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Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy.
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Inmunoglobulina M , Embarazo , Infección por el Virus Zika , Virus Zika , Animales , Femenino , Ratones , Embarazo/inmunología , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Epítopos , Pruebas de Neutralización , Infección por el Virus Zika/inmunología , Inmunoglobulina M/inmunología , Inmunoglobulina M/aislamiento & purificaciónRESUMEN
Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state-dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV-induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcγ receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM+ virions can also contribute to pathogenesis during primary DENV infections.
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Anticuerpos Monoclonales , Anticuerpos Antivirales , Virus del Dengue , Dengue , Microscopía por Crioelectrón , Proteínas del Envoltorio Viral/metabolismo , Virión/metabolismo , Animales , RatonesRESUMEN
BACKGROUND: Understanding the role of social determinants of health disparities (SDHDs) in surgical outcomes can better prepare providers to improve postoperative care. In this study, we use International Classification of Diseases (ICD) codes to identify SDHDs and investigate the risk of postoperative complication rates among patients undergoing total shoulder arthroplasty (TSA). METHODS: A retrospective cohort analysis was conducted using a national insurance claims database. Using ICD and Current Procedural Terminology (CPT) codes, patients who underwent primary TSA with at least 2 years of follow-up in the database were identified. Patients with a history of SDHDs were identified using appropriate ICD-9 and ICD-10 codes. Patients were grouped in one of 2 cohorts: (1) patients with no history of SDHDs (control) and (2) patients with a history of SDHDs (SDHD group) prior to TSA. The SDHD and control groups were matched 1:1 for comorbidities and demographics prior to conducting multivariable analysis for 90-day medical complications and 2-year surgical complications. RESULTS: After matching, there were 8023 patients in the SDHD group and 8023 patients in the control group. The SDHD group had significantly higher odds for 90-day medical complications including heart failure, cerebrovascular accident, renal failure, deep vein thrombosis, pneumonia, sepsis, and urinary tract infection. Additionally, the SDHD group had significantly higher odds for revision surgery within 2 years following TSA. Patients in the SDHD group also had a significantly longer length of hospital stay following TSA. DISCUSSION: This study highlights the association between SDHDs and postoperative complications following TSA. Quantifying the risk of complications and differences in length of stay for TSA patients with a history of SDHDs is important in determining value-based payment models and risk stratifying to optimize patient care.
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Artroplastía de Reemplazo de Hombro , Humanos , Estudios Retrospectivos , Artroplastía de Reemplazo de Hombro/efectos adversos , Determinantes Sociales de la Salud , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , ComorbilidadRESUMEN
BACKGROUND: Recurrent anterior shoulder instability remains the most common complication from a prior shoulder dislocation, especially among young and active individuals who engage in athletic activities. This instability can lead to repeated subluxation or dislocations of the humeral head from the glenoid fossa. The purpose of this study is to compare postoperative recurrence rates, instability-related revision and return to sport (RTS) rates between isolated arthroscopic Bankart repair (ABR) and ABR with remplissage (ABR + R) for anterior shoulder instability with subcritical glenoid bone loss (GBL) and a Hill-Sachs lesion (HSL). METHODS: PubMed, Embase, and Web of Science were searched on June 2022. Studies sought were those comparing postoperative outcomes of ABR + R versus isolated ABR for subcritical GBL and an HSL. Study quality was evaluated using the revised Cochrane tool. Redislocations, instability-related revisions, and RTS rates were extracted and pooled estimates were calculated using the random-effect model. RESULTS: Twelve studies were included with a mean follow-up of 48.2 months for isolated ABR and 43.2 months for ABR + R. The meta-analytic comparison demonstrated that ABR + R resulted in statistically significant improvement in Rowe and American Shoulder and Elbow Surgeons scores by 6.5 and 2.2 points, respectively; however, the improvements in patient-reported outcomes were not clinically meaningful. ABR + R resulted in reduced external rotation at the side by 1° which was not clinically meaningful and there was no significant difference in terms of forward elevation. ABR + R resulted in a statistically significant reduction of overall postoperative recurrences (odds ratio [OR]: 9.36), postoperative dislocations (OR: 6.28), instability-related revision (OR: 3.46), and RTS to any level (OR: 2.85). CONCLUSION: The addition of remplissage to ABR for recurrent anterior shoulder instability with subcritical GBL and HSL results in significantly lower postoperative instability recurrence, lower instability-related revisions, and higher RTS to any level.
