Structural basis for cooperativity of human monoclonal antibodies to meningococcal factor H-binding protein

Monoclonal antibody (mAb) cooperativity is a phenomenon triggered when mAbs couples promote increased bactericidal killing compared to individual partners. Cooperativity has been deeply investigated among mAbs elicited by factor H-binding protein (fHbp), a Neisseria meningitidis surface-exposed lipoprotein and one of the key antigens included in both serogroup B meningococcus vaccine Bexsero and Trumenba. Here we report the structural and functional characterization of two cooperative mAbs pairs isolated from Bexsero vaccines. The 3D electron microscopy structures of the human mAb-fHbp-mAb cooperative complexes indicate that the angle formed between the antigen binding fragments (fAbs) assume regular angle and that fHbp is able to bind simultaneously and stably the cooperative mAbs pairs and human factor H (fH) in vitro. These findings shed light on molecular basis of the antibody-based mechanism of protection driven by simultaneous recognition of the different epitopes of the fHbp and underline that cooperativity is crucial in vaccine efficacy

Cryotomography of budding influenza a virus reveals filaments with diverse morphologies that mostly do not bear a genome at their distal end

Influenza viruses exhibit striking variations in particle morphology between strains. Clinical isolates of influenza A virus have been shown to produce long filamentous particles while laboratory-adapted strains are predominantly spherical. However, the role of the filamentous phenotype in the influenza virus infectious cycle remains undetermined. We used cryo-electron tomography to conduct the first three-dimensional study of filamentous virus ultrastructure in particles budding from infected cells. Filaments were often longer than 10 microns and sometimes had bulbous heads at their leading ends, some of which contained tubules we attribute to M1 while none had recognisable ribonucleoprotein (RNP) and hence genome segments. Long filaments that did not have bulbs were infrequently seen to bear an ordered complement of RNPs at their distal ends. Imaging of purified virus also revealed diverse filament morphologies; short rods (bacilliform virions) and longer filaments. Bacilliform virions contained an ordered complement of RNPs while longer filamentous particles were narrower and mostly appeared to lack this feature, but often contained fibrillar material along their entire length. The important ultrastructural differences between these diverse classes of particles raise the possibility of distinct morphogenetic pathways and functions during the infectious process

Aptamers for respiratory syncytial virus detection.

The identification of the infectious agents is pivotal for appropriate care of patients with viral diseases. Current viral diagnostics rely on selective detection of viral nucleic acid or protein components. In general, detection of proteins rather than nucleic acids is technically more suitable for rapid tests. However, protein-based virus identification methods depend on antibodies limiting the practical applicability of these approaches. Aptamers rival antibodies in target selectivity and binding affinity, and excel in terms of robustness and cost of synthesis. Although aptamers have been generated for virus identification in laboratory settings, their introduction into routine virus diagnostics has not been realized, yet. Here, we demonstrate that the rationally designed SELEX protocol can be applied on whole virus to select aptamers, which can potentially be applied for viral diagnostics. This approach does not require purified virus protein or complicated virus purification. The presented data also illustrate that corroborating the functionality of aptamers with various approaches is essential to pinpoint the most appropriate aptamer amongst the panel of candidates obtained by the selection. Our protocol yielded aptamers capable of detecting respiratory syncytial virus (RSV), an important pathogen causing severe disease especially in young infants, at clinically relevant concentrations in complex matrices

High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study

Objectives: Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines.Materials and methods: 176 surgically resected stage I-IV lung adenocarcinomas were histologically reclassified according to WHO 2015 guidelines. A modified classification subdividing the acinar subtype into classic acinar, complex glandular and cribriform subtypes was further applied and potentially prognostic histopathological characteristics such as tumor-infiltrating lymphocytes were evaluated. 148 patients with stage I-III tumors and complete follow-up data were included in the survival analyses. TMB was determined by a commercial next generation sequencing panel from 131 tumors, out of which 105 had survival data available.Results: Predominant micropapillary, solid and complex glandular as well as nonpredominant cribriform histological subtypes were associated with significantly shorter survival. High TMB concentrated in micropapillary, solid and acinar predominant subtypes. Interestingly, TMB >= 14 mutations/MB conferred a stage- and histology-independent survival benefit compared to TMB < 14 in multivariable analysis for overall (HR 0.284, 95% CI 0.14-0.59, P=0.001) and disease-specific survival (HR 0.213, 95% CI 0.08-0.56, P=0.002).Conclusion: TMB was an independent biomarker of favorable prognosis in our cohort of lung adenocarcinoma despite being associated with predominant histological subtypes considered aggressive

