On Spike-Timing-Dependent-Plasticity, Memristive Devices, and Building a Self-Learning Visual Cortex

In this paper we present a very exciting overlap between emergent nanotechnology and neuroscience, which has been discovered by neuromorphic engineers. Specifically, we are linking one type of memristor nanotechnology devices to the biological synaptic update rule known as spike-time-dependent-plasticity (STDP) found in real biological synapses. Understanding this link allows neuromorphic engineers to develop circuit architectures that use this type of memristors to artificially emulate parts of the visual cortex. We focus on the type of memristors referred to as voltage or flux driven memristors and focus our discussions on a behavioral macro-model for such devices. The implementations result in fully asynchronous architectures with neurons sending their action potentials not only forward but also backward. One critical aspect is to use neurons that generate spikes of specific shapes. We will see how by changing the shapes of the neuron action potential spikes we can tune and manipulate the STDP learning rules for both excitatory and inhibitory synapses. We will see how neurons and memristors can be interconnected to achieve large scale spiking learning systems, that follow a type of multiplicative STDP learning rule. We will briefly extend the architectures to use three-terminal transistors with similar memristive behavior. We will illustrate how a V1 visual cortex layer can assembled and how it is capable of learning to extract orientations from visual data coming from a real artificial CMOS spiking retina observing real life scenes. Finally, we will discuss limitations of currently available memristors. The results presented are based on behavioral simulations and do not take into account non-idealities of devices and interconnects. The aim of this paper is to present, in a tutorial manner, an initial framework for the possible development of fully asynchronous STDP learning neuromorphic architectures exploiting two or three-terminal memristive type devices. All files used for the simulations are made available through the journal web site1

Sheets of branched poly(lactic acid) obtained by one step reactive extrusion calendering process: Melt rheology analysis

One-step reactive extrusion-calendering process (REX-Calendering) was used in order to obtain sheets of 1mm from two PD,L-LA extrusion grades modified with a styrene-acrylic multifunctional oligomeric agent. In a preliminary internal mixer study, torque versus time was monitored in order to determine chain extender ratios and reaction time. Once all parameters were optimized, reactive extrusion experiments were performed. Independently of the processing method employed, under the same processing conditions, PD,L-LA with the lower D enantiomer molar content revealed a higher reactivity towards the reactive agent, induced by its higher thermal sensitivity. REXCalendering process seemed to minimize the degradations reactions during processing, although a competition between degradation and chain extension/branching reactions took place in both processes. Finally, the rheological characterization revealed a higher degree of modification in the melt rheological behaviour for REX-Calendered samples

