consumidor , Dieta , Promoção da Saúde , Estações do Ano , Bebidas , Feminino , Humanos , Masculino , África do SulRESUMO
Leadership support has been identified as an essential component of successful workplace health promotion (WHP) programs. However, there is little research in this area and even less theoretical conceptualization on ways in which leadership support for WHP is related to improved employee wellbeing. In this paper, we developed and tested a model of leadership support for WHP and employee wellbeing outcomes using employer and employee data gathered from 71 South African organizations. A theoretical model based on social exchange theory was developed. It was hypothesized that perceptions of company commitment to health promotion mediates the relationship between leadership support, the provision of WHP facilities and employee wellbeing. A hierarchical structural equation modeling technique was used to test the model. We determined that leaders' support for WHP was important insofar as they also provided health promotion facilities to their employees. No direct relationship was found between leadership support alone and employee wellbeing.
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Promoção da Saúde/organização & administração , Nível de Saúde , Liderança , Cultura Organizacional , Local de Trabalho/organização & administração , Adulto , Esgotamento Profissional/epidemiologia , Feminino , Humanos , Relações Interpessoais , Satisfação no Emprego , Masculino , Pessoa de Meia-Idade , Saúde Ocupacional , África do SulRESUMO
Herpes simplex encephalitis (HSE) is the most common single cause of viral encephalitis in infants and children. Treated or untreated, it can be associated with considerable morbidity and mortality, and its presentation is usually insidious and non-specific. Prompt and careful investigation is important in order to establish the diagnosis so that treatment can be optimised. We address some common questions arising when diagnosing and treating presumed HSE throughout childhood.
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Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Criança , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
We tested a voluntary self-control commitment device to help grocery shoppers make healthier food purchases. Participants, who were already enrolled in a large-scale incentive program that discounts the price of eligible groceries by 25%, were offered the chance to put their discount on the line. Agreeing households pledged that they would increase their purchases of healthy food by 5 percentage points above their household baseline for each of 6 months. If they reached that goal, their discount was awarded as usual; otherwise, their discount was forfeited for that month. Thirty-six percent of households that were offered the binding commitment agreed; they subsequently showed an average 3.5-percentage-point increase in healthy grocery items purchased in each of the 6 months; households that declined the commitment and control-group households that were given a hypothetical option to precommit did not show such an increase. These results suggest that self-aware consumers will seize opportunities to create restrictive choice environments for themselves, even at some risk of financial loss.
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Comportamento de Escolha , Comportamento do Consumidor/economia , Comportamentos Relacionados com a Saúde , Recompensa , Adulto , HumanosRESUMO
In an effort to explore the coordination chemistry of the coordinative sulfur centers in arachno-ruthenaborane [(Cp*Ru)2(B3H8)(CS2H)] (arachno-1), we have thermolyzed arachno-1 with group-6 metal carbonyls [M(CO)5·THF] (M = Cr, Mo and W). The reaction of arachno-1 with [Cr(CO)5·THF] resulted in the formation of hetero-trimetallic triply bridging borylene [(Cp*Ru)2(µ-CO)(µ3-CH2S2-κ2S':κ2S''){Cr(CO)3}(µ3-BH)] (2), bridging boryl-borylene [(Cp*Ru)2(µ-CO){(µ3-BH(CH2S2)-κ2B:κ2S':κ1S'')}{Cr(CO)3}(µ3-BH)] (3), and sulfido bridged hetero-trimetallic complex [(Cp*Ru)2(µ-CO)3{Cr(CO)3}(µ3-S)] (4). In 2, one side of Ru2Cr-triangle features a µ3-BH ligand while the other side is quadruply bridged by a methanedithiolato ligand in an unsymmetrical fashion. Unlike 2, in complex 3, one side of the Ru2Cr-triangle has a µ3-BH ligand while the opposite side is bridged by a boryl ligand BH(CH2S2) in an unsymmetrical way (µ3-κ2:κ2:κ1) to the metal centers. Interestingly, when the similar reactions of arachno-1 were performed with heavier group-6 metal carbonyls [M(CO)5·THF] (M = Mo and W), it led to the formation of methanedithiolato bridged hetero-trimetallic chain complexes, [{Cp*Ru(CO)}2(µ-CO)2(µ3-CH2S2-κ2S':κ2S''){M(CO)2}] (5, M = Mo; 6, M = W) and sulfido-bridged hetero-trimetallic complexes [(Cp*Ru)2(µ-CO)3{M(CO)3}(µ3-S)] (7, M = Mo; 8, M = W), analogous to 4. In complexes 5 and 6, a Ru2M-chain is symmetrically bridged by a methanedithiolato ligand. On the other hand, in complexes 4, 7, and 8, a sulfido ligand coordinates to two ruthenium and one group-6 metal atoms in µ3-fashion. All the complexes have been characterized by 1H NMR, 13C NMR, UV-vis, IR spectroscopy, and mass spectrometry and their structural architectures have been unambiguously established by single crystal X-ray diffraction studies. In addition, theoretical investigations provided valuable insights into their electronic structures and bonding properties.