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Artroscopía , Lesiones de Bankart , Inestabilidad de la Articulación , Reoperación , Volver al Deporte , Luxación del Hombro , Humanos , Artroscopía/métodos , Lesiones de Bankart/cirugía , Inestabilidad de la Articulación/cirugía , Luxación del Hombro/cirugía , Articulación del Hombro/cirugía , Articulación del Hombro/fisiopatología , RecurrenciaRESUMEN
BACKGROUND: Orthopedic residency and fellowship applicants with a strong research record are highly valued for their potential in continuing academic excellence. Despite this, the association between research productivity during training and future academic productivity as an attending orthopedic surgeon is not well-established. We assess the effects of research output during different periods of surgical training as well as residency location on long-term academic productivity as an attending shoulder and elbow surgeon. METHODS: A search of the 2022-2023 American Shoulder and Elbow Surgeons Fellowship Directory was conducted to identify a list of orthopedic shoulder and elbow fellowship faculty members. Each surgeon's residency, fellowship and current institution of practice were determined and stratified by geographic location. Total publication counts acquired before residency, during residency, during fellowship, and after fellowship were collected for each faculty member. Attending publication rates and H-indices were calculated. A multivariate linear regression model was created, and significance was set at a P value <.05. RESULTS: A total of 149 shoulder and elbow fellowship faculty members representing 34 fellowship programs were identified. The average number of total publications per surgeon was 88.8 ± 102. The average attending publication rate was 5.29 ± 6.89 publications per year. The average H-index for included surgeons was 27.8 ± 24.4. The number of publications acquired before residency (ß = 0.293; P < .001), during residency (ß = 0.110; P = .025) and during fellowship (ß = 0.593; P < .001) were significantly associated with an increased attending publication rate, but no association was observed with the H-index [before residency (ß = -0.221; P = .574), during residency (ß = 0.045; P = .866), during fellowship (ß = 0.198; P = .678)]. There were no significant differences in total publication count (P = .397), attending publication rate (P = .237), or H-index (P = .364) based on location of residency training. DISCUSSION: Research output before and during surgical training is predictive of continued academic productivity as a shoulder and elbow surgeon. In particular, greater productivity during surgical fellowship was most predictive of academic output as an attending. While long-term academic productivity does not seem to be influenced by the geographic location of residency training, attending surgeons practicing in the Midwest had significantly greater total publication counts and H-indices but similar annual publication rates.
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Zika virus (ZIKV) is a major human pathogen and member of the Flavivirus genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-resolution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.
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Anticuerpos Monoclonales/inmunología , Epítopos/inmunología , Infección por el Virus Zika/inmunología , Virus Zika/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Microscopía por Crioelectrón/métodos , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Vacunación/métodos , Proteínas del Envoltorio Viral/inmunologíaRESUMEN
BACKGROUND: Patients today have access to an increasing number of health resources to guide medical decision making, including specialist health care providers, the Internet, friends, and family members. No prior studies, to our knowledge, have comprehensively explored health information-seeking behavior (HISB) for patients being managed for shoulder pain. OBJECTIVE: Our primary objective is to identify which health resources patients use and find helpful in a cohort of patients being either evaluated or managed for shoulder pain. With increased access to the Internet and its use, we also hope to quantify the extent of use of Internet resources and identify predictors of patient use. METHODS: We interviewed a cohort of new and follow-up patients being surgically or nonoperatively managed for shoulder pain by a single fellowship-trained orthopedic surgeon. All patients were administered a questionnaire to determine HISB, which evaluated the types of resources used and those deemed most helpful in guiding medical decision making. For patients using the Internet, specific websites were documented. Additional variables that were collected included age, gender, ethnicity, and highest education attained. Multivariable logistic regression was used to evaluate predictors of Internet use. RESULTS: This study included 242 patients. A discussion with an orthopedic surgeon was reported to be the most informative for nonoperatively treated patients, first postoperative patients, and operative follow-up patients. Patients at the first postoperative visit reported YouTube as their preferred resource almost 4 times more than new patients (odds ratio [OR] 3.9, P = .015). Search engine use was significantly higher in patients at the first postoperative visit (OR 5.8, P = .004) and patients at subsequent surgical follow-up (OR 8.3, P = .001) compared with new patients. Having an undergraduate (OR 0.1, P = .037) or graduate degree (OR 0.03, P = .01) had a significant inverse association with difficulty of using Internet resources. Patients of Black race reported significantly higher rates of distrust for Internet resources than those of White race (OR 5.8, P < .001). CONCLUSION: This study highlights the patterns of HISB among patients with shoulder conditions. A face-to-face discussion with a physician or a shoulder surgeon was the most crucial resource for information compared to other resources. This study has also defined the preferred Internet resources for patients at different time points of care and the reasons for refraining from seeking health information on the Internet. Such findings can aid shoulder surgeons in understanding the optimal methods for delivering health information for different patient demographics and different phases of their care.
