Immune-Complex Mimics as a Molecular Platform for Adjuvant-Free Vaccine Delivery

Protein-based vaccine development faces the difficult challenge of finding robust yet non-toxic adjuvants suitable for humans. Here, using a molecular engineering approach, we have developed a molecular platform for generating self-adjuvanting immunogens that do not depend on exogenous adjuvants for induction of immune responses. These are based on the concept of Immune Complex Mimics (ICM), structures that are formed between an oligomeric antigen and a monoclonal antibody (mAb) to that antigen. In this way, the roles of antigens and antibodies within the structure of immune complexes are reversed, so that a single monoclonal antibody, rather than polyclonal sera or expensive mAb cocktails can be used. We tested this approach in the context of Mycobacterium tuberculosis (MTB) infection by linking the highly immunogenic and potentially protective Ag85B with the oligomeric Acr (alpha crystallin, HspX) antigen. When combined with an anti-Acr monoclonal antibody, the fusion protein formed ICM which bound to C1q component of the complement system and were readily taken up by antigen-presenting cells in vitro. ICM induced a strong Th1/Th2 mixed type antibody response, which was comparable to cholera toxin adjuvanted antigen, but only moderate levels of T cell proliferation and IFN-γ secretion. Unfortunately, the systemic administration of ICM did not confer statistically significant protection against intranasal MTB challenge, although a small BCG-boosting effect was observed. We conclude that ICM are capable of inducing strong humoral responses to incorporated antigens and may be a suitable vaccination approach for pathogens other than MTB, where antibody-based immunity may play a more protective role

The Predictive Nature of Individual Differences in Early Associative Learning and Emerging Social Behavior

Across the first year of life, infants achieve remarkable success in their ability to interact in the social world. The hierarchical nature of circuit and skill development predicts that the emergence of social behaviors may depend upon an infant's early abilities to detect contingencies, particularly socially-relevant associations. Here, we examined whether individual differences in the rate of associative learning at one month of age is an enduring predictor of social, imitative, and discriminative behaviors measured across the human infant's first year. One-month learning rate was predictive of social behaviors at 5, 9, and 12 months of age as well as face-evoked discriminative neural activity at 9 months of age. Learning was not related to general cognitive abilities. These results underscore the importance of early contingency learning and suggest the presence of a basic mechanism underlying the ontogeny of social behaviors

The neural correlates of social attention: automatic orienting to social and nonsocial cues

Previous evidence suggests that directional social cues (e.g., eye gaze) cause automatic shifts in attention toward gaze direction. It has been proposed that automatic attentional orienting driven by social cues (social orienting) involves a different neural network from automatic orienting driven by nonsocial cues. However, previous neuroimaging studies on social orienting have only compared gaze cues to symbolic cues, which typically engage top-down mechanisms. Therefore, we directly compared the neural activity involved in social orienting to that involved in purely automatic nonsocial orienting. Twenty participants performed a spatial cueing task consisting of social (gaze) cues and automatic nonsocial (peripheral squares) cues presented at short and long stimulus (cue-to-target) onset asynchronies (SOA), while undergoing fMRI. Behaviorally, a facilitation effect was found for both cue types at the short SOA, while an inhibitory effect (inhibition of return: IOR) was found only for nonsocial cues at the long SOA. Imaging results demonstrated that social and nonsocial cues recruited a largely overlapping fronto-parietal network. In addition, social cueing evoked greater activity in occipito-temporal regions at both SOAs, while nonsocial cueing recruited greater subcortical activity, but only for the long SOA (when IOR was found). A control experiment, including central arrow cues, confirmed that the occipito-temporal activity was at least in part due to the social nature of the cue and not simply to the location of presentation (central vs. peripheral). These results suggest an evolutionary trajectory for automatic orienting, from predominantly subcortical mechanisms for nonsocial orienting to predominantly cortical mechanisms for social orienting

A randomised clinical trial on a comprehensive geriatric assessment and intensive home follow-up after hospital discharge: the Transitional Care Bridge

