Combined therapy with GABA and proinsulin/alum acts synergistically to restore long-term normoglycemia by modulating T-cell autoimmunity and promoting β-cell replication in newly diabetic NOD mice.

Antigen-based therapies (ABTs) fail to restore normoglycemia in newly diabetic NOD mice, perhaps because too few β-cells remain by the time that ABT-induced regulatory responses arise and spread. We hypothesized that combining a fast-acting anti-inflammatory agent with an ABT could limit pathogenic responses while ABT-induced regulatory responses arose and spread. γ-Aminobutyric acid (GABA) administration can inhibit inflammation, enhance regulatory T-cell (Treg) responses, and promote β-cell replication in mice. We examined the effect of combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly diabetic NOD mice. Proinsulin/alum monotherapy failed to correct hyperglycemia, while GABA monotherapy restored normoglycemia for a short period. Combined treatment restored normoglycemia in the long term with apparent permanent remission in some mice. Proinsulin/alum monotherapy induced interleukin (IL)-4- and IL-10-secreting T-cell responses that spread to other β-cell autoantigens. GABA monotherapy induced moderate IL-10 (but not IL-4) responses to β-cell autoantigens. Combined treatment synergistically reduced spontaneous type 1 T-helper cell responses to autoantigens, ABT-induced IL-4 and humoral responses, and insulitis, but enhanced IL-10 and Treg responses and promoted β-cell replication in the islets. Thus, combining ABT with GABA can inhibit pathogenic T-cell responses, induce Treg responses, promote β-cell replication, and effectively restore normoglycemia in newly diabetic NOD mice. Since these treatments appear safe for humans, they hold promise for type 1 diabetes intervention

Antagonistic and cooperative AGO2-PUM interactions in regulating mRNAs.

Approximately 1500 RNA-binding proteins (RBPs) profoundly impact mammalian cellular function by controlling distinct sets of transcripts, often using sequence-specific binding to 3' untranslated regions (UTRs) to regulate mRNA stability and translation. Aside from their individual effects, higher-order combinatorial interactions between RBPs on specific mRNAs have been proposed to underpin the regulatory network. To assess the extent of such co-regulatory control, we took a global experimental approach followed by targeted validation to examine interactions between two well-characterized and highly conserved RBPs, Argonaute2 (AGO2) and Pumilio (PUM1 and PUM2). Transcriptome-wide changes in AGO2-mRNA binding upon PUM knockdown were quantified by CLIP-seq, and the presence of PUM binding on the same 3'UTR corresponded with cooperative and antagonistic effects on AGO2 occupancy. In addition, PUM binding sites that overlap with AGO2 showed differential, weakened binding profiles upon abrogation of AGO2 association, indicative of cooperative interactions. In luciferase reporter validation of candidate 3'UTR sites where AGO2 and PUM colocalized, three sites were identified to host antagonistic interactions, where PUM counteracts miRNA-guided repression. Interestingly, the binding sites for the two proteins are too far for potential antagonism due to steric hindrance, suggesting an alternate mechanism. Our data experimentally confirms the combinatorial regulatory model and indicates that the mostly repressive PUM proteins can change their behavior in a context-dependent manner. Overall, the approach underscores the importance of further elucidation of complex interactions between RBPs and their transcriptome-wide extent

Workflow Critical Path: A Data-oriented Critical path metric for Holistic HPC Workflows

Current trends in HPC, such as the push to exascale, convergence with Big Data, and growing complexity of HPC applications, have created gaps that traditional performance tools do not cover. One example is Holistic HPC Workflows — HPC workflows comprising multiple codes, paradigms, or platforms that are not developed using a workflow management system. To diagnose the performance of these applications, we define a new metric called Workflow Critical Path (WCP), a data-oriented metric for Holistic HPC Workflows. WCP constructs graphs that span across the workflow codes and platforms, using data states as vertices and data mutations as edges. Using cloud-based technologies, we implement a prototype called Crux, a distributed analysis tool for calculating and visualizing WCP. Our experiments with a workflow simulator on Amazon Web Services show Crux is scalable and capable of correctly calculating WCP for common Holistic HPC workflow patterns. We explore the use of WCP and discuss how Crux could be used in a production HPC environment

Evaluating the Construct Validity of Text Embeddings with Application to Survey Questions

Text embedding models from Natural Language Processing can map text data (e.g. words, sentences, documents) to supposedly meaningful numerical representations (a.k.a. text embeddings). While such models are increasingly applied in social science research, one important issue is often not addressed: the extent to which these embeddings are valid representations of constructs relevant for social science research. We therefore propose the use of the classic construct validity framework to evaluate the validity of text embeddings. We show how this framework can be adapted to the opaque and high-dimensional nature of text embeddings, with application to survey questions. We include several popular text embedding methods (e.g. fastText, GloVe, BERT, Sentence-BERT, Universal Sentence Encoder) in our construct validity analyses. We find evidence of convergent and discriminant validity in some cases. We also show that embeddings can be used to predict respondent's answers to completely new survey questions. Furthermore, BERT-based embedding techniques and the Universal Sentence Encoder provide more valid representations of survey questions than do others. Our results thus highlight the necessity to examine the construct validity of text embeddings before deploying them in social science research.Comment: Under revie