Mediation effect of depressive symptoms in the relationship between perceived control and wellbeing in patients with heart failure and their partners

Background: As treatment has improved, patients with heart failure live longer, and the care mostly takes place at home with partners providing the main assistance. Perceived control over heart failure is important in managing self-care activities to maintain health in patients and their family. Depressive symptoms are associated with impaired health status in patients with heart failure and their family. However, there is limited knowledge about how depressive symptoms affect the relationship between health status and perceived control over heart failure in patients with heart failure and their cohabiting partners. Aim: The aim of this study was to examine whether the relationship between perceived control and health status (i.e. mental and physical) was mediated by depressive symptoms in patients with heart failure and their partners. Methods: In this secondary data analysis, we included 132 heart failure patients and 132 partners who completed measures of depressive symptoms (the Beck depression inventory II), perceived control (the control attitude scale), and physical and mental health status (the short form-36) instruments. The mediation effect of depression was examined using a series of multiple regression in patients and their family caregivers separately. Results: We found a mediator effect of depressive symptoms in the relationship between perceived control and mental health status in both patients and partners. The relationship between perceived control and physical health status was mediated by depressive symptoms in the patients, not in the partners. Conclusion: Efforts to improve self-care management and maintenance by targeting perceived control may be more effective if depressive symptoms are also effectively managed.Funding Agencies|Linkoping University; Swedish Science Council</p

Quality of life and family function are poorest when both patients with heart failure and their caregivers are depressed

Aims Patients with heart failure (HF) and their family caregivers commonly experience depressive symptoms associated with low quality of life (QOL) at the individual level. However, there is a lack of knowledge about how QOL and family function are associated with depressive symptoms at the dyad level. The aim of this article is to compare QOL and family function among dyads stratified by depressive symptoms. Methods and results Outpatients with HF and their primary caregivers completed the Beck Depression Inventory-II for depressive symptoms, the Short Form 36 for physical and mental QOL, and the McMaster Family Assessment Device for a family function. Analysis of variance was used to compare QOL and family function among the four dyad groups. A total of 91 dyads were categorized into four groups: neither member having depressive symptoms (43.9%), only the caregiver having depressive symptoms (13.2%), only the patient having depressive symptoms (23.1%), and both members having depressive symptoms (20.9%). Dyads without depressive symptoms had the highest levels of physical and mental QOL among the groups. The dyads with both members having depressive symptoms had the lowest levels of physical and mental QOL (P &amp;lt; 0.001) and the lowest levels of general family functioning, problem-solving ability, and communication ability (P &amp;lt; 0.001). Intermediate levels of QOL were seen in dyads with only one member having depressive symptoms, and a similar pattern of intermediate scores was found in all three subscales of family function. Conclusion Dyads with both members having depressive symptoms may be at greatest risk of having poor QOL and low family functioning.Funding Agencies|National Institutes of Nursing ResearchUnited States Department of Health &amp; Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Nursing Research (NINR) [K23NR010011]</p

Trajectory of self-care behaviour in patients with heart failure: the impact on clinical outcomes and influencing factors

Background: Patients self-care behaviour is still suboptimal in many heart failure (HF) patients and underlying mechanisms on how to improve self-care need to be studied. Aims: (1) To describe the trajectory of patients self-care behaviour over 1 year, (2) to clarify the relationship between the trajectory of self-care and clinical outcomes, and (3) to identify factors related to changes in self-care behaviour. Methods: In this secondary analysis of the COACH-2 study, 167 HF patients (mean age 73 years) were included. Self-care behaviour was assessed at baseline and after 12 months using the European Heart Failure Self-care Behaviour scale. The threshold score of amp;gt; 70 was used to define good self-care behaviour. Results: Of all patients, 21% had persistent poor self-care behaviour, and 27% decreased from good to poor. Self-care improved from poor to good in 10%; 41% had a good self-care during both measurements. Patients who improved self-care had significantly higher perceived control than those with persistently good self-care at baseline. Patients who decreased their self-care had more all-cause hospitalisations (35%) and cardiovascular hospitalisations (26%) than patients with persistently good self-care (2.9%, p amp;lt; 0.05). The prevalence of depression increased at 12 months in both patients having persistent poor self-care (0% to 21%) and decreasing self-care (4.4% to 22%, both p amp;lt; 0.05). Conclusion: Perceived control is a positive factor to improve self-care, and a decrease in self-care is related to worse outcomes. Interventions to reduce psychological distress combined with self-care support could have a beneficial impact on patients decreasing or persistently poor self-care behaviour.Funding Agencies|Netherlands Heart Foundation (NHF)Netherlands Heart Foundation [2008B083]</p