Innovation and strategy: Does it make a difference! A linear study of micro & SMEs

Innovation is known to be used by some businesses to help them differentiate their trading position within a specific locale. Research has also proven that by adopting a strategy, aims can be achieved and turnover increased. This study will endeavour to use these two key areas to evaluate how, they are used and to what extent they can improve business performance. The study was carried using 145 Micro and SME business, located within the rural county of Lincolnshire. The businesses were taken from specific locations on a random basis which included rural, remote rural and urban settings. Initial findings found that businesses situated within remote areas performed better than those within the other test areas, leading to the conclusion that they use innovation as a strategy to outperform their business rivals

Excess Circulating Alternatively Activated Myeloid (M2) Cells Accelerate ALS Progression While Inhibiting Experimental Autoimmune Encephalomyelitis

Circulating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS) in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs), representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease.We tested this working hypothesis in amyotrophic lateral sclerosis (ALS) and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2) cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1) mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS), revealed a two-fold increase in the percentage of circulating MDSCs (LIN(-/Low)HLA-DR(-)CD33(+)) compared to controls.Taken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might represent a risk factor and a novel target for therapeutic intervention in ALS at least at the early stage

A study of topological insulators in three dimensions

In this work we study four interesting effects in the field of topological insulators: the Witten effect, the Wormhole effect, topological Anderson insulators and the absence of bulk magnetic order in magnetically doped topological insulators. According to the Witten effect, a unit magnetic monopole placed inside a medium with non zero θ is predicted to bind a fractional electric charge. We conduct a first test of the Witten effect based on the recently established fact that the electromagnetic response of a topological insulator is given by the axion term θ(e²/2πh)B·E, and that θ=π for strong topological insulators. We establish the Wormhole effect, in which a strong topological insulator, with an infinitely thin solenoid of magnetic half flux quantum carries protected gapless and spin filtered one-dimensional fermionic modes, which represent a distinct bulk manifestation of the topologically non-trivial insulator. We demonstrate that not only are strong topological insulators robust to disorder but, remarkably, under certain conditions disorder can become fundamentally responsible for their existence. We show that disorder, when sufficiently strong, can transform an ordinary metal with strong spin-orbit coupling into a strong topological ‘Anderson’ insulator, a new topological phase of matter in three dimensions. Finally, we lay out the hypothesis that a temperature window exists in which the surface of magnetically doped topological insulators is magnetically ordered but the bulk is not. We present a simple and intuitive argument why this is so, and a mean-field calculation for two simple tight binding topological insulator models which shows that indeed a sizeable regime such as described above could exist. This indicates a possible physical explanation for the results seen in recent experiments.Science, Faculty ofPhysics and Astronomy, Department ofGraduat

The Membrane-Activated Chelator Stroke Intervention (MACSI) Trial of DP-b99 in Acute Ischemic Stroke: A Randomized, Double-Blind, Placebo-Controlled, Multinational Pivotal Phase III Study

Rationale Zinc is both a direct neurotoxin and a signaling mediator in multiple early and late detrimental processes following ischemia. DP-b99, a lipophilic moderate-affinity chelator of zinc, is a first-in-class multitargeted neuroprotective agent for ischemic stroke. DP-b99 has completed several Phase I studies and two double-blind placebo-controlled Phase II trials, which supported the safety of DP-b99 and were consistent with a beneficial effect on poststroke recuperation. Aim: Membrane-Activated Chelator Stroke Intervention is a Phase III study. The primary objective is to evaluate the safety and therapeutic effects of intravenous 1.0 mg/kg/day DP-b99, initiated within nine-hours of stroke onset in patients with moderately severe hemispheric acute ischemic stroke, through the analysis across the whole distribution of scores of the primary efficacy endpoint of the modified Rankin Scale, 90 days after the stroke. Methods The Membrane-Activated Chelator Stroke Intervention study is a randomized, double-blind, placebo-controlled, multicenter, multinational, parallel-arm trial comparing a placebo group to a group treated with intravenous DP-b99 for four consecutive days. Non-rtPA-treated acute ischemic stroke patients - with a baseline NIHSS score of 10-16 and a clinical syndrome that includes language dysfunction, visual field defect and/or neglect - will be stratified on a 1 : 1 basis to one of the two treatments. Half will be randomized within 0-4.5 h of stroke onset. Follow-up after the four treatment days will occur on days 12, 30 and 90. An interim futility analysis will be performed after primary endpoint data have been collected for 50% of 770 subjects planned to be enrolled. A data and safety monitoring board will assess safety data and will oversee the interim analysis. Conclusion This Phase III Membrane-Activated Chelator Stroke Intervention trial is based on promising data derived from previous Phase I and II DP-b99 trials and capitalizes on lessons learned from failures of past stroke studies in relation to neuroprotection, patient selection and data analysis

Automatic Evaluation of Aspects of Performance and Scheduling in Playing the Piano

