Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination

Natural infections expose the immune system to escalating antigen and inflammation over days to weeks, whereas nonlive vaccines are single bolus events. We explored whether the immune system responds optimally to antigen kinetics most similar to replicating infections, rather than a bolus dose. Using HIV antigens, we found that administering a given total dose of antigen and adjuvant over 1–2 wk through repeated injections or osmotic pumps enhanced humoral responses, with exponentially increasing (exp-inc) dosing profiles eliciting >10-fold increases in antibody production relative to bolus vaccination post prime. Computational modeling of the germinal center response suggested that antigen availability as higher-affinity antibodies evolve enhances antigen capture in lymph nodes. Consistent with these predictions, we found that exp-inc dosing led to prolonged antigen retention in lymph nodes and increased Tfh cell and germinal center B-cell numbers. Thus, regulating the antigen and adjuvant kinetics may enable increased vaccine potency.National Institute of Allergy and Infectious Diseases (U.S.) (Awards UM1AI100663)National Institute of Allergy and Infectious Diseases (U.S.) (Awards AI110657

Facility type and primary care performance in sub-district health promotion hospitals in Northern Thailand

This paper examines primary care performance in three types of community health facilities in five provinces in northern Thailand. Tambon (sub-district) health promotion hospitals (THPHs) were introduced in 2009 to upgrade the services offered by the previous health centres, but were hampered by shortages of trained doctors and nurses. The Ministry of Public Health (MoPH) designated three categories of THPH, defined according to whether they were regularly staffed by a medical practitioner, a qualified nurse or non-clinical public health officers. While the plan is to move over time to doctor-staffed THPHs, many rural areas rely on facilities staffed by public health officers or nurses. The study used structured interviews to measure patient views on performance, defined in terms of accessibility, continuity, comprehensiveness, co-ordination and community orientation, in 23 THPHs divided across the three types. Counter-intuitively it was the THPHs staffed by public health officers which achieved the highest scores, followed by nurse-staffed facilities and then doctor-staffed facilities. The sharpest differences found were in the scores for accessibility, continuity, and comprehensiveness of care. The authors argue that these are associated with local services, which rural patients in particular value more than services offered by doctors on rotation in larger outpatient department-like centres. Patients value these aspects of care more than professional skill-mix per se. This is not an argument for delaying an increase in use of qualified staff, but an indication of the need to do this in a way that preserves the features of local services that patients value

Pro- vs. retro-foreland basins

Alpine-type mountain belts formed by continental collision are characterised by a strong cross-sectional asymmetry driven by the dominant underthrusting of one plate beneath the other. Such mountain belts are £anked on either side by two peripheral foreland basins, one over the underthrust plate and one over the over-riding plate; these have been termed pro- and retro-foreland basins, respectively. Numerical modelling that incorporates suitable tectonic boundary conditions, and models orogenesis from growth to a steady-state form (i.e. where accretionary in£ux equals erosional out£ux), predicts contrasting basin development to these two end-member basin types. Pro-foreland basins are characterised by: (1)Accelerating tectonic subsidence driven primarily by the translation of the basin ¢ll towards the mountain belt at the convergence rate. (2) Stratigraphic onlap onto the cratonic margin at a rate at least equal to the plate convergence rate. (3) A basin in¢ll that records the most recent development of the mountain belt with a preserved interval determined by the width of the basin divided by the convergence rate. In contrast, retro-foreland basins are relatively stable, are not translated into the mountain belt once steady-state is achieved, and are consequently characterised by: (1) A constant tectonic subsidence rate during growth of the thrustwedge, with zero tectonic subsidence during the steady-state phase (i.e. ongoing accretion-erosion, but constant load). (2)Relatively little stratigraphic onlap driven only by the growth of the retro-wedge. (3)Abasin ¢ll that records the entire growth phase of the mountain belt, but only a condensed representation of steady-state conditions. Examples of pro-foreland basins include the Appalachian foredeep, the west Taiwan foreland basin, theNorthAlpine ForelandBasin and the EbroBasin (southern Pyrenees). Examples of retro-foreland basins include the SouthWestlandBasin (SouthernAlps,NewZealand), theAquitaine Basin (northern Pyrenees), and the Po Basin (southern European Alps).We discuss how this new insight into the variability of collisional foreland basins can be used to better interpret mountain belt evolution and the hydrocarbon potential of these basins types

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research.

The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) Muscarinic receptor antagonists-originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) Histamine receptor antagonists-searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H1) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) Phenothiazines and dopamine receptor antagonists-investigations of their pharmacology as "sedatives" (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D2) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) Metoclopramide and selective 5-hydroxytryptamine3(5-HT3) receptor antagonists-metoclopramide was initially assumed to act only via D2 receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine4 receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT3 receptors. The latter led to identification of selective 5-HT3 receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin1receptor antagonists-antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway

Long noncoding RNA and its contribution to autism spectrum disorders

Recent studies have indicated that long noncoding RNAs (lncRNAs) play important roles in multiple processes, such as epigenetic regulation, gene expression regulation, development, nutrition‐related and other diseases, toxic response, and response to drugs. Although the functional roles and mechanisms of several lncRNAs have been discovered, a better understanding of the vast majority of lncRNAs remains elusive. To understand the functional roles and mechanisms of lncRNAs is critical because these transcripts represent the majority of the transcriptional output of the mammalian genome. Recent studies have also suggested that lncRNAs are more abundant in the human brain and are involved in neurodevelopment and neurodevelopmental disorders, including autism spectrum disorders (ASDs). In this study, we review several known functions of lncRNAs and the potential contribution of lncRNAs to ASDs and to other genetic syndromes that have a similar clinical presentation to ASDs, such as fragile X syndrome and Rett syndrome.This work was supported by Guangdong Natural Science Foundation (Grant No: 2015A030313455) and National Science Foundation of China (Grant No 81302445).Published versio

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson’s disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5- and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway

CRISPR-Mediated Slamf1Δ/Δ Slamf5Δ/Δ Slamf6Δ/Δ Triple Gene Disruption Reveals NKT Cell Defects but Not T Follicular Helper Cell Defects.

SAP (SH2D1A) is required intrinsically in CD4 T cells to generate germinal center responses and long-term humoral immunity. SAP binds to SLAM family receptors, including SLAM, CD84, and Ly108 to enhance cytokine secretion and sustained T cell:B cell adhesion, which both improve T follicular helper (Tfh) cell aid to germinal center (GC) B cells. To understand the overlapping roles of multiple SLAM family receptors in germinal center responses, Slamf1Δ/Δ Slamf5Δ/Δ Slamf6Δ/Δ triple gene disruption (Slamf1,5,6Δ/Δ) mice were generated using CRISPR-Cas9 gene editing to eliminate expression of SLAM (CD150), CD84, and Ly108, respectively. Gene targeting was highly efficient, with 6 of 6 alleles disrupted in 14 of 23 pups and the majority of alleles disrupted in the remaining pups. NKT cell differentiation in Slamf1,5,6Δ/Δ mice was defective, but not completely absent. The remaining NKT cells exhibited substantially increased 2B4 (SLAMF4) expression. Surprisingly, there were no overt defects in germinal center responses to acute viral infections or protein immunizations in Slamf1,5,6Δ/Δ mice, unlike Sh2d1a-/- mice. Similarly, in the context of a competitive environment, SLAM family receptor expressing GC Tfh cell, GC B cell, and plasma cell responses exhibited no advantages over Slamf1,5,6Δ/Δ cells