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Background: Total knee arthroplasty (TKA) has become a common surgical intervention for human immunodeficiency virus (HIV)-positive patients who develop osteonecrosis of the knee. This paper summarized existing literature regarding the outcomes of HIV-positive patients undergoing TKA in 4 subsections: (1) complications; (2) survivorship analyses; (3) patient-reported outcomes; and (4) infections. Methods: A review of PubMed was performed, searching for articles focused on HIV-positive patients undergoing TKA. There were 6 reports selected, containing 4765 HIV-positive patients, and data regarding the various domains was tabulated and analyzed. To ensure article quality, a methodology score and level of evidence were determined for selected studies. Results: Complication rates for HIV-positive patients were low, with a larger study reporting that 7.8% of HIV-positive patients developed a complication in comparison to 8% of HIV-negative patients. Survivorship analyses showed similar results, with a study reporting implant survivorship of 98% for HIV-positive and 99% for HIV-negative patients. There were no differences in patient-reported outcomes; HIV-positive patients improved from baseline with respect to the mean Knee Society objective and mean Knee Society functional scores, and the University of California, Los Angeles self-reported activity levels. The infection rate for HIV-positive patients was low, with a larger database study reporting that 0.6% of HIV-positive patients developed a wound infection in comparison to 0.4% of HIV-negative patients. Conclusions: A TKA is an effective treatment for HIV-positive patients who develop osteonecrosis of the knee. Results showed similar patient-reported outcomes, implant survivorships, revisions, and complication rates when compared to non-HIV patients.
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The survival of Legionella spp. as intracellular pathogens relies on the combined action of protein effectors delivered inside their eukaryotic hosts by the Dot/Icm (defective in organelle trafficking/intracellular multiplication) type IVb secretion system. The specific repertoire of effector arsenals varies dramatically across over 60 known species of this genera with Legionella pneumophila responsible for most cases of Legionnaires' disease in humans encoding over 360 Dot/Icm effectors. However, a small subset of "core" effectors appears to be conserved across all Legionella species raising an intriguing question of their role in these bacteria's pathogenic strategy, which for most of these effectors remains unknown. L. pneumophila Lpg0103 effector, also known as VipF, represents one of the core effector families that features a tandem of Gcn5-related N-acetyltransferase (GNAT) domains. Here, we present the crystal structure of the Lha0223, the VipF representative from Legionella hackeliae in complex with acetyl-coenzyme A determined to 1.75 Å resolution. Our structural analysis suggested that this effector family shares a common fold with the two GNAT domains forming a deep groove occupied by residues conserved across VipF homologs. Further analysis suggested that only the C-terminal GNAT domain of VipF effectors retains the active site composition compatible with catalysis, whereas the N-terminal GNAT domain binds the ligand in a non-catalytical mode. We confirmed this by in vitro enzymatic assays which revealed VipF activity not only against generic small molecule substrates, such as chloramphenicol, but also against poly-L-lysine and histone-derived peptides. We identified the human eukaryotic translation initiation factor 3 (eIF3) complex co-precipitating with Lpg0103 and demonstrated the direct interaction between the several representatives of the VipF family, including Lpg0103 and Lha0223 with the K subunit of eIF3. According to our data, these interactions involve primarily the C-terminal tail of eIF3-K containing two lysine residues that are acetylated by VipF. VipF catalytic activity results in the suppression of eukaryotic protein translation in vitro, revealing the potential function of VipF "core" effectors in Legionella's pathogenic strategy.IMPORTANCEBy translocating effectors inside the eukaryotic host cell, bacteria can modulate host cellular processes in their favor. Legionella species, which includes the pneumonia-causing Legionella pneumophila, encode a widely diverse set of effectors with only a small subset that is conserved across this genus. Here, we demonstrate that one of these conserved effector families, represented by L. pneumophila VipF (Lpg0103), is a tandem Gcn5-related N-acetyltransferase interacting with the K subunit of human eukaryotic initiation factor 3 complex. VipF catalyzes the acetylation of lysine residues on the C-terminal tail of the K subunit, resulting in the suppression of eukaryotic translation initiation factor 3-mediated protein translation in vitro. These new data provide the first insight into the molecular function of this pathogenic factor family common across Legionellae.