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Conducta en la Búsqueda de Información , Hombro , Humanos , Internet , Dolor de Hombro/terapia , Estudiantes , Encuestas y CuestionariosRESUMEN
AIM: There is a requirement for an expansive and up to date review of the management of emergency colorectal conditions seen in adults. The primary objective is to provide detailed evidence-based guidelines for the target audience of general and colorectal surgeons who are responsible for an adult population and who practise in Great Britain and Ireland. METHODS: Surgeons who are elected members of the Association of Coloproctology of Great Britain and Ireland Emergency Surgery Subcommittee were invited to contribute various sections to the guidelines. They were directed to produce a pathology-based document using literature searches that were systematic, comprehensible, transparent and reproducible. Levels of evidence were graded. Each author was asked to provide a set of recommendations which were evidence-based and unambiguous. These recommendations were submitted to the whole guideline group and scored. They were then refined and submitted to a second vote. Only those that achieved >80% consensus at level 5 (strongly agree) or level 4 (agree) after two votes were included in the guidelines. RESULTS: All aspects of care (excluding abdominal trauma) for emergency colorectal conditions have been included along with 122 recommendations for management. CONCLUSION: These guidelines provide an up to date and evidence-based summary of the current surgical knowledge in the management of emergency colorectal conditions and should serve as practical text for clinicians managing colorectal conditions in the emergency setting.
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Cirugía Colorrectal , Procedimientos Quirúrgicos del Sistema Digestivo , Consenso , Servicio de Urgencia en Hospital , Humanos , Reino UnidoRESUMEN
Cybercriminals are taking advantage of the COVID-19 outbreak and offering COVID-19-related scams to unsuspecting people. Currently, there is a lack of studies that focus on protecting people from COVID-19-related cybercrimes. Drawing upon Cultivation Theory and Protection Motivation Theory, we develop a research model to examine the cultivation effect of government social media on peoples' information security behavior towards COVID-19 scams. We employ structural equation modeling to analyze 240 survey responses collected from social media followers of government accounts. Our results suggest that government social media account followers' participation influences their information security behavior through perceived severity, perceived vulnerability, self-efficacy, and response efficacy. Our study highlights the importance of government social media for information security management during crises.
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Electrocatalytic water oxidation occurs at fluoride-doped tin oxide (FTO) electrodes that have been surface-modified by addition of Co(II). On the basis of X-ray photoelectron spectroscopy and transmission electron microscopy measurements, the active surface site appears to be a single site or small-molecule assembly bound as Co(II), with no evidence for cobalt oxide film or cluster formation. On the basis of cyclic voltammetry measurements, surface-bound Co(II) undergoes a pH-dependent 1e(-)/1H(+) oxidation to Co(III), which is followed by pH-dependent catalytic water oxidation. O2 reduction at FTO occurs at -0.33 V vs NHE, allowing for in situ detection of oxygen as it is formed by water oxidation on the surface. Controlled-potential electrolysis at 1.61 V vs NHE at pH 7.2 resulted in sustained water oxidation catalysis at a current density of 0.16 mA/cm(2) with 29,000 turnovers per site over an electrolysis period of 2 h. The turnover frequency for oxygen production per Co site was 4 s(-1) at an overpotential of 800 mV at pH 7.2. Initial experiments with Co(II) on a mesoporous, high-surface-area nanoFTO electrode increased the current density by a factor of ~5.
