A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice

Studies in gene-targeted mice have demonstrated that factor B of the alternative complement pathway plays an important role in several disease models, but an exogenous inhibitor of factor B has not previously been available. We have developed an inhibitory monoclonal antibody directed against a critical epitope on mouse factor B and have tested it in a model of antiphospholipid (aPL) antibody (Ab)-induced fetal loss. Gene-targeted factor B-deficient mice (fB-/-) were injected with a fusion protein comprised of the second and third short consensus repeat (SCR) domains of mouse factor B linked to a mouse IgG1 Fc domain. Hybridomas were made from splenocytes of the immunized mouse. One mAb, designated 1379, produced an IgG1 antibody that inhibited alternative pathway activation in vitro and in vivo by preventing formation of the C3bBb complex. Strikingly, this mAb inhibited alternative pathway activation in serum from mice, rats, humans, monkeys, pigs and horses. Fab fragments made from this mAb also inhibited alternative pathway activation. Epitope mapping demonstrated that this antibody binds to factor B within the third SCR domain. When mAb 1379 was administered to mice that also received human IgG containing antiphospholipid antibodies, it provided significant protection from antiphospholipid antibody-induced complement activation and fetal loss. Thus, this mAb to factor B has broad species reactivity and effectively inhibits alternative pathway activation. The mAb protects mice in an in vivo model of antiphospholipid antibody syndrome, demonstrating the therapeutic potential for the inhibition of factor B in this disease.     

Coordinated multivesicular release at a mammalian ribbon synapse

Traditional models of synaptic transmission hold that release sites within an active zone operate independently. Although the release of multiple vesicles (multivesicular release; MVR) from single active zones occurs at some central synapses, MVR is not thought to require coordination among release sites. Ribbon synapses seem to be optimized to release many vesicles over an extended period, but the dynamics of MVR at ribbon synapses is unknown. We examined MVR at a ribbon synapse in a retinal slice preparation using paired recordings from presynaptic rod bipolar and postsynaptic AII amacrine cells. When evoked release was highly desynchronized, discrete postsynaptic events were larger than quantal miniature excitatory postsynaptic currents (mEPSCs) but had the same time course. The amplitude of these multiquantal mEPSCs, which seem to arise from the essentially simultaneous release of multiple vesicles, was reduced by lowering release probability. The release synchrony reflected in these multivesicular events suggests that release within an active zone is coordinated during MVR.     

Virtual patient simulator for distributed collaborative medical education

Project TOUCH (Telehealth Outreach for Unified Community Health; http://hsc.unm.edu/touch) investigates the feasibility of using advanced technologies to enhance education in an innovative problem-based learning format currently being used in medical school curricula, applying specific clinical case models, and deploying to remote sites/workstations. The University of New Mexico's School of Medicine and the John A. Burns School of Medicine at the University of Hawai'i face similar health care challenges in providing and delivering services and training to remote and rural areas. Recognizing that health care needs are local and require local solutions, both states are committed to improving health care delivery to their unique populations by sharing information and experiences through emerging telehealth technologies by using high-performance computing and communications resources. The purpose of this study is to describe the deployment of a problem-based learning case distributed over the National Computational Science Alliance's Access Grid. Emphasis is placed on the underlying technical components of the TOUCH project, including the virtual reality development tool Flatland, the artificial intelligence-based simulation engine, the Access Grid, high-performance computing platforms, and the software that connects them all. In addition, educational and technical challenges for Project TOUCH are identified.     

Human monoclonal anti-DNA antibodies react as lymphocytotoxic antibodies

Two out of 25 monoclonal anti-DNA autoantibodies that were produced by human-human hybridoma were found to have lymphocytotoxic activity. The antibodies reacted with normal B and T lymphocytes at cold (4 degrees C) as well as at warm (37 degrees C) temperatures. The lymphocytotoxic activity of the monoclonal anti-DNA antibodies could be inhibited by prior incubation of the antibodies with either polynucleotides, e.g. poly(I), poly(dT) or anti-idiotypic antibodies, that had been raised against a dominant anti-DNA antibody. The cross-reactivity between nuclear material and lymphocyte membrane raises the question whether these apparently diverse materials have a shared epitope. The cross-reactivity between anti-DNA antibodies and lymphocyte membrane may account in part for the lymphopenia observed in systemic lupus erythematosus patients.     

Retinoic acid is required for endodermal pouch morphogenesis and not for pharyngeal endoderm specification.

