Nonlinear multiplicative dendritic integration in neuron and network models

Neurons receive inputs from thousands of synapses distributed across dendritic trees of complex morphology. It is known that dendritic integration of excitatory and inhibitory synapses can be highly non-linear in reality and can heavily depend on the exact location and spatial arrangement of inhibitory and excitatory synapses on the dendrite. Despite this known fact, most neuron models used in artificial neural networks today still only describe the voltage potential of a single somatic compartment and assume a simple linear summation of all individual synaptic inputs. We here suggest a new biophysical motivated derivation of a single compartment model that integrates the non-linear effects of shunting inhibition, where an inhibitory input on the route of an excitatory input to the soma cancels or “shunts” the excitatory potential. In particular, our integration of non-linear dendritic processing into the neuron model follows a simple multiplicative rule, suggested recently by experiments, and allows for strict mathematical treatment of network effects. Using our new formulation, we further devised a spiking network model where inhibitory neurons act as global shunting gates, and show that the network exhibits persistent activity in a low firing regime

Cottonseed Meal and Gossypol Toxicity Studies with Ruminants and Non-Ruminants

Animal Nutritio

A suicide gene approach using the human pro-apoptotic protein tBid inhibits HIV-1 replication

<p>Abstract</p> <p>Background</p> <p>Regulated expression of suicide genes is a powerful tool to eliminate specific subsets of cells and will find widespread usage in both basic and applied science. A promising example is the specific elimination of human immunodeficiency virus type 1 (HIV-1) infected cells by LTR-driven suicide genes. The success of this approach, however, depends on a fast and effective suicide gene, which is expressed exclusively in HIV-1 infected cells. These preconditions have not yet been completely fulfilled and, thus, success of suicide approaches has been limited so far. We tested truncated Bid (tBid), a human pro-apoptotic protein that induces apoptosis very rapidly and efficiently, as suicide gene for gene therapy against HIV-1 infection.</p> <p>Results</p> <p>When tBid was introduced into the HIV-1 LTR-based, Tat- and Rev-dependent transgene expression vector pLRed(INS)₂R, very efficient induction of apoptosis was observed within 24 hours, but only in the presence of both HIV-1 regulatory proteins Tat and Rev. Induction of apoptosis was not observed in their absence. Cells containing this vector rapidly died when transfected with plasmids containing full-length viral genomic DNA, completely eliminating the chance for HIV-1 replication. Viral replication was also strongly reduced when cells were infected with HIV-1 particles.</p> <p>Conclusions</p> <p>This suicide vector has the potential to establish a safe and effective gene therapy approach to exclusively eliminate HIV-1 infected cells before infectious virus particles are released.</p

Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects of the axoneme underlie the disease, which is characterised by chronic respiratory symptoms and obstructive lung disease, infertility and body axis laterality defects. We applied a next-generation sequencing approach to identify the gene responsible for this phenotype in two consanguineous families

Stillbirth differences according to regions of origin: an analysis of the German perinatal database, 2004-2007

Reeske A, Kutschmann M, Razum O, Spallek J. Stillbirth differences according to regions of origin: an analysis of the German perinatal database, 2004-2007. BMC Pregnancy and Childbirth. 2011;11(1): 63.Background: Stillbirth is a sensitive indicator for access to, and quality of health care and social services in a society. If a particular population group e. g. migrants experiences higher rates of stillbirth, this might be an indication of social deprivation or barriers to health care. This study examines differences in risk of stillbirth for women of different regions of origin compared to women from Germany in order to identify high risk groups/target groups for prevention strategies. Methods: We used the BQS dataset routinely compiled to examine perinatal outcomes in Germany nationwide. Participation of hospitals and completeness of data has been about 98% in recent years. Data on all live births and stillbirths were obtained for the period 2004 to 2007 (N = 2,670,048). We calculated crude and stratified mortality rates as well as corresponding relative mortality risks. Results: A significantly elevated stillbirth rate was found for women from the Middle East and North Africa (incl. Turkey) (RR 1.34, CI 1.22-1.55). The risk was slightly attenuated for low SES. An elevated risk was also found for women from Asia (RR 1.18, CI 1.02-1.65) and from Mediterranean countries (RR 1.14, CI 0.93-1.28). No considerable differences either in use and timing of antenatal care or preterm birth and low birthweight were observed between migrant and non-migrant women. After stratification for light for gestational age, the relative risk of stillbirth for women from the Middle East/North Africa increased to 1.63 (95% CI 1.25-2.13). When adjusted for preterm births with low birthweight, women from Eastern Europe and the Middle East/North Africa experienced a 26% (43%) higher risk compared with women from Germany. Conclusions: We found differences in risk of stillbirth among women from Middle East/North Africa, especially in association with low SES and low birthweight for gestational age. Our findings suggest a need for developing and evaluating socially and culturally sensitive health promotion and prevention programmes for this group. The findings should also stimulate discussion about the quality and appropriateness of antenatal and perinatal care of pregnant women and newborns with migrant backgrounds

Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus

The NKG2D receptor stimulates natural killer cell and T cell responses upon engagement of ligands associated with malignancies and certain autoimmune diseases. However, conditions of persistent NKG2D ligand expression can lead to immunosuppression. In cancer patients, tumor expression and shedding of the MHC class I–related chain A (MICA) ligand of NKG2D drives proliferative expansions of NKG2D+CD4+ T cells that produce interleukin-10 (IL-10) and transforming growth factor-β, as well as Fas ligand, which inhibits bystander T cell proliferation in vitro. Here, we show that increased frequencies of functionally equivalent NKG2D+CD4+ T cells are inversely correlated with disease activity in juvenile-onset systemic lupus erythematosus (SLE), suggesting that these T cells may have regulatory effects. The NKG2D+CD4+ T cells correspond to a normally occurring small CD4 T cell subset that is autoreactive, primed to produce IL-10, and clearly distinct from proinflammatory and cytolytic CD4 T cells with cytokine-induced NKG2D expression that occur in rheumatoid arthritis and Crohn's disease. As classical regulatory T cell functions are typically impaired in SLE, it may be clinically significant that the immunosuppressive NKG2D+CD4+ T cells appear functionally uncompromised in this disease

Comparative analyses of vertebrate posterior HoxD clusters reveal atypical cluster architecture in the caecilian Typhlonectes natans

<p>Abstract</p> <p>Background</p> <p>The posterior genes of the <it>HoxD </it>cluster play a crucial role in the patterning of the tetrapod limb. This region is under the control of a global, long-range enhancer that is present in all vertebrates. Variation in limb types, as is the case in amphibians, can probably not only be attributed to variation in <it>Hox </it>genes, but is likely to be the product of differences in gene regulation. With a collection of vertebrate genome sequences available today, we used a comparative genomics approach to study the posterior <it>HoxD </it>cluster of amphibians. A frog and a caecilian were included in the study to compare coding sequences as well as to determine the gain and loss of putative regulatory sequences.</p> <p>Results</p> <p>We sequenced the posterior end of the <it>HoxD </it>cluster of a caecilian and performed comparative analyses of this region using <it>HoxD </it>clusters of other vertebrates. We determined the presence of conserved non-coding sequences and traced gains and losses of these footprints during vertebrate evolution, with particular focus on amphibians. We found that the caecilian <it>HoxD </it>cluster is almost three times larger than its mammalian counterpart. This enlargement is accompanied with the loss of one gene and the accumulation of repeats in that area. A similar phenomenon was observed in the coelacanth, where a different gene was lost and expansion of the area where the gene was lost has occurred. At least one phylogenetic footprint present in all vertebrates was lost in amphibians. This conserved region is a known regulatory element and functions as a boundary element in neural tissue to prevent expression of <it>Hoxd </it>genes.</p> <p>Conclusion</p> <p>The posterior part of the <it>HoxD </it>cluster of <it>Typhlonectes natans </it>is among the largest known today. The loss of <it>Hoxd-12 </it>and the expansion of the intergenic region may exert an influence on the limb enhancer, by having to bypass a distance seven times that of regular <it>HoxD </it>clusters. Whether or not there is a correlation with the loss of limbs remains to be investigated. These results, together with data on other vertebrates show that the tetrapod <it>Hox </it>clusters are more variable than previously thought.</p

Induction of antigen-specific tolerance through hematopoietic stem cell-mediated gene therapy: the future for therapy of autoimmune disease?

Based on the principle that immune ablation followed by HSC-mediated recovery purges disease-causing leukocytes to interrupt autoimmune disease progression, hematopoietic stem cell transplantation (HSCT) has been increasingly used as a treatment for severe autoimmune diseases. Despite clinically-relevant outcomes, HSCT is associated with serious iatrogenic risks and is suitable only for the most serious and intractable diseases. A further limitation of autologous HSCT is that relapse rates can be high, suggesting disease-causing leukocytes are incompletely purged or the environmental and genetic determinants that drive disease remain active. Incorporation of antigen-specific tolerance approaches that synergise with autologous HSCT could reduce or prevent relapse. Further, by reducing the requirement for highly toxic immune-ablation and instead relying on antigen-specific tolerance, the clinical utility of HSCT could be significantly diversified. Substantial progress has been made exploring HSCT-mediated induction of antigen-specific tolerance in animal models but studies have focussed on primarily on prevention of autoimmune diseases. However, as diagnosis of autoimmune disease is often not made until autoimmune disease is well developed and populations of autoantigen-specific pathogenic effector and memory T cells have become well established, immunotherapies must be developed to address effector and memory T-cell responses which have traditionally been considered the key impediment to immunotherapy. Here, focusing on T-cell mediated autoimmune diseases we review progress made in antigen-specific immunotherapy using HSCT-mediated approaches, induction of tolerance in effector and memory T cells and the challenges for progression and clinical application of antigen-specific ‘tolerogenic’ HSCT therapy

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Design principles of the sparse coding network and the role of sister cells in the olfactory system of Drosophila

Sensory systems face the challenge to represent sensory inputs in a way to allow easy readout of sensory information by higher brain areas. In the olfactory system of the fly drosopohila melanogaster, projection neurons (PNs) of the antennal lobe (AL) convert a dense activation of glomeruli into a sparse, high-dimensional firing pattern of Kenyon cells (KCs) in the mushroom body (MB). Here we investigate the design principles of the olfactory system of drosophila in regard to the capabilities to discriminate odor quality from the MB representation and its robustness to different types of noise. We focus on understanding the role of highly correlated homotypic projection neurons (sister cells) found in the glomeruli of flies. These cells are coupled by gap-junctions and receive almost identical sensory inputs, but target randomly different KCs in MB. We show that sister cells might play a crucial role in increasing the robustness of the MB odor representation to noise. Computationally, sister cells thus might help the system to improve the generalization capabilities in face of noise without impairing the discriminability of odor quality at the same time