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Cobalto/química , Flúor/química , Oxígeno/análisis , Oxígeno/química , Compuestos de Estaño/química , Agua/química , Electrodos , Oxidación-Reducción , Propiedades de SuperficieRESUMEN
BACKGROUND: In 2009, the American Academy of Orthopaedic Surgeons released a consensus recommending venous thromboembolism (VTE) prophylaxis after total shoulder arthroplasty (TSA). The purpose of this study was to examine the (1) change in incidence of 90-day VTE, deep vein thrombosis (DVT), and pulmonary embolism; (2) change in utilization of chemoprophylaxis; and (3) change in the economic burden associated with VTE after TSA from 2010 to 2019. METHODS: Using the PearlDiver database, national data from 2010 to 2019 were used to identify patients who underwent primary TSA for osteoarthritis and/or rotator cuff arthropathy. Exclusions entailed liver pathology, coagulopathy, or those on prior prescribed blood thinners before TSA. Multivariable regression was used controlling for age and Charlson Comorbidity Index for all years with 2010 as the reference year. RESULTS: From 2010 to 2019, there was a reduction in VTE rates from 0.89% in 2010 to 0.78% in 2019. Regarding implant type, there was no notable change in incidence of VTE, DVT, and pulmonary embolism within 90 days after anatomic TSA. Notable reductions were observed in both VTE and DVT after reverse TSA from 2010 to 2019. Prescribed chemical VTE prophylaxis utilization after TSA markedly increased from 4.41% in 2010 to 11.70% utilization in 2019. The utilization of aspirin markedly increased from 17.27% in 2010 to 65.17% in 2019. Among anticoagulants, the utilization of direct factor Xa inhibitors increased from 0.0% utilization in 2010 to 66.09% utilization in 2019. The added reimbursements associated with VTE after TSA markedly decreased from $14,122 in 2010 to $4,348 in 2019. CONCLUSION: The incidence and economic burden associated with VTE after TSA have markedly declined following the 2010 American Academy of Orthopaedic Surgeons clinical practice guidelines. This reduction can be attributed to both an increase in VTE prevention through increased utilization of prescribed chemoprophylaxis and improvement in VTE treatment strategies. LEVEL OF EVIDENCE: Therapeutic, III.
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Artroplastía de Reemplazo de Hombro , Cirujanos Ortopédicos , Embolia Pulmonar , Tromboembolia Venosa , Humanos , Estados Unidos/epidemiología , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control , Artroplastía de Reemplazo de Hombro/efectos adversos , Factores de Riesgo , Anticoagulantes/uso terapéutico , Embolia Pulmonar/epidemiología , Embolia Pulmonar/etiología , Embolia Pulmonar/prevención & control , Estudios RetrospectivosRESUMEN
Orthopedic surgeons commonly perform corticosteroid injections. These injections have systemic side effects, including suppression of the hypothalamic-pituitary adrenal axis. Due to this suppression, there is a theoretical risk of corticosteroid injections affecting the efficacy of the novel COVID-19 vaccines. This potential interaction led the American Academy of Orthopedic Surgeons to recommend, "avoiding musculoskeletal corticosteroid injections for two weeks before and one week after COVID vaccine administration." This review examines the literature underlying this recommendation. An extensive literature review was performed through PubMed, MEDLINE, and Google Scholar from database inception to May 2022. Keywords searched were COVID, coronavirus, vaccine, vaccination, steroids, and corticosteroids. Search results included articles written in the English language and encompassed reviews, case series, empirical studies, and basic science articles. There is no definitive evidence that corticosteroid injections affect COVID-19 vaccine efficacy or increase the risk of contracting COVID. The authors recommend orthopedic surgeons follow the AAOS guidelines, which recommend avoiding injections two weeks before and one week following COVID vaccine administration. Additional research is needed to better define this theoretical risk, especially since there is good evidence that injections suppress the hypothalamic-pituitary-adrenal-axis.