Maximizing resource usage in multifold molecular dynamics with rCUDA

[EN] The full-understanding of the dynamics of molecular systems at the atomic scale is of great relevance in the fields of chemistry, physics, materials science, and drug discovery just to name a few. Molecular dynamics (MD) is a widely used computer tool for simulating the dynamical behavior of molecules. However, the computational horsepower required by MD simulations is too high to obtain conclusive results in real-world scenarios. This is mainly motivated by two factors: (1) the long execution time required by each MD simulation (usually in the nanoseconds and microseconds scale, and beyond) and (2) the large number of simulations required in drug discovery to study the interactions between a large library of compounds and a given protein target. To deal with the former, graphics processing units (GPUs) have come up into the scene. The latter has been traditionally approached by launching large amounts of simulations in computing clusters that may contain several GPUs on each node. However, GPUs are targeted as a single node that only runs one MD instance at a time, which translates into low GPU occupancy ratios and therefore low throughput. In this work, we propose a strategy to increase the overall throughput of MD simulations by increasing the GPU occupancy through virtualized GPUs. We use the remote CUDA (rCUDA) middleware as a tool to decouple GPUs from CPUs, and thus enabling multi-tenancy of the virtual GPUs. As a working test in the drug discovery field, we studied the binding process of a novel flavonol to DNA with the GROningen MAchine for Chemical Simulations (GROMACS) MD package. Our results show that the use of rCUDA provides with a 1.21x speed-up factor compared to the CUDA counterpart version while requiring a similar power budget.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was jointly supported by the Fundación Séneca (Agencia Regional de Ciencia y Tecnología, Región de Murcia) under grants (20524/PDC/18, 20813/PI/ 18, and 20988/PI/18) and by the Spanish MEC and Eur-opean Commission FEDER under grants TIN2015-66972-C5-3-R, TIN2016-78799-P, and CTQ2017-87974-R (AEI/FEDER, UE). Researchers from the Universitat Politècnica de València are supported by the Generalitat Valenciana under grant PROMETEO/2017/077.Prades, J.; Imbernon, B.; Reaño González, C.; Peña-García, J.; Cerón-Carrasco, JP.; Silla Jiménez, F.; Pérez-Sánchez, H. (2020). Maximizing resource usage in multifold molecular dynamics with rCUDA. 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Structure and dynamics of molecular networks: A novel paradigm of drug discovery. Pharmacology & Therapeutics, 138(3), 333-408. doi:10.1016/j.pharmthera.2013.01.016Franco, A. A. (2013). Multiscale modelling and numerical simulation of rechargeable lithium ion batteries: concepts, methods and challenges. RSC Advances, 3(32), 13027. doi:10.1039/c3ra23502eFrisch MJ, Trucks GW, Schlegel HB, et al. (2016) Gaussian 16 Revision A.03. Wallingford, CT: Gaussian. Inc.Halder, D., & Purkayastha, P. (2018). A flavonol that acts as a potential DNA minor groove binder as also an efficient G-quadruplex loop binder. Journal of Molecular Liquids, 265, 69-76. doi:10.1016/j.molliq.2018.05.117Hess, B., Kutzner, C., van der Spoel, D., & Lindahl, E. (2008). GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. Journal of Chemical Theory and Computation, 4(3), 435-447. doi:10.1021/ct700301qHornak, V., Abel, R., Okur, A., Strockbine, B., Roitberg, A., & Simmerling, C. 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Comparison of simple potential functions for simulating liquid water. The Journal of Chemical Physics, 79(2), 926-935. doi:10.1063/1.445869Kitchen, D. B., Decornez, H., Furr, J. R., & Bajorath, J. (2004). Docking and scoring in virtual screening for drug discovery: methods and applications. Nature Reviews Drug Discovery, 3(11), 935-949. doi:10.1038/nrd1549Lagarde, N., Zagury, J.-F., & Montes, M. (2015). Benchmarking Data Sets for the Evaluation of Virtual Ligand Screening Methods: Review and Perspectives. Journal of Chemical Information and Modeling, 55(7), 1297-1307. doi:10.1021/acs.jcim.5b00090Noroozi, M., Angerson, W. J., & Lean, M. E. (1998). Effects of flavonoids and vitamin C on oxidative DNA damage to human lymphocytes. The American Journal of Clinical Nutrition, 67(6), 1210-1218. doi:10.1093/ajcn/67.6.1210Patra, M., Hyvönen, M. T., Falck, E., Sabouri-Ghomi, M., Vattulainen, I., & Karttunen, M. (2007). Long-range interactions and parallel scalability in molecular simulations. Computer Physics Communications, 176(1), 14-22. doi:10.1016/j.cpc.2006.07.017Pezeshgi Modarres, H., Dorokhov, B. D., Popov, V. O., Ravin, N. V., Skryabin, K. G., & Dal Peraro, M. (2015). Understanding and Engineering Thermostability in DNA Ligase from Thermococcus sp. 1519. Biochemistry, 54(19), 3076-3085. doi:10.1021/bi501227bPhillips, J. C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., … Schulten, K. (2005). Scalable molecular dynamics with NAMD. Journal of Computational Chemistry, 26(16), 1781-1802. doi:10.1002/jcc.20289Prades, J., Reaño, C., Silla, F., Imbernón, B., Pérez-Sánchez, H., & Cecilia, J. M. (2018). Increasing Molecular Dynamics Simulations Throughput by Virtualizing Remote GPUs with rCUDA. Proceedings of the 47th International Conference on Parallel Processing Companion - ICPP ’18. doi:10.1145/3229710.3229734Pronk, S., Páll, S., Schulz, R., Larsson, P., Bjelkmar, P., Apostolov, R., … Lindahl, E. (2013). 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Modeling the longitudinal latent effect of pregabalin on self-reported changes in sleep disturbances in outpatients with generalized anxiety disorder managed in routine clinical practice