<p>Abstract</p> <p>Background</p> <p>Older patients are at high risk for poor outcomes after acute hospital admission. The mortality rate in these patients is approximately 20%, whereas 30% of the survivors decline in their level of activities of daily living (ADL) functioning three months after hospital discharge. Most diseases and geriatric conditions that contribute to poor outcomes could be subject to pro-active intervention; not only during hospitalization, but also after discharge. This paper presents the design of a randomised controlled clinical trial concerning the effect of a pro-active, multi-component, nurse-led transitional care program following patients for six months after hospital admission.</p> <p>Methods/Design</p> <p>Three hospitals in the Netherlands will participate in the multi-centre, double-blind, randomised clinical trial comparing a pro-active multi-component nurse-led transitional care program to usual care after discharge. All patients acutely admitted to the Department of Internal Medicine who are 65 years and older, hospitalised for at least 48 hours and are at risk for functional decline are invited to participate in the study. All patients will receive integrated geriatric care by a geriatric consultation team during hospital admission. Randomization, which will be stratified by study site and cognitive impairment, will be conducted during admission. The intervention group will receive the transitional care bridge program, consisting of a handover moment with a community care Care Nurse (CN) during hospital admission and five home visits after discharge. The control group will receive 'care as usual' after discharge. The main outcome is the level of ADL functioning six months after discharge compared to premorbid functioning measured with the Katz ADL index. Secondary outcomes include; survival, cognitive functioning, quality of life, and health care utilization, satisfaction of the patient and primary care giver with the transitional care bridge program. All outcomes will be measured at three, six and twelve months after discharge. Approximately 674 patients will be enrolled to either the intervention or control group.</p> <p>Discussion</p> <p>The study will provide new knowledge on a combined intervention of integrated care during hospital admission, a proactive handover moment before discharge and intensive home visits after discharge.</p> <p>Trial registration</p> <p><b>Trial registration number: NTR 2384</b></p

Strength of Social Tie Predicts Cooperative Investment in a Human Social Network

Social networks – diagrams which reflect the social structure of animal groups – are increasingly viewed as useful tools in behavioural ecology and evolutionary biology. Network structure may be especially relevant to the study of cooperation, because the action of mechanisms which affect the cost:benefit ratio of cooperating (e.g. reciprocity, punishment, image scoring) is likely to be mediated by the relative position of actor and recipient in the network. Social proximity could thus affect cooperation in a similar manner to biological relatedness. To test this hypothesis, we recruited members of a real-world social group and used a questionnaire to reveal their network. Participants were asked to endure physical discomfort in order to earn money for themselves and other group members, allowing us to explore relationships between willingness to suffer a cost on another's behalf and the relative social position of donor and recipient. Cost endured was positively correlated with the strength of the social tie between donor and recipient. Further, donors suffered greater costs when a relationship was reciprocated. Interestingly, participants regularly suffered greater discomfort for very close peers than for themselves. Our results provide new insight into the effect of social structure on the direct benefits of cooperation

Livelihood and vulnerability in the wake of Typhoon Yolanda: lessons of community and resilience

Livelihood strategies that are crafted in ‘extra-ordinary’ post-disaster conditions should also be able to function once some semblance of normalcy has resumed. This article aims to show that the vulnerability experienced in relation to Typhoon Yolanda was, and continues to be, directly linked to inadequate livelihood assets and opportunities. We examine the extent to which various livelihood strategies lessened vulnerability post-Typhoon Yolanda and argue that creating conditions under which disaster survivors have the freedom to pursue sustainable livelihood is essential in order to foster resilience and reduce vulnerability against future disasters. We offer suggestions to improve future relief efforts, including suggestions made by the survivors themselves. We caution against rehabilitation strategies that knowingly or unknowingly, resurrect pre-disaster vulnerability. Strategies that foster dependency, fail to appreciate local political or ecological conditions or undermine cooperation and cohesion in already vulnerable communities will be bound to fail. Some of the livelihood strategies that we observed post-Typhoon Yolanda failed on some or all of these points. It is important for future policy that these failings are addressed

Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice

10.1038/srep03754Scientific Reports4

Genome-wide association trans-ethnic meta-analyses identifies novel associations regulating coagulation Factor VIII and von Willebrand Factor plasma levels

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. METHODS: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. RESULTS: We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events

Pharmacologic prophylaxis for atrial fibrillation following cardiac surgery: a systematic review

Atrial Fibrillation (AF) is the most common arrhythmia occurring after cardiac surgery. Its incidence varies depending on type of surgery. Postoperative AF may cause hemodynamic deterioration, predispose to stroke and increase mortality. Effective treatment for prophylaxis of postoperative AF is vital as reduces hospitalization and overall morbidity. Beta - blockers, have been proved to prevent effectively atrial fibrillation following cardiac surgery and should be routinely used if there are no contraindications. Sotalol may be more effective than standard b-blockers for the prevention of AF without causing an excess of side effects. Amiodarone is useful when beta-blocker therapy is not possible or as additional prophylaxis in high risk patients. Other agents such as magnesium, calcium channels blocker or non-antiarrhythmic drugs as glycose-insulin - potassium, non-steroidal anti-inflammatory drugs, corticosteroids, N-acetylcysteine and statins have been studied as alternative treatment for postoperative AF prophylaxis

Normative modelling of brain morphometry across the lifespan with CentileBrain: algorithm benchmarking and model optimisation

The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with regional morphometric data from 37 407 healthy individuals (53% female and 47% male; aged 3–90 years) from 87 datasets from Europe, Australia, the USA, South Africa, and east Asia following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The multivariate fractional polynomial regression (MFPR) emerged as the preferred algorithm, optimised with non-linear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3000 study participants. This model can inform about the biological and behavioural implications of deviations from typical age-related neuroanatomical changes and support future study designs. The model and scripts described here are freely available through CentileBrain