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Hypothesis: The management of superior labrum anterior to posterior (SLAP) tears typically consists of either repair or biceps tenodesis (BT). While repair is more frequently recommended in younger patients, patients older than 40 years are often treated with BT. The purpose of this study is to determine whether there has been a change in utilization of these procedures over the past decade with respect to patient age as well as compare reoperation rates between the two procedures. Methods: The Pearldiver database was queried to identify BT and SLAP repairs indicated for SLAP tears performed from 2010 to 2019. The primary outcome was utilization rate, stratified by age. A secondary outcome was 2-year shoulder reoperation rates. Trends were reported in terms of compounded annual growth rate. Outcome analysis was conducted using univariate and multivariable analysis. Results: From 2010 to 2019, SLAP repair was the most common procedure performed for SLAP tears. Regardless of age, BT performed for SLAP tear had a significantly increased utilization rate; whereas, SLAP repair had a significantly decreased utilization rate. SLAP repair was more commonly performed in younger patients compared to BT. Following multivariable analysis, patients who underwent SLAP repair had significantly higher odds (odds ratio (OR): 1.453; 95% confidence interval (CI): 1.26-1.68; P < .001) of requiring an arthroscopic reoperation within 2 years when compared to those who underwent BT with no significant difference with respect to 2-year open reoperation. Conclusion: Although SLAP repair is still more commonly used to treat SLAP tears than BT, especially for younger patients, the utilization of SLAP repair is decreasing while BT is increasing. The increased utilization of BT may be associated with lower rates of shoulder reoperation for problematic SLAP tears.
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Background: This systematic review and network meta-analysis compare clinical outcomes of three different subscapularis management techniques in anatomic total shoulder arthroplasty: lesser tuberosity osteotomy, subscapularis peel, and subscapularis tenotomy. Methods: PubMed, Web of Science, Embase, and Cochrane's trial registry were searched in July 2021. Comparative studies and case series evaluating the outcomes of these three techniques were included. The network meta-analysis was performed only on comparative studies. Results: Twenty-three studies were included. Both lesser tuberosity osteotomy and subscapularis peel had significantly higher Western Ontario Osteoarthritis Scores compared to subscapularis tenotomy, but no difference in American Shoulder and Elbow Society Scores. Subscapularis peel had superior external rotation compared to lesser tuberosity osteotomy. However, no difference was found in external rotation between subscapularis peel and subscapularis tenotomy or between subscapularis tenotomy and lesser tuberosity osteotomy. The overall weighted average for lesser tuberosity osteotomy bony union was 93.6%, whereas the overall weighted average for subscapularis tendon healing was 79.4% and 87% for subscapularis tenotomy and subscapularis peel, respectively. Discussion: This network meta-analysis demonstrated that lesser tuberosity osteotomy and subscapularis peel were associated with the high union and subscapularis healing rates and may be associated with improved shoulder function and quality of life, compared to subscapularis tenotomy. Lesser tuberosity osteotomy and subscapularis peel demonstrate a trend of superior outcomes compared to subscapularis tenotomy during anatomic total shoulder arthroplasty.
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Zika virus (ZIKV) nonstructural protein 5 (NS5) plays a critical role in viral RNA replication and mediates key virus-host cell interactions. As with other flavivirus NS5 proteins, ZIKV NS5 is primarily found in the nucleus. We previously reported that the NS5 protein of dengue virus, another flavivirus, localized to centrosomes during cell division. Here we show that ZIKV NS5 also relocalizes from the nucleus to centrosomes during mitosis. In infected cells with supernumerary centrosomes, NS5 was present at all centrosomes. Transient expression of NS5 in uninfected cells confirmed that centrosomal localization was independent of other viral proteins. Live-cell imaging demonstrated that NS5-GFP accumulated at centrosomes shortly after break down of nuclear membrane and remained there through mitosis. Cells expressing NS5-GFP took longer to complete mitosis than control cells. Finally, an analysis of ZIKV NS5 binding partners revealed several centrosomal proteins, providing potential direct links between NS5 and centrosomes.