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Legionella pneumophila , Legionella , Doença dos Legionários , Humanos , Acetiltransferases/metabolismo , Fator de Iniciação 3 em Eucariotos/metabolismo , Lisina/metabolismo , Fator de Iniciação 3 em Procariotos/metabolismo , Legionella/genética , Legionella pneumophila/genética , Biossíntese de Proteínas , Proteínas de Bactérias/metabolismoRESUMO
Antimicrobial agents are essential in reducing illness and mortality brought on by infectious diseases in both humans and animals. However, the therapeutic effect of antibiotics has diminished due to an increase in antimicrobial drug resistance (AMR). This article provides a retrospective analysis of AMR in Shigella infections in India, showing a rise in resistance that has contributed to a global burden. Shigella spp. are widespread and the second-leading cause of diarrheal death in people of all ages. The frequency and mortality rates of Shigella infections are decreased by antibiotic treatment. However, the growth of broad-spectrum antibiotic resistance is making it more difficult to treat many illnesses. Reduced cell permeability, efflux pumps, and the presence of enzymes that break down antibiotics are the causes of resistance. AMR is a multifaceted and cross-sectoral problem that affects humans, animals, food, and the environment. As a result, there is a growing need for new therapeutic approaches, and ongoing surveillance of Shigella spp. infections which should definitely be improved for disease prevention and management. This review emphasizes on the epidemiological data of India, and antimicrobial resistance in Shigella spp.
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Antibacterianos , Farmacorresistência Bacteriana , Disenteria Bacilar , Shigella , Humanos , Índia/epidemiologia , Shigella/efeitos dos fármacos , Disenteria Bacilar/tratamento farmacológico , Disenteria Bacilar/epidemiologia , Disenteria Bacilar/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , AnimaisRESUMO
Legionella are freshwater Gram-negative bacteria that in their normal environment infect protozoa. However, this adaptation also allows Legionella to infect human alveolar macrophages and cause pneumonia. Central to Legionella pathogenesis are more than 330 secreted effectors, of which there are nine core effectors that are conserved in all pathogenic species. Despite their importance, the biochemical function of several core effectors remains unclear. To address this, we have taken a structural approach to characterize the core effector of unknown function LceB, or Lpg1356, from Legionella pneumophila. Here, we solve an X-ray crystal structure of LceB using an AlphaFold model for molecular replacement. The experimental structure shows that LceB adopts a Sel1-like repeat (SLR) fold as predicted. However, the crystal structure captured multiple conformations of LceB, all of which differed from the AlphaFold model. A comparison of the predicted model and the experimental models suggests that LceB is highly flexible in solution. Additionally, the molecular analysis of LceB using its close structural homologs reveals sequence and structural motifs of known biochemical function. Specifically, LceB harbors a repeated KAAEQG motif that both stabilizes the SLR fold and is known to participate in protein-protein interactions with eukaryotic host proteins. We also observe that LceB forms several higher-order oligomers in solution. Overall, our results have revealed that LceB has conformational flexibility, self-associates, and contains a molecular surface for binding a target host-cell protein. Additionally, our data provides structural insights into the SLR family of proteins that remain poorly studied.