Anxiety disorders are among the most common psychiatric illnesses, with generalized anxiety disorder (GAD) being one of the most common. Sleep disturbances are highly prevalent in GAD patients. While treatment with pregabalin has been found to be associated with significant improvement in GAD-related sleep disturbance across many controlled clinical trials, mediational analysis has suggested that a substantial portion of this effect could be the result of a direct effect of pregabalin. Thus, the objective of this study was to model the longitudinal latent effect of pregabalin or usual care (UC) therapies on changes in sleep in outpatients with GAD under routine clinical practice. Male and female GAD outpatients, aged 18 years or above, from a 6-month prospective noninterventional trial were analyzed. Direct and indirect effects of either pregabalin or UC changes in anxiety symptoms (assessed with Hamilton Anxiety Scale) and sleep disturbances (assessed with Medical Outcomes Study-Sleep Scale [MOS-S]) were estimated by a conditional latent curve model applying structural equation modeling. A total of 1,546 pregabalin-naïve patients were analyzed, 984 receiving pregabalin and 562 UC. Both symptoms of anxiety and sleep disturbances were significantly improved in both groups, with higher mean (95% confidence interval) score reductions in subjects receiving pregabalin: −15.9 (−15.2; −16.6) vs −14.5 (−13.5; −15.5), P =0.027, in Hamilton Anxiety Scale; and −29.7 (−28.1; −31.3) vs −24.0 (−21.6; −26.4), P <0.001, in MOS-S. The conditional latent curve model showed that the pregabalin effect on sleep disturbances was significant (γ =−3.99, P <0.001), after discounting the effect on reduction in anxiety symptoms. A mediation model showed that 70% of the direct effect of pregabalin on sleep remained after discounting the mediated effect of anxiety improvement. A substantial proportion of the incremental improvements in anxiety-related sleep disturbances with pregabalin vs UC were explained by its direct effect, not mediated by improvements in anxiety symptom

Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01)

Altres ajuts: Agustí Barnadas: Honoraria: Pfizer. Consulting or Advisory Role: Pfizer, Novartis, Eli Lilly. Speakers'Bureau: Roche, Pfizer, Novartis, Genomic Health International. Travel, Accommodations, Expenses: Roche, Pfizer; Miguel A. Seguí: Consulting or Advisory Role: Roche, Pfizer, Novartis, Amgen, Eisai, Eli Lilly. Speakers' Bureau: Roche, Pfizer, Amgen. Research Funding: Roche (Inst), Novartis (Inst). Travel, Accommodations, Expenses: Roche, Pfizer, Novartis, Amgen.Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P =.136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P =.0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P =.0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation

Stability of SARS-CoV-2 spike antigens against mutations

Modern health care needs preventive vaccines and therapeutic treatments with stability against pathogen mutations to cope with current and future viral infections. At the beginning of the COVID-19 pandemic, our analytic and predictive tool identified a set of eight short SARS-CoV-2 S-spike protein epitopes that had the potential to persistently avoid mutation. Here a combination of genetic, Systems Biology and protein structure analyses confirm the stability of our identified epitopes against viral mutations. Remarkably, this research spans the whole period of the pandemic, during which 93.9% of the eight peptides remained invariable in the globally predominant 43 circulating variants, including Omicron. Likewise, the selected epitopes are conserved in 97% of all 1,514 known SARS-CoV-2 lineages. Finally, experimental analyses performed with these short peptides showed their specific immunoreactivity. This work opens a new perspective on the design of next-generation vaccines and antibody therapies that will remain reliable against future pathogen mutations.Dr. Lozano-Perez acknowledges the European Commission ERDF/FEDER Operational Program 'Murcia' CCI No. 2007ES161PO001 (Project No. 14-20/20). Miodrag Grbic acknowledges support from the NSERC Discovery grant (Canada). This work also has received funding from the Department of Education of the Basque Government via the Consolidated Research Group MATH MODE (IT1456-22). Besides, Ildefonso Martinez De la Fuente and Iker Malaina were supported by the UPV/EHU and Basque Center of Applied Mathematics, grant US21/27N