Because tissues from all three germ layers contribute to the pharyngeal arches, it is not surprising that all major signaling pathways are involved in their development. We focus on the role of retinoic acid (RA) signaling because it has been recognized for quite some time that alterations in this pathway lead to craniofacial malformations. Several studies exist that describe phenotypes observed upon RA perturbations in pharyngeal arch development; however, these studies did not address whether RA plays multiple roles at distinct time points during development. Here, we report the resulting phenotypes in the hindbrain, the neural crest-derived tissues, and the pharyngeal endoderm when RA synthesis is disrupted during zebrafish gastrulation and pharyngeal arch morphogenesis. Our results demonstrate that RA is required for the post-gastrulation morphogenesis and segmentation of endodermal pouches, and that loss of RA does not affect the length of the pharyngeal ectoderm or medial endoderm along the anterior-posterior axis. We also provide evidence that RA is not required for the specification of pharyngeal pouch endoderm and that the pharyngeal endoderm consists of at least two different cell populations, of which the pouch endoderm is sensitive to RA and the more medial pharyngeal endoderm is not. These results demonstrate that the developmental processes underlying pharyngeal arch defects differ depending on when RA signaling is disturbed during development.     

Early appearance of inhibitory input to the MNTB supports binaural processing during development

Despite the peripheral and central immaturities that limit auditory processing in juvenile animals, they are able to lateralize sounds using binaural cues. This study explores a central mechanism that may compensate for these limitations during development. Interaural time and level difference processing by neurons in the superior olivary complex depends on synaptic inhibition from the medial nucleus of the trapezoid body (MNTB), a group of inhibitory neurons that is activated by contralateral sound stimuli. In this study, we examined the maturation of coding properties of MNTB neurons and found that they receive an inhibitory influence from the ipsilateral ear that is modified during the course of postnatal development. Single neuron recordings were obtained from the MNTB in juvenile (postnatal day 15-19) and adult gerbils. Approximately 50% of all recorded MNTB neurons were inhibited by ipsilateral sound stimuli, but juvenile neurons displayed a much greater suppression of firing as compared with those in adults. A comparison of the prepotential and postsynaptic action potential indicated that inhibition occurred at the presynaptic level, likely within the cochlear nucleus. A simple linear model of level difference detection by lateral superior olivary neurons that receive input from MNTB suggested that inhibition of the MNTB may expand the response of LSO neurons to physiologically realistic level differences, particularly in juvenile animals, at a time when these cues are reduced.     

Between a hygiene rock and a hygienic hard place: Avoiding SARS-CoV-2 while needing environmental exposures for immunity

Suboptimal understanding of concepts related to hygiene by the general public, clinicians and researchers is a persistent problem in health and medicine. Although hygiene is necessary to slow or prevent deadly pandemics of infectious disease such as coronavirus disease 2019 (COVID-19), hygiene can have unwanted effects. In particular, some aspects of hygiene cause a loss of biodiversity from the human body, characterized by the almost complete removal of intestinal worms (helminths) and protists. Research spanning more than half a century documents that this loss of biodiversity results in an increased propensity for autoimmune disease, allergic disorders, probably neuropsychiatric problems and adverse reactions to infectious agents. The differences in immune function between communities with and communities without helminths have become so pronounced that the reduced lethality of severe acute respiratory syndrome coronavirus 2 in low-income countries compared to high-income countries was predicted early in the COVID-19 pandemic. This prediction, based on the maladaptive immune responses observed in many cases of COVID-19 in high-income countries, is now supported by emerging data from low-income countries. Herein, hygiene is subdivided into components involving personal choice versus components instituted by community wide systems such as sewage treatment facilities and water treatment plants. The different effects of personal hygiene and systems hygiene are described, and appropriate measures to alleviate the adverse effects of hygiene without losing the benefits of hygiene are discussed. Finally, text boxes are provided to function as stand-alone, public-domain handouts with the goal of informing the public about hygiene and suggesting solutions for biomedical researchers and policy makers.Lay Summary: Hygiene related to sewer systems and other technology can have adverse effects on immune function, and is distinct from personal hygiene practices such as hand washing and social distancing. Dealing with the drawbacks of hygiene must be undertaken without compromising the protection from infectious disease imposed by hygiene.     

Association between Fruit and Vegetable Intakes and Mental Health in the Australian Diabetes Obesity and Lifestyle Cohort

Increasing prevalence of mental health disorders within the Australian population is a serious public health issue. Adequate intake of fruits and vegetables (FV), dietary fibre (DF) and resistant starch (RS) is associated with better mental and physical health. Few longitudinal studies exist exploring the temporal relationship. Using a validated food frequency questionnaire, we examined baseline FV intakes of 5845 Australian adults from the AusDiab study and estimated food group-derived DF and RS using data from the literature. Perceived mental health was assessed at baseline and 5 year follow up using SF-36 mental component summary scores (MCS). We conducted baseline cross-sectional analysis and prospective analysis of baseline dietary intake with perceived mental health at 5 years. Higher baseline FV and FV-derived DF and RS intakes were associated with better 5 year MCS (p < 0.001). A higher FV intake (754 g/d vs. 251 g/d, Q4 vs. Q1) at baseline had 41% lower odds (OR = 0.59: 95% CI 0.46–0.75) of MCS below population average (<47) at 5 year follow up. Findings were similar for FV-derived DF and RS. An inverse association was observed with discretionary food-derived DF and RS. This demonstrates the association between higher intakes of FV and FV-derived DF and RS with better 5 year mental health outcomes. Further RCTs are necessary to understand mechanisms that underlie this association including elucidation of causal effects.