Recombinant forms of adeno-associated virus (rAAV) are vectors of choice in the development of treatments for a number of genetic dispositions. Greater understanding of AAV's molecular virology is ...needed to underpin needed improvements in efficiency and specificity. Recent advances have included identification of a near-universal entry receptor, AAVR, and structures detected by cryo-electron microscopy (EM) single particle analysis (SPA) that revealed, at high resolution, only the domains of AAVR most tightly bound to AAV. Here, cryogenic electron tomography (cryo-ET) is applied to reveal the neighboring domains of the flexible receptor. For AAV5, where the PKD1 domain is bound strongly, PKD2 is seen in three configurations extending away from the virus. AAV2 binds tightly to the PKD2 domain at a distinct site, and cryo-ET now reveals four configurations of PKD1, all different from that seen in AAV5. The AAV2 receptor complex also shows unmodeled features on the inner surface that appear to be an equilibrium alternate configuration. Other AAV structures start near the 5-fold axis, but now β-strand A is the minor conformer and, for the major conformer, partially ordered N termini near the 2-fold axis join the canonical capsid jellyroll fold at the βA-βB turn. The addition of cryo-ET is revealing unappreciated complexity that is likely relevant to viral entry and to the development of improved gene therapy vectors.
With 150 clinical trials for 30 diseases under way, AAV is a leading gene therapy vector. Immunotoxicity at high doses used to overcome inefficient transduction has occasionally proven fatal and highlighted gaps in fundamental virology. AAV enters cells, interacting through distinct sites with different domains of the AAVR receptor, according to AAV clade. Single domains are resolved in structures by cryogenic electron microscopy. Here, the adjoining domains are revealed by cryo-electron tomography of AAV2 and AAV5 complexes. They are in flexible configurations interacting minimally with AAV, despite measurable dependence of AAV2 transduction on both domains.
Coagulopathy in traumatic brain injury (CTBI) is a well-established phenomenon, but its mechanism is poorly understood. Various studies implicate protein C activation related to the global insult of ...hemorrhagic shock or brain tissue factor release with resultant platelet dysfunction and depletion of coagulation factors. We hypothesized that the platelet dysfunction of CTBI is a distinct phenomenon from the coagulopathy following hemorrhagic shock.
We used thrombelastography with platelet mapping as a measure of platelet function, assessing the degree of inhibition of the adenosine diphosphate (ADP) and arachidonic acid (AA) receptor pathways. First, we studied the early effect of TBI on platelet inhibition by performing thrombelastography with platelet mapping on rats. We then conducted an analysis of admission blood samples from trauma patients with isolated head injury (n = 70). Patients in shock or on clopidogrel or aspirin were excluded.
In rats, ADP receptor inhibition at 15 minutes after injury was 77.6% ± 6.7% versus 39.0% ± 5.3% for controls (p < 0.0001). Humans with severe TBI (Glasgow Coma Scale GCS score ≤ 8) showed an increase in ADP receptor inhibition at 93.1% (interquartile range IQR, 44.8-98.3%; n = 29) compared with 56.5% (IQR, 35-79.1%; n = 41) in milder TBI and 15.5% (IQR, 13.2-29.1%) in controls (p = 0.0014 and p < 0.0001, respectively). No patient had significant hypotension or acidosis. Parallel trends were noted in AA receptor inhibition.
Platelet ADP and AA receptor inhibition is a prominent early feature of CTBI in humans and rats and is linked to the severity of brain injury in patients with isolated head trauma. This phenomenon is observed in the absence of hemorrhagic shock or multisystem injury. Thus, TBI alone is shown to be sufficient to induce a profound platelet dysfunction.
Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to ...matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
With empirical research on team resilience on the rise, there is a need for an integrative conceptual model that delineates the essential elements of this concept and offers a heuristic for the ...integration of findings across studies. To address this need, we propose a multilevel model of team resilience that originates in the resources of individual team members and emerges as a team‐level construct through dynamic person–situation interactions that are triggered by adverse events. In so doing, we define team resilience as an emergent outcome characterized by the trajectory of a team's functioning, following adversity exposure, as one that is largely unaffected or returns to normal levels after some degree of deterioration in functioning. This conceptual model offers a departure point for future work on team resilience and reinforces the need to incorporate inputs and process mechanisms inherent within dynamic interactions among individual members of a team. Of particular, importance is the examination of these inputs, process mechanisms and emergent states, and outcomes over time, and in the context of task demands, objectives, and adverse events.
Practitioner points
Team resilience as a dynamic, multilevel phenomenon requires clarity on the individual‐ and team‐level factors that foster its emergence within occupational and organizational settings.
An understanding of the nature (e.g., timing, chronicity) of adverse events is key to studying and intervening to foster team resilience within occupational and organizational settings.
Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn ...errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination.
Objectives: To estimate cumulative live birth rates (CLBRs) following repeated assisted reproductive technology (ART) ovarian stimulation cycles, including all fresh and frozen/thaw embryo transfers ...(complete cycles).
