Unsupervised Character Recognition with Graphene Memristive Synapses

Memristive devices being applied in neuromorphic computing are envisioned to significantly improve the power consumption and speed of future computing platforms. The materials used to fabricate such devices will play a significant role in their viability. Graphene is a promising material, with superb electrical properties and the ability to be produced sustainably. In this paper, we demonstrate that a fabricated graphene-pentacene memristive device can be used as synapses within Spiking Neural Networks (SNNs) to realise Spike Timing Dependent Plasticity (STDP) for unsupervised learning in an efficient manner. Specifically, we verify operation of two SNN architectures tasked for single digit (0-9) classification: (i) a simple single-layer network, where inputs are presented in 5x5 pixel resolution, and (ii) a larger network capable of classifying the Modified National Institute of Standards and Technology (MNIST) dataset, where inputs are presented in 28x28 pixel resolution. Final results demonstrate that for 100 output neurons, after one training epoch, a test set accuracy of up to 86% can be achieved, which is higher than prior art using the same number of output neurons. We attribute this performance improvement to homeostatic plasticity dynamics that we used to alter the threshold of neurons during training. Our work presents the first investigation of the use of green-fabricated graphene memristive devices to perform a complex pattern classification task. This can pave the way for future research in using graphene devices with memristive capabilities in neuromorphic computing architectures. In favour of reproducible research, we make our code and data publicly available https://anonymous.4open.science/r/c69ab2e2-b672-4ebd-b266-987ee1fd65e7.

Super-immunity by broadly protective nanobodies to sarbecoviruses

Vaccine boosters and infection can facilitate the development of SARS-CoV-2 antibodies with improved potency and breadth. Here, we observed super-immunity in a camelid extensively immunized with the SARS-CoV-2 receptor-binding domain (RBD). We rapidly isolated a large repertoire of specific ultrahigh-affinity nanobodies that bind strongly to all known sarbecovirus clades using integrative proteomics. These pan-sarbecovirus nanobodies (psNbs) are highly effective against SARS-CoV and SARS-CoV-2 variants including the Omicron, with the best median neutralization potency at single-digit ng/ml. Structural determinations of 13 psNbs with the SARS-CoV-2 spike or RBD revealed five epitope classes, providing insights into the mechanisms and evolution of their broad activities. The highly evolved psNbs target small, flat, and flexible epitopes that contain over 75% of conserved RBD surface residues. Their potencies are strongly and negatively correlated with the distance of the epitopes to the receptor binding sites. A highly potent, inhalable and bispecific psNb (PiN-31) was developed. Our findings inform on the development of broadly protective vaccines and therapeutics.

Quercetin and Luteolin Are Single-digit Micromolar Inhibitors of the SARS-CoV-2 RNA-dependent RNA Polymerase

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. Among the viral proteins, RNA-dependent RNA polymerase (RdRp) is responsible for viral genome replication and has emerged as one of the most promising targets for pharmacological intervention against SARS-CoV-2. To this end, we experimentally tested luteolin and quercetin for their ability to inhibit the RdRp enzyme. These two compounds are ancestors of flavonoid natural compounds known for a variety of basal pharmacological activities. Luteolin and quercetin returned a single-digit IC50 of 4.6 µM and 6.9 µM, respectively. Then, through dynamic docking simulations, we identified possible binding modes of these compounds to a recently published cryo-EM structure of RdRp. Collectively, these data indicate that these two compounds are a valid starting point for further optimization and development of a new class of RdRp inhibitors to treat SARS-CoV-2 and potentially other viral infections.