Tamir-Ostrover H, Baruch G, Peleg O, et al. Automatic Evaluation of Aspects of Performance and Scheduling in Playing the Piano. Presented at the 30th ACM Conference on User Modeling, Adaptation and Personalization (UMAP), Barcelona.There is a growing trend to teach playing an instrument such as a piano at home using an automated system. A key component of such systems is the ability to rate performance of the learner in order to provide feedback and select appropriate exercises. In this study, we expand on previous works that have developed automatic evaluation systems for an overall grade by also providing predic- tions for specific aspects of performance: pitch, rhythm, tempo, and articulation & dynamics, as well as scheduling what is an appropri- ate next task. We describe how a set of salient features is extractedUMAP ’22, July 4–7, 2022, Barcelona, Spain by comparing MIDI performance data of three piano players to an ideal performance, how the features used for evaluation are selected, and evaluate using linear regression how well the selected features are able to predict the mean scores given by a group of domain experts (piano teachers). Relatively good R 2 scores (0.54 to 0.68) are achieved using a small number of features (2 - 4). Such automatic evaluation of different aspects of performance can be used as a part of an automatic learning system, and to help provide learners with detailed feedback on their performance

Dysregulated Levels of Circulating Autoantibodies against Neuronal and Nervous System Autoantigens in COVID-19 Patients

BACKGROUND: COVID-19 is a heterogenous disease resulting in long-term sequela in predisposed individuals. It is not uncommon that recovering patients endure non-respiratory ill-defined manifestations, including anosmia, and neurological and cognitive deficit persisting beyond recovery-a constellation of conditions that are grouped under the umbrella of long-term COVID-19 syndrome. Association between COVID-19 and autoimmune responses in predisposed individuals was shown in several studies. AIM AND METHODS: To investigate autoimmune responses against neuronal and CNS autoantigens in SARS-CoV-2-infected patients, we performed a cross-sectional study with 246 participants, including 169 COVID-19 patients and 77 controls. Levels of antibodies against the acetylcholine receptor, glutamate receptor, amyloid β peptide, alpha-synucleins, dopamine 1 receptor, dopamine 2 receptor, tau protein, GAD-65, N-methyl D-aspartate (NMDA) receptor, BDNF, cerebellar, ganglioside, myelin basic protein, myelin oligodendrocyte glycoprotein, S100-B, glial fibrillary acidic protein, and enteric nerve were measured using an Enzyme-Linked Immunosorbent Assay (ELISA). Circulating levels of autoantibodies were compared between healthy controls and COVID-19 patients and then classified by disease severity (mild [ = 74], severe [ = 65], and requiring supplemental oxygen [ = 32]). RESULTS: COVID-19 patients were found to have dysregulated autoantibody levels correlating with the disease severity, e.g., IgG to dopamine 1 receptor, NMDA receptors, brain-derived neurotrophic factor, and myelin oligodendrocyte glycoprotein. Elevated levels of IgA autoantibodies against amyloid β peptide, acetylcholine receptor, dopamine 2 receptor, myelin basic protein, and α-synuclein were detected in COVID-19 patients compared with healthy controls. Lower IgA autoantibody levels against NMDA receptors, and IgG autoantibodies against glutamic acid decarboxylase 65, amyloid β peptide, tau protein, enteric nerve, and S100-B were detected in COVID-19 patients versus healthy controls. Some of these antibodies have known clinical correlations with symptoms commonly reported in the long COVID-19 syndrome. CONCLUSIONS: Overall, our study shows a widespread dysregulation in the titer of various autoantibodies against neuronal and CNS-related autoantigens in convalescent COVID-19 patients. Further research is needed to provide insight into the association between these neuronal autoantibodies and the enigmatic neurological and psychological symptoms reported in COVID-19 patients

Gender difference in HIV-1 RNA viral loads.

OBJECTIVES: To test and characterize the dependence of viral load on gender in different countries and racial groups as a function of CD4 T-cell count. METHODS: Plasma viral load data were analysed for > 30,000 HIV-infected patients attending clinics in the USA [HIV Insight (Cerner Corporation, Vienna, VA, USA) and Plum Data Mining LLC (East Meadow, NY, USA) databases] and the Netherlands (Athena database; HIV Monitoring Foundation, Amsterdam, Netherlands). Log-normal regression models were used to test for an effect of gender on viral load while adjusting for covariates and allowing the effect to depend on CD4 T-cell count. Sensitivity analyses were performed to test the robustness of conclusions to assumptions regarding viral loads below the lower limit of quantification (LLOQ). RESULTS: After adjusting for covariates, women had (nonsignificantly) lower viral loads than men (HIV Insight: -0.053 log(10) HIV-1 RNA copies/mL, P = 0.202; Athena: -0.005 log(10) copies/mL, P = 0.667; Plum: -0.072 log(10) copies/mL, P = 0.273). However, further investigation revealed that the gender effect depended on CD4 T-cell count. Women had consistently higher viral loads than men when CD4 T-cell counts were at most 50 cells/microL, and consistently lower viral loads than men when CD4 T-cell counts were greater than 350 cells/microL. These effects were remarkably consistent when estimated independently for the racial groups with sufficient data available in the HIV Insight and Plum databases. CONCLUSIONS: The consistent relationship between gender-related differences in viral load and CD4 T-cell count demonstrated here explains the diverse findings previously published

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function

International audienceAutoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles