Live Demonstration: Multiplexing AER Asynchronous Channels over LVDS Links with Flow-Control and Clock- Correction for Scalable Neuromorphic Systems

In this live demonstration we exploit the use of a serial link for fast asynchronous communication in massively parallel processing platforms connected to a DVS for realtime implementation of bio-inspired vision processing on spiking neural networks

Sequential Assembly of Centromeric Proteins in Male Mouse Meiosis

The assembly of the mitotic centromere has been extensively studied in recent years, revealing the sequence and regulation of protein loading to this chromosome domain. However, few studies have analyzed centromere assembly during mammalian meiosis. This study specifically targets this approach on mouse spermatocytes. We have found that during prophase I, the proteins of the chromosomal passenger complex Borealin, INCENP, and Aurora-B load sequentially to the inner centromere before Shugoshin 2 and MCAK. The last proteins to be assembled are the outer kinetochore proteins BubR1 and CENP-E. All these proteins are not detected at the centromere during anaphase/telophase I and are then reloaded during interkinesis. The loading sequence of the analyzed proteins is similar during prophase I and interkinesis. These findings demonstrate that the interkinesis stage, regularly overlooked, is essential for centromere and kinetochore maturation and reorganization previous to the second meiotic division. We also demonstrate that Shugoshin 2 is necessary for the loading of MCAK at the inner centromere, but is dispensable for the loading of the outer kinetochore proteins BubR1 and CENP-E

A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data

Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF < 1 %), compared to imputation using the SNP chip alone. Also, we investigated the systematic effect of reference panels on imputation quality using five reference panels and three genotype panels. The best performing approach was the combination of the study specific reference panel and the genotype panel of combined data. Conclusions: Our study demonstrates that combined datasets, including SNP chips and exome chips, enhances both the imputation quality and genomic coverage of rare variants

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Physical activity attenuates the influence of FTO variants on obesity risk : a meta-analysis of 218,166 adults and 19,268 children

BACKGROUND: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). METHODS AND FINDINGS: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction)  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. CONCLUSIONS: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

High-Speed Serial Interfaces for Event-Driven Neuromorphic Systems

Neuromorphic Engineering is the discipline of building sensory processing artificial systems inspired in the neural processing found in living beings. Biological neural brains show massive connectivity among neurons, which is not realistic to mimic using wires within silicon chips or between chips. Address- Event-Representation is a technology widely used among neuromorphic engineers to emulate such massive interconnectivity by time-multiplexing fast digital channels by transmitting “Address Events” between neurons that mimic the neural spikes transmitted in biology. Here we show on-going progress on bitserial SATA AER inter-FPGA communications for multi-tile scalable neuromorphic systems.Ministerio de Economía y Competitividad TEC2012-37868-C04- 02/01Junta de Andalucía TIC-6091Ministry of Science and Higher Education of the Republic of Poland AGH UST no. 11.11.120.612European Union PRI-PIMCHI-2011-0768European Union FP7 grant HBP (The Human Brain Project) 604102European Union H2020 EU grant ECOMODE 64409

Live demonstration: multiplexing AER asynchronous channels over LVDS Links with Flow-Control and Clock-Correction for Scalable Neuromorphic Systems

Paper presented at the 2017 IEEE International Symposium on Circuits and Systems (ISCAS), held in Baltimore, MD, USA, on 28-31 May 2017.We propose demonstration of a serial link for fast asynchronous communication in massively parallel platforms connected to DVS for real-time implementation of bio-inspired vision processing and spiking neural networks

Trace element bioaccumulation, tissue distribution, and elimination in odontocetes stranded in Florida and Georgia, USA over a 15-year period (2007-2021).

Odontocetes obtain nutrients including essential elements through their diet and are exposed to heavy metal contaminants via ingestion of contaminated prey. We evaluated the prevalence, concentration, and tissue distribution of essential and non-essential trace elements, including heavy metal toxicants, in tissue (blubber, kidney, liver, skeletal muscle, skin) and fecal samples collected from 90 odontocetes, representing nine species, that stranded in Georgia and Florida, USA during 2007-2021. Samples were analyzed for concentrations of seven essential (cobalt, copper, iron, manganese, molybdenum, selenium, zinc) and five non-essential (arsenic, cadmium, lead, mercury, thallium) elemental analytes using inductively-coupled plasma mass spectrometry. Rissos dolphins (Grampus griseus) and short-finned pilot whales (Globicephala macrorhynchus) had the highest median concentrations of mercury, cadmium, and lead, while dwarf sperm whales (Kogia sima) had the lowest. Adult pygmy and dwarf sperm whales that stranded in 2019-2021 had higher concentrations of arsenic, copper, iron, lead, manganese, selenium, thallium, and zinc compared to those that stranded in 2010-2018, suggesting an increasing risk of exposure over time. The highest concentrations of many elements (e.g., cadmium, cobalt, copper, manganese, molybdenum, thallium, zinc) were in fecal samples, illustrating the usefulness of this noninvasively collected sample. Aside from fecal samples, hepatic tissues had the highest concentrations of iron, manganese, mercury, molybdenum, and selenium in most species; renal tissues had the highest concentrations of cadmium; skin had the highest concentrations of zinc; and copper, arsenic, and lead concentrations were primarily distributed among the liver and kidneys. Phylogenetic differences in patterns of trace element concentrations likely reflect species-specific differences in diet, trophic level, and feeding strategies, while heterogeneous distributions of elemental analytes among different organ types reflect differences in elemental biotransformation, elimination, and storage. This study illustrates the importance of monitoring toxic contaminants in stranded odontocetes, which serve as important sentinels of environmental contamination, and whose health may be linked to human health

Trace element bioaccumulation, tissue distribution, and elimination in odontocetes stranded in Florida and Georgia, USA over a 15-year period (2007–2021)

Odontocetes obtain nutrients including essential elements through their diet and are exposed to heavy metal contaminants via ingestion of contaminated prey. We evaluated the prevalence, concentration, and tissue distribution of essential and non-essential trace elements, including heavy metal toxicants, in tissue (blubber, kidney, liver, skeletal muscle, skin) and fecal samples collected from 90 odontocetes, representing nine species, that stranded in Georgia and Florida, USA during 2007–2021. Samples were analyzed for concentrations of seven essential (cobalt, copper, iron, manganese, molybdenum, selenium, zinc) and five non-essential (arsenic, cadmium, lead, mercury, thallium) elemental analytes using inductively-coupled plasma mass spectrometry. Risso's dolphins (Grampus griseus) and short-finned pilot whales (Globicephala macrorhynchus) had the highest median concentrations of mercury, cadmium, and lead, while dwarf sperm whales (Kogia sima) had the lowest. Adult pygmy and dwarf sperm whales that stranded in 2019–2021 had higher concentrations of arsenic, copper, iron, lead, manganese, selenium, thallium, and zinc compared to those that stranded in 2010–2018, suggesting an increasing risk of exposure over time. The highest concentrations of many elements (e.g., cadmium, cobalt, copper, manganese, molybdenum, thallium, zinc) were in fecal samples, illustrating the usefulness of this noninvasively collected sample. Aside from fecal samples, hepatic tissues had the highest concentrations of iron, manganese, mercury, molybdenum, and selenium in most species; renal tissues had the highest concentrations of cadmium; skin had the highest concentrations of zinc; and copper, arsenic, and lead concentrations were primarily distributed among the liver and kidneys. Phylogenetic differences in patterns of trace element concentrations likely reflect species-specific differences in diet, trophic level, and feeding strategies, while heterogeneous distributions of elemental analytes among different organ types reflect differences in elemental biotransformation, elimination, and storage. This study illustrates the importance of monitoring toxic contaminants in stranded odontocetes, which serve as important sentinels of environmental contamination, and whose health may be linked to human health