Adapting the Form of the sanitary and hygienic characteristics of working conditions to the new Sanitary Law

Introduction. The current Form No. 362-1/y-2001 "The sanitary and hygienic characteristics for the working conditions of an employee having suspicion of an occupational disease (poisoning)" does not meet the requirements of Sanitary Law developed within the framework of the "regulatory guillotine". It complicates the investigation of occupational diseases and carrying out an objective examination of the connection between the disease and the profession. The study aims to analyze the Form for the sanitary and hygienic characteristics (SHC) of working conditions and substantiate proposals for its adaptation to the current regulatory legal acts to objectify the investigation of occupational diseases cases and the examination of the connection between the disease and the profession. Materials and methods. We carried out the expert-analytical study. We analyzed and compared data from Rospotrebnadzor (2001-2020) on occupational morbidity and Rosstat (2014-2020) on employment in harmful and (or) hazardous working conditions. We also studied the SHC (503) submitted for examination of the connection between disease and profession (including forensic medical examination). The structure of the Form for the completeness of the presentation of issues on various aspects of working conditions, the quality of the compilation and content of the SHS was determined in accordance with the current Sanitary Law. The authors evaluated the structure of the Form for the presentation of questions on various aspects of working conditions, determined the quality of the compilation and content of the SHC in accordance with the current Sanitary Law. Results. With a decrease in the number of newly registered cases of occupational diseases over 20 years by more than 3.7 times, the share of workers in harmful and(or) hazardous working conditions in the main types of economic activity decreased in 2020 relative to 2014 in 1,1 time (37.3%). A comparative assessment of the standardized indicators of harmful production factors specified in the SHC and the ones approved in SanPiN 1.2.3685-21 revealed their complete inconsistency. The results of in-depth analysis of 503 SGH allowed us to determine the most typical errors in assessing production factors at workplaces: incorrect assessment of standardized single-digit noise indicators (equivalent sound level A for an 8-hour working day), vibration (equivalent level corrected along the Z-, Y-, X-axes ); lack of data on dust load and the average value of air temperature - THC-index; assessment of the labour severity without considering the technological operations performed, etc. We noted the predominant assessment of working conditions by the main factor developing an occupational disease, without considering the accompanying risk factors that aggravate its effect. We also noted a significant underestimation of the levels when assessing the general transport, technological and technological vibration due to the differences between hygienic standards and the norms adopted in the Methodology for conducting a special assessment of working conditions. SCH contains no information on lighting, biological factor, labour intensity in 67.0-75.0% of cases. Conclusion. We substantiated proposals for improving Form No. 362-1/y-2001 of the SHC of working conditions, considering an electronic form of the document, revising the instructions for filling out the SHC.

Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identified two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generated a bispecific antibody. Lead antibodies showed strong inhibitory activity against historical SARS-CoV-2 and several emerging variants of concern. We solved several cryo-EM structures at ~3 Angstrom resolution of these neutralizing antibodies in complex with prefusion spike trimer ectodomain, and revealed distinct epitopes, binding patterns, and conformations. The lead clones also showed potent efficacy in vivo against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We also generated and characterized a humanized antibody to facilitate translation and drug development. The humanized clone also has strong potency against both the original virus and the B.1.617.2 Delta variant. These mAbs expand the repertoire of therapeutics against SARS-CoV-2 and emerging variants.

First eddy covariance flux measurements of semi-volatile organic compounds with the PTR3-TOF-MS

We present first eddy covariance flux measurements with the PTR3-TOF-MS, a novel proton transfer time of flight reaction mass spectrometer. During 3 weeks in spring 2016, the instrument recorded 10 Hz data of biogenic volatile organic compounds above a boreal forest, on top of a measurement tower at the SMEAR (Station for Measuring Ecosystem –Atmosphere Relations) II station in Hyytiälä, Finland. Flux and concentration data of isoprene, monoterpenes, and sesquiterpenes were compared to the literature. Due to the improved instrument sensitivity and a customized wall-less inlet design, we could detect fluxes of semi-volatile and low-volatility organic compounds with less than single-digit picomol per square meter per second (pmolm-2s-1) values for the first time. These compounds include sesquiterpene oxidation products and diterpenes. Daytime diterpene fluxes were in the range of 0.05 to 0.15 pmolm-2s-1, which amounts to about 0.25 % to 0.5 % of the daytime sesquiterpene flux above canopy.

