Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse.

Insulin-dependent diabetes mellitus (IDDM) is thought to be an immunologically mediated disease resulting in the complete destruction of the insulin-producing islets of Langerhans. It has become increasingly clear that autoreactive T cells play a major role in the development and progression of this disease. In this study, we examined the role of the CD28/B7 costimulation pathway in the development and progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse model. Female NOD mice treated at the onset of insulitis (2-4 wk of age) with CTLA4Ig immunoglobulin (Ig) (a soluble CD28 antagonist) or a monoclonal antibody (mAb) specific for B7-2 (a CD28 ligand) did not develop diabetes. However, neither of these treatments altered the disease process when administered late, at > 10 wk of age. Histological examination of islets from the various treatment groups showed that while CTLA4Ig and anti-B7-2 mAb treatment blocked the development of diabetes, these reagents had little effect on the development or severity of insulitis. Together these results suggest that blockade of costimulatory signals by CTLA4Ig or anti-B7-2 acts early in disease development, after insulitis but before the onset of frank diabetes. NOD mice were also treated with mAbs to another CD28 ligand, B7-1. In contrast to the previous results, the anti-B7-1 treatment significantly accelerated the development of disease in female mice and, most interestingly, induced diabetes in normally resistant male mice. A combination of anti-B7-1 and anti-B7-2 mAbs also resulted in an accelerated onset of diabetes, similar to that observed with anti-B7-1 mAb treatment alone, suggesting that anti-B7-1 mAb's effect was dominant. Furthermore, treatment with anti-B7-1 mAbs resulted in a more rapid and severe infiltrate. Finally, T cells isolated from the pancreas of these anti-B7-1-treated animals exhibited a more activated phenotype than T cells isolated from any of the other treatment groups. These studies demonstrate that costimulatory signals play an important role in the autoimmune process, and that different members of the B7 family have distinct regulatory functions during the development of autoimmune diabetes

Are riparian forest reserves sources of invertebrate biodiversity spillover and associated ecosystem functions in oil palm landscapes?

The world's forested landscapes are increasingly fragmented. The effects of fragmentation on community composition have received more attention than the effects on ecological processes, particularly in the tropics. The extent to which populations from forest fragments move (spillover) into surrounding agricultural areas is of particular interest. This process can retain connectivity between populations and alter the rate of beneficial or detrimental ecological functions. We tested whether riparian forest fragments (riparian reserves), are sources of two functionally important invertebrate groups (dung beetles and scavenging ants) within oil palm plantations in Malaysia. We also assessed whether forest fragments enhance rates of associated ecosystem functions (dung and bait removal). We found that oil palm sites with and without adjacent riparian reserves had similar overall beetle and ant communities and functional rates. However, dung beetle species richness, abundance and diversity declined with distance from a riparian reserve, providing evidence for a weak spillover effect. In addition, dung beetle community metrics within a riparian reserve predicted corresponding values in adjacent oil palm areas. These relationships did not hold for dung removal, ant community metrics or bait removal. Taken together, our results indicate that although riparian reserves are an important habitat in their own right, under the conditions in which we sampled they have a limited role as sources of functionally important invertebrates. Crucially, our results suggest that contiguous habitat corridors are important for maintaining connectivity of invertebrate populations, as forest dependent species may not easily be able to disperse through the agricultural matrix.We thank EPU Malaysia, Sabah Biodiversity Council and SEARRP for providing research permissions for field work in Sabah. The SAFE project coordinators (Ed Turner, Johnny Larenus and MinSheng Khoo), research assistants Max Gray and Joana Ferreira, as well as several members of the SAFE project field staff provided logistical support and helped with data collection. Bridget Gray helped with data entry and verification The Hope Entomological Collections at the Oxford University Museum of Natural History provided resources for species' identification. CLG was supported by a NERC DTG studentship (NE/I528526/1) and TMF by Yayasan Sime Darby, the Czech Science Foundation (grant numbers 14-32302S, 16-09427S) and an Australian Research Council Discovery Grant (DP140101541). EMS was funded by a NERC HMTF grant (NE/K016261/1).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.biocon.2015.12.01

Numerical Algebraic Geometry: A New Perspective on String and Gauge Theories

The interplay rich between algebraic geometry and string and gauge theories has recently been immensely aided by advances in computational algebra. However, these symbolic (Gr\"{o}bner) methods are severely limited by algorithmic issues such as exponential space complexity and being highly sequential. In this paper, we introduce a novel paradigm of numerical algebraic geometry which in a plethora of situations overcomes these short-comings. Its so-called 'embarrassing parallelizability' allows us to solve many problems and extract physical information which elude the symbolic methods. We describe the method and then use it to solve various problems arising from physics which could not be otherwise solved.Comment: 36 page

Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population

Background: Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in TRDN-encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome and sudden unexplained death in the young is unknown. Methods: Exome sequencing was performed on 599 sudden infant death syndrome and 258 sudden unexplained death in the young cases. Allele frequencies of all TRDN null variants identified in the cardiac-specific isoform of TRDN in the Genome Aggregation Database were used to determine the estimated prevalence and ethnic distribution of TKOS. Results: No triadin null individuals were identified in 599 sudden infant death syndrome and 258 sudden unexplained death in the young exomes. Using the Genome Aggregation Database, we estimate the overall prevalence of TKOS to be ≈1:22.7 million individuals. However, TKOS prevalence is 5.5-fold higher in those of African descent (≈1:4.1 million). Conclusions: TKOS is an exceedingly rare clinical entity that does not contribute meaningfully to either sudden infant death syndrome or sudden unexplained death in the young. However, despite its rarity and absence in large sudden death cohorts, TKOS remains a malignant and potentially lethal disorder which requires further research to better care for these patients

Novel Characteristics of Valveless Pumping

This study investigates the occurrence of valveless pumping in a fluidfilled system consisting of two open tanks connected by an elastic tube. We show that directional flow can be achieved by introducing a periodic pinching applied at an asymmetrical location along the tube, and that the flow direction depends on the pumping frequency. We propose a relation between wave propagation velocity, tube length, and resonance frequencies associated with shifts in the pumping direction using numerical simulations. The eigenfrequencies of the system are estimated from the linearized system, and we show that these eigenfrequencies constitute the resonance frequencies and the horizontal slope frequencies of the system; 'horizontal slope frequency' being a new concept. A simple model is suggested, explaining the effect of the gravity driven part of the oscillation observed in response to the tank and tube diameter changes. Results are partly compared with experimental findings.Art. no. 22450

Pediatric Cardiac Xenotransplantation: Recommendations for the Ethical Design of Clinical Trials

For children with complex congenital heart problems, cardiac allotransplantation is sometimes the best therapeutic option. However, availability of hearts for pediatric patients is limited, resulting in a long and growing waitlist, and a high mortality rate while waiting. Cardiac xenotransplantation has been proposed as one therapeutic alternative for neonates and infants, either in lieu of allotransplantation or as a bridge until an allograft becomes available. Scientific and clinical developments in xenotransplantation appear likely to permit cardiac xenotransplantation clinical trials in adults in the coming years. The ethical issues around xenotransplantation of the heart and other organs and tissues have recently been examined, but to date, only limited literature is available on the ethical issues that are attendant with pediatric heart xenotransplantation. Here, we summarize the ethical issues, focusing on (i) whether cardiac xenotransplantation should proceed in adults or children first, (ii) pediatric recipient selection for initial xenotransplantation trials, (iii) special problems regarding informed consent in this context, and (iv) related psychosocial and public perception considerations. We conclude with specific recommendations regarding ethically informed design of pediatric heart xenotransplantation trials

The Chiral Dipolar Hard Sphere Model

A simple molecular model of chiral molecules is presented in this paper : the chiral dipolar hard sphere model. The discriminatory interaction between enantiomers is represented by electrostatic (or magnetic) dipoles-dipoles interactions : short ranged steric repulsion are represented by hard sphere potential and, in each molecule, two point dipoles are located inside the sphere. The model is described in detail and some of its elementary properties are given ; in particular, it is shown that the that the knowledge of only three multipole spherical components (namely : $Q_{10}$, $Q_{21}$ and $Q_{22}$) allows to compute all multipole spherical components of the model. Despite, the simplicity of the model, it is shown also that the energy landscape of the interaction between two enantiomers is quite rich, this renders systems of chiral dipolar hard sphere very interesting and complicated to study. Few preliminary Monte Carlo simulation results are also reported in the paper. Last, but not least, this paper is dedicated to Jean-Jacques Weis.Comment: 28 pages, 14 Figures, 3 Tables. To appear in Molecular Physic

Progression of Neuropsychiatric Symptoms over Time in an Incident Parkinson's Disease Cohort (ICICLE-PD).

BACKGROUND: Cross-sectional studies have identified that the prevalence of neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) ranges from 70-89%. However, there are few longitudinal studies determining the impact of NPS on quality of life (QoL) in PD patients and their caregivers. We seek to determine the progression of NPS in early PD. METHODS: Newly diagnosed idiopathic PD cases (n = 212) and age-matched controls (n = 99) were recruited into a longitudinal study. NPS were assessed using the Neuropsychiatric Inventory with Caregiver Distress scale (NPI-D). Further neuropsychological and clinical assessments were completed by participants, with reassessment at 18 and 36 months. Linear mixed-effects modelling determined factors associated with NPI-D and QoL over 36 months. RESULTS: Depression, anxiety, apathy and hallucinations were more frequent in PD than controls at all time points (p < 0.05). Higher motor severity at baseline was associated with worsening NPI-D scores over time (β = 0.1, p < 0.05), but not cognition. A higher NPI total score was associated with poorer QoL at any time point (β = 0.3, p < 0.001), but not changed in QoL scores. CONCLUSION: NPS are significantly associated with poorer QoL, even in early PD. Screening for NPS from diagnosis may allow efficient delivery of better support and treatment to patients and their families

The complete mitochondrial genome of the foodborne parasitic pathogen Cyclospora cayetanensis

Cyclospora cayetanensis is a human-specific coccidian parasite responsible for several food and water-related outbreaks around the world, including the most recent ones involving over 900 persons in 2013 and 2014 outbreaks in the USA. Multicopy organellar DNA such as mitochondrion genomes have been particularly informative for detection and genetic traceback analysis in other parasites. We sequenced the C. cayetanensis genomic DNA obtained from stool samples from patients infected with Cyclospora in Nepal using the Illumina MiSeq platform. By bioinformatically filtering out the metagenomic reads of non-coccidian origin sequences and concentrating the reads by targeted alignment, we were able to obtain contigs containing Eimeria-like mitochondrial, apicoplastic and some chromosomal genomic fragments. A mitochondrial genomic sequence was assembled and confirmed by cloning and sequencing targeted PCR products amplified from Cyclospora DNA using primers based on our draft assembly sequence. The results show that the C. cayetanensis mitochondrion genome is 6274 bp in length, with 33% GC content, and likely exists in concatemeric arrays as in Eimeria mitochondrial genomes. Phylogenetic analysis of the C. cayetanensis mitochondrial genome places this organism in a tight cluster with Eimeria species. The mitochondrial genome of C. cayetanensis contains three protein coding genes, cytochrome (cytb), cytochrome C oxidase subunit 1 (cox1), and cytochrome C oxidase subunit 3 (cox3), in addition to 14 large subunit (LSU) and nine small subunit (SSU) fragmented rRNA genes