Municipal distribution of breast cancer mortality among women in Spain

<p>Abstract</p> <p>Background</p> <p>Spain has one of the lowest rates of breast cancer in Europe, though estimated incidence has risen substantially in recent decades. Some years ago, the Spanish Cancer Mortality Atlas showed Spain as having a heterogeneous distribution of breast cancer mortality at a provincial level. This paper describes the municipal distribution of breast cancer mortality in Spain and its relationship with socio-economic indicators.</p> <p>Methods</p> <p>Breast cancer mortality was modelled using the Besag-York-Molliè autoregressive spatial model, including socio-economic level, rurality and percentage of population over 64 years of age as surrogates of reproductive and lifestyle risk factors. Municipal relative risks (RRs) were independently estimated for women aged under 50 years and for those aged 50 years and over. Maps were plotted depicting smoothed RR estimates and the distribution of the posterior probability of RR>1.</p> <p>Results</p> <p>In women aged 50 years and over, mortality increased with socio-economic level, and was lower in rural areas and municipalities with higher proportion of old persons. Among women aged under 50 years, rurality was the only statistically significant explanatory variable.</p> <p>For women older than 49 years, the highest relative risks were mainly registered for municipalities located in the Canary Islands, Balearic Islands, the Mediterranean coast of Catalonia and Valencia, plus others around the Ebro River. In premenopausal women, the pattern was similar but tended to be more homogeneous. In mainland Spain, a group of municipalities with high RRs were located in Andalusia, near the left bank of the Guadalquivir River.</p> <p>Conclusion</p> <p>As previously observed in other contexts, mortality rates are positively related with socio-economic status and negatively associated with rurality and the presence of a higher proportion of people over age 64 years. Taken together, these variables represent the influence of lifestyle factors which have determined the increase in breast cancer frequency over recent decades. The results for the younger group of women suggest an attenuation of the socio-economic gradient in breast cancer mortality in Spain. The geographical variation essentially suggests the influence of other environmental variables, yet the descriptive nature of this study does not allow for the main determinants to be established.</p

A colorectal cancer susceptibility new variant at 4q26 in the Spanish population identified by genome-wide association analysis

BACKGROUND: Non-hereditary colorectal cancer (CRC) is a complex disorder resulting from the combination of genetic and non-genetic factors. Genome-wide association studies (GWAS) are useful for identifying such genetic susceptibility factors. However, the single loci so far associated with CRC only represent a fraction of the genetic risk for CRC development in the general population. Therefore, many other genetic risk variants alone and in combination must still remain to be discovered. The aim of this work was to search for genetic risk factors for CRC, by performing single-locus and two-locus GWAS in the Spanish population. RESULTS: A total of 801 controls and 500 CRC cases were included in the discovery GWAS dataset. 77 single nucleotide polymorphisms (SNP)s from single-locus and 243 SNPs from two-locus association analyses were selected for replication in 423 additional CRC cases and 1382 controls. In the meta-analysis, one SNP, rs3987 at 4q26, reached GWAS significant p-value (p = 4.02×10(-8)), and one SNP pair, rs1100508 CG and rs8111948 AA, showed a trend for two-locus association (p = 4.35×10(-11)). Additionally, our GWAS confirmed the previously reported association with CRC of five SNPs located at 3q36.2 (rs10936599), 8q24 (rs10505477), 8q24.21(rs6983267), 11q13.4 (rs3824999) and 14q22.2 (rs4444235). CONCLUSIONS: Our GWAS for CRC patients from Spain confirmed some previously reported associations for CRC and yielded a novel candidate risk SNP, located at 4q26. Epistasis analyses also yielded several novel candidate susceptibility pairs that need to be validated in independent analyses

The wide-field, multiplexed, spectroscopic facility WEAVE : survey design, overview, and simulated implementation

Funding for the WEAVE facility has been provided by UKRI STFC, the University of Oxford, NOVA, NWO, Instituto de Astrofísica de Canarias (IAC), the Isaac Newton Group partners (STFC, NWO, and Spain, led by the IAC), INAF, CNRS-INSU, the Observatoire de Paris, Région Île-de-France, CONCYT through INAOE, Konkoly Observatory (CSFK), Max-Planck-Institut für Astronomie (MPIA Heidelberg), Lund University, the Leibniz Institute for Astrophysics Potsdam (AIP), the Swedish Research Council, the European Commission, and the University of Pennsylvania.WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366-959 nm at R ∼ 5000, or two shorter ranges at R ∼ 20,000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for ∼ 3 million stars and detailed abundances for ∼ 1.5 million brighter field and open-cluster stars; (ii) survey ∼ 0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey  ∼ 400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z 1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z > 2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.PostprintPeer reviewe