Design, setting and participants: Prospective follow‐up of 56 652 women commencing ART in Australian and New Zealand during 2009–2012, and followed until 2014 or the first treatment‐dependent live birth.
Main outcome measures: CLBRs and cycle‐specific live birth rates were calculated for up to eight cycles, stratified by the age of the women (< 30, 30–34, 35–39, 40–44, > 44 years). Conservative CLBRs assumed that women discontinuing treatment had no chance of achieving a live birth if had they continued treatment; optimal CLBRs assumed that they would have had the same chance as women who continued treatment.
Results: The overall CLBR was 32.7% (95% CI, 32.2–33.1%) in the first cycle, rising by the eighth cycle to 54.3% (95% CI, 53.9–54.7%) (conservative) and 77.2% (95% CI, 76.5–77.9%) (optimal). The CLBR decreased with age and number of complete cycles. For women who commenced ART treatment before 30 years of age, the CLBR for the first complete cycle was 43.7% (95% CI, 42.6–44.7%), rising to 69.2% (95% CI, 68.2–70.1%) (conservative) and 92.8% (95% CI, 91.6–94.0) (optimal) for the seventh cycle. For women aged 40–44 years, the CLBR was 10.7% (95% CI, 10.1–11.3%) for the first complete cycle, rising to 21.0% (95% CI, 20.2–21.8%) (conservative) and 37.9% (95% CI, 35.9–39.9%) (optimal) for the eighth cycle.
Conclusion: CLBRs based on complete cycles are meaningful estimates of ART success, reflecting contemporary clinical practice and encouraging safe practice. These estimates can be used when counselling patients and to inform public policy on ART treatment.
Summary
•Of the women who gave birth in Australia in 2018, 47% had overweight or obesity, with obesity being associated with both maternal and fetal complications.
•Bariatric surgery improves ...fertility and some pregnancy‐related outcomes.
•Following bariatric surgery, pregnancy should be delayed by at least 12–18 months due to adverse pregnancy outcomes associated with rapid weight loss.
•Contraception should be prescribed after bariatric surgery, although the effectiveness of the oral contraceptive pill may be reduced due to malabsorption and contraceptive devices such as intrauterine devices should be considered as first line therapy.
•After bariatric surgery, women should undergo close monitoring for nutritional insufficiencies before, during and after pregnancy. Expert opinion recommends these women undergo dietary assessment and supplementation to prevent micronutrient deficiencies.
•Bariatric surgeons, bariatric medical practitioners, bariatric dieticians, the patient’s usual general practitioner, obstetricians, and maternity specialists should be involved to assist in the multidisciplinary management of these complex patients.
This study aims at proposing a semiautomated sea ice segmentation workflow utilizing Sentinel-1 synthetic aperture radar imagery. The workflow consists of two main steps. First, preferable features ...in sea ice interpretation were determined with a random forest feature selection method. Second, an unsupervised graph-cut image segmentation was performed. The workflow was tested on 13 Sentinel-1A images from January to June 2016, and the results were evaluated on open water segmentation per ice charts provided by Canada Ice Service. The results showed that the proposed workflow was able to segment Sentinel-1 images in to appropriate number of classes, and the potential water identification rate reached 95%.
Elevated d-dimers in injured patients with paradoxically low fibrinolysis activity measured by viscoelastic assays have been speculated to be “occult” fibrinolysis. However, an alternative ...explanation is that these patients have previously activated their fibrinolytic system and have shut it down by the time of blood draw, and would gain no benefit in clot strength with tranexamic acid (TXA). We hypothesize that TXA will not increase clot strength in injured patients with low fibrinolytic activity measured by thrombelastography (TEG), despite biomarkers of fibrinolysis activation.
Three TEG assays (rapid, tissue plasminogen activator, and functional fibrinogen) were run on trauma patients. The tissue plasminogen activator TEG served as a functional assay to quantify depletion of fibrinolysis inhibitors (DFI). Patients were stratified by DFI vs non-DFI and then by rapid TEG lysis at 30 minutes phenotype cutoffs. Response to TXA was evaluated with functional fibrinogen TEG by calculating percent change in clot strength with the addition of exogenous TXA in the TEG cup.
Six hundred and thirty patients with a median new injury severity score of 20 were analyzed. Depletion of fibrinolysis inhibitors was present in 116 (18%). The DFI patients had significantly increased d-dimer (p < 0.001) and lower fibrinogen (p < 0.001). The DFI patients had increased rates of massive transfusion (33% vs 3.3%; p < 0.001) and mortality (40% vs 6.2%; p < 0.001). Among DFI patients, TXA significantly improved fibrin clot strength with hyperfibrinolysis (+19% clot strength; p < 0.001) but not with shutdown (+1.2%) or physiologic (-2.5%).
Patients with DFI have multiple abnormalities of their coagulation system, but only DFI patients with hyperfibrinolysis have improved fibrin clot strength with TXA.
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