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Centrosoma/metabolismo , Proteínas no Estructurales Virales/metabolismo , Células HEK293 , Humanos , MitosisRESUMEN
Zika virus (ZIKV), a mosquito-borne human flavivirus that causes microcephaly and other neurological disorders, has been a recent focus for the development of flavivirus vaccines and therapeutics. We report here a 4.0 Å resolution structure of the mature ZIKV in complex with ADI-30056, a ZIKV-specific human monoclonal antibody (hMAb) isolated from a ZIKV infected donor with a prior dengue virus infection. The structure shows that the hMAb interactions span across the E protein dimers on the virus surface, inhibiting conformational changes required for the formation of infectious fusogenic trimers similar to the hMAb, ZIKV-117. Structure-based functional analysis, and structure and sequence comparisons, identified ZIKV residues essential for neutralization and crucial for the evolution of highly potent E protein crosslinking Abs in ZIKV. Thus, this epitope, ZIKV's "Achilles heel", defined by the contacts between ZIKV and ADI-30056, could be a suitable target for the design of therapeutic antibodies.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Coinfección , Reacciones Cruzadas/inmunología , Infecciones por Flavivirus/inmunología , Flavivirus/inmunología , Infección por el Virus Zika/inmunología , Virus Zika/inmunología , Secuencia de Aminoácidos , Animales , Chlorocebus aethiops , Dengue/inmunología , Virus del Dengue/inmunología , Mapeo Epitopo , Epítopos/química , Epítopos/inmunología , Infecciones por Flavivirus/virología , Humanos , Imagenología Tridimensional , Modelos Moleculares , Pruebas de Neutralización , Conformación Proteica , Células Vero , Virus Zika/ultraestructura , Infección por el Virus Zika/virologíaRESUMEN
Among the several arthropod-borne human flaviviral diseases, the recent outbreak of Zika virus (ZIKV) has caused devastating birth defects and neurological disorders, challenging the world with another major public health concern. We report here the refined structure of the mature ZIKV at a resolution of 3.1 Å as determined by cryo-electron microscopic single-particle reconstruction. The improvement in the resolution, compared with previous enveloped virus structures, was the result of optimized virus preparation methods and data processing techniques. The glycoprotein interactions and surface properties of ZIKV were compared with other mosquito-borne flavivirus structures. The largest structural differences and sequence variations occur at the glycosylation loop associated with receptor binding. Probable drug binding pockets were identified on the viral surface. These results also provide a structural basis for the design of vaccines against ZIKV.
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Flavivirus/química , Virus Zika/química , Virus Zika/ultraestructura , Microscopía por Crioelectrón , Diseño de Fármacos , Flavivirus/metabolismo , Glicoproteínas/química , Glicoproteínas/metabolismo , Unión Proteica , Imagen Individual de Molécula/métodos , Relación Estructura-Actividad , Estructuras Virales/química , Vacunas Virales/química , Vacunas Virales/farmacología , Virus Zika/metabolismoRESUMEN
The current Zika virus (ZIKV) epidemic is characterized by severe pathogenicity in both children and adults. Sequence changes in ZIKV since its first isolation are apparent when pre-epidemic strains are compared with those causing the current epidemic. However, the residues that are responsible for ZIKV pathogenicity are largely unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of the immature ZIKV at 9-Å resolution. The cryo-EM map was fitted with the crystal structures of the precursor membrane and envelope glycoproteins and was shown to be similar to the structures of other known immature flaviviruses. However, the immature ZIKV contains a partially ordered capsid protein shell that is less prominent in other immature flaviviruses. Furthermore, six amino acids near the interface between pr domains at the top of the spikes were found to be different between the pre-epidemic and epidemic ZIKV, possibly influencing the composition and structure of the resulting viruses.
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Proteínas de la Cápside/ultraestructura , Virus Zika/ultraestructura , Aedes , Animales , Proteínas de la Cápside/química , Línea Celular , Microscopía por Crioelectrón , Glicosilación , Modelos Moleculares , Procesamiento Proteico-Postraduccional , Estructura Cuaternaria de Proteína , Virión/ultraestructuraRESUMEN
Defecating disorders are a common and complex problem. There are a range of anatomical and functional bowel abnormalities that can lead to this condition. Treatment is difficult and needs a multidisciplinary approach. First line treatment for defecating disorders is conservative. For those that fail conservative treatment, some may respond to surgical therapy but with variable results. The aim of this review is to offer an overview of defecating disorders as well as provide an algorithm on how to diagnose and treat them with the help of a multidisciplinary and multimodal approach.