Quantum Gates with Oscillating Exchange Interaction

Two-qubit gates between spin qubits are often performed using a rectangular or an adiabatic exchange interaction pulse resulting in a CZ gate. An oscillating exchange pulse not only performs a CZ gate, but also enables the iSWAP gate, which offers more flexibility to perform quantum algorithms. We provide a detailed description for two-qubit gates using resonant and off-resonant exchange pulses, give conditions for performing the respective gates, and compare their performance to the state-of-the-art static counterpart. We find that for relatively low charge noise the gates still perform reliably and can outperform the conventional CZ gate

Creating chimeras: Embryonic stem cells incorporated

Gene modification within the murine genome has become a powerful and invaluable tool to investigate development. One example of the utility of such technology is providing a method by which researchers can follow cells throughout development via the introduced genetic modifications.Fil: Pascottini, Osvaldo Bogado. University of Chicago; Estados UnidosFil: Goszczynski, Daniel Estanislao. University of Chicago; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Nguyen, Alexandra L.. University of Chicago; Estados Unido

The influence of mixed solvents volatility on charge state distribution of peptides during positive electrospray ionization mass spectrometry

Understanding the mechanisms that control and concentrate the observed electrospray ionisation (ESI) response from peptides is important. Controlling these mechanisms can improve signal-to-noise ratio in the mass spectrum, and enhances the generation of intact ions, and thus, improves the detection of peptides when analysing mixtures. The effects of different mixtures of aqueous: organic solvents (25, 50, 75%; v/v): formic acid solution (at pH 3.26) compositions on the ESI response and chargestate distribution (CSD) during mass spectrometry (MS) were determined in a group of biologically active peptides (molecular wt range 1.3 - 3.3 kDa). The ESI response is dependent on type of organic solvent in the mobile phase mixture and therefore, solvent choice affects optimal ion intensities. As expected, intact peptide ions gave a more intense ESI signal in polar protic solvent mixtures than in the low polarity solvent. However, for four out of the five analysed peptides, neither the ESI response nor the CSD were affected by the volatility of the solvent mixture. Therefore, in solvent mixtures, as the composition changes during the evaporation processes, the pKb of the amino acid composition is a better predictor of multiple charging of the peptides

Prevalence of Dyskinesia and OFF by 30-Minute Intervals Through the Day and Assessment of Daily Episodes of Dyskinesia and OFF: Novel Analyses of Diary Data from Gocovri Pivotal Trials.

BACKGROUND: Parkinson\u27s disease (PD) patients using levodopa commonly develop dyskinesia and OFF episodes that reduce quality of life. OBJECTIVE: Evaluate prevalence of troublesome dyskinesia and OFF through the day, assessed by 30-minute intervals, as well as the mean number and duration of troublesome dyskinesia and OFF episodes, transitions between PD states, and effects of Gocovri® (amantadine) extended release capsules on these episodes. METHODS: Evaluate diary data from pooled Gocovri phase 3, placebo-controlled trials-analyzed for 17 hours following wake-up-at baseline and week 12. RESULTS: Diaries were evaluable for 162 patients. At baseline, 67% of patients woke up OFF, with prevalence decreasing to 13% at 2 hours and then remaining relatively steady at ∼12% (range, 6-17%) across half-hour intervals thereafter. Troublesome dyskinesia prevalence rose steadily from 5% to 24% over the first 2 hours, then fluctuated between 20% and 44% through the rest of the waking day. At baseline, patients experienced a mean of 3.0 daily episodes of troublesome dyskinesia (average duration 2.0 hours each), and 2.2 daily episodes of OFF (average duration 1.1 hour each). At week 12, Gocovri-treated patients showed greater reductions than placebo in troublesome dyskinesia and OFF episodes per day (treatment difference: -1.0 episodes and -0.4 episodes, respectively) and average episode duration (treatment difference: -0.6 hours and -0.3 hours, respectively). Mean duration of individual episodes of ON without troublesome dyskinesia (Good ON) increased by 5.0 hours for Gocovri, compared with 2.0 hours for placebo. Patients taking Gocovri experienced 2.2 fewer transitions between states than patients taking placebo. CONCLUSIONS: Troublesome dyskinesia and OFF occurred in the morning and throughout the waking day. Gocovri-treated patients experienced fewer, shorter episodes of both troublesome dyskinesia and OFF, thereby increasing the duration of continuous Good ON episodes and reducing the frequency of transitions between motor states