Improvement of multi-digital multiplicating devices structures in different theoretical and numerical bases

The article proposes methods for improving the structures of multi-bit multipliers, which are characterized by increased speed, reduced structural complexity of the device and reduced structural complexity of inputs and outputs depending on the bit multipliers (512-2048 bits), respectively (1024- 4096) times, compared with known multipliers based on classic single-digit full adders. Optimization of structures of multi-bit multipliers is offered. Comparative estimates of structural, functional and relative functional and structural complexities of their circuit implementations are given. The use of optimized circuit solutions of multipliers allows to significantly improve the system characteristics of complex computing devices with a large number of such components in the crystals of microelectronic technologies.

Influence of Single-Digit Exclusions on Grip Strength in Healthy Male Adults

Grip strength (GS) of the human hand is vital to deal with objects of various sizes and shapes in daily life. The strength deteriorates if one or more digits of the hand are amputated. The main aim of this study was to determine the influence of single-digit exclusions on the GS. Healthy adults ( n = 102, male) with an age range of 20 to 70 years (mean ± SD, 31.92 ± 13.14 years) participated in the study. The movements of unused digits were restrained using splints to avoid digit enslaving effects. T (Thumb), (I) Index, M (Middle), R (Ring), L (Little) digits were chosen for exclusion based on the digit configurations. The digit configurations were IMRL, MRLT, IMRT IRLT and, IMLT with exclusions T, I, L, M, and, R respectively. The results of two-way ANOVA with repeated measures showed no significant interaction ( p = 0.923) between hand dominance and digit configurations. But statistical significance ( p = 0.000) was observed in digit configurations and hand dominance individually. The results of posthoc analysis using Bonferroni corrected pairwise comparisons showed no statistical significance ( p = 0.004) between IRLT and IMLT of both hands since the corrected p-value was 0.003. The outcomes of the F-test showed no statistical significance ( p > 0.05) between the digit configurations IMRLT, IMRL; IMRL, MRLT; MRLT, IMRT; IRLT, IMLT individually within dominant (D) and non-dominant (ND) hands. When the F-test was performed using the same digit configurations between both hands, statistical significance was not observed in all the configurations except IMLT ( p < 0.05). The results of the Pearson correlation of GS were observed to be very strong between the same digit configurations of D and ND hands.

Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC50 values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.

Math fluency from elementary to middle school: differentiating recognition from inferential fluency

Fluency in mental arithmetic is often regarded as a foundational math skill best measured as a single construct. Here we examine the potential benefits of distinguishing between inferential fluency and recognition fluency in elementary and middle school students. Depending on the problem at hand, a student’s fluency may reflect reliance on inferential versus recognition processes. Here we studied single digit arithmetic problems that appear in a widely used 3-minute math fluency assessment across a large (n=914), diverse cohort of 3rd- 7th grade students. A novel tablet-based paradigm enabled us to aggregate performance across different problem types by devising a simple yet objective heuristic to designate problems as likely to draw upon recognition versus inferential fluency in this population. Effects of fluency type were evident across accuracy, response time, and combined responses per minute (RPM) metrics. A novel yet theoretically informative interaction emerged between fluency type and the operation effect. Both fluency types showed sensitivity to grade effects, SES effects, and global achievement levels on state-mandated math assessments. Inferential fluency proved to be a stronger predictor of global achievement than either recognition fluency or more traditional aggregate raw scores. Finally, we demonstrate how differentiating these two fluency types provides novel insights into how relationships between SES and global math achievement are mediated by both inferential and recognition fluency, but not equally. We propose that differentiating inferential from recognition fluency is an initial step toward testing a proposed SIRPA (shift from inferential to recognition processes in arithmetic) model of math development.