Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes.

We previously demonstrated that a spontaneous Th1 response against glutamate decarboxylase (GAD65) arises in NOD mice at four weeks in age and subsequently T cell autoimmunity spreads both intramolecularly and intermolecularly. Induction of passive tolerance to GAD65, through inactivation of reactive T cells before the onset of autoimmunity, prevented determinant spreading and the development of insulin-dependent diabetes mellitus (IDDM). Here, we examined whether an alternative strategy, designed to induce active tolerance via the engagement of Th2 immune responses to GAD65, before the spontaneous onset of autoimmunity, could inhibit the cascade of Th1 responses that lead to IDDM. We observed that a single intranasal administration of GAD65 peptides to 2-3-wk-old NOD mice induced high levels of IgG1 antibodies to GAD65. GAD65 peptide treated mice displayed greatly reduced IFN gamma responses and increased IL-5 responses to GAD65, confirming the diversion of the spontaneous GAD65 Th1 response toward a Th2 phenotype. Consistent with the induction of an active tolerance mechanism, splenic CD4+ (but not CD8+) T cells from GAD65 peptide-treated mice, inhibited the adoptive transfer of IDDM to NOD-scid/scid mice. This active mechanism not only inhibited the development of proliferative T cell responses to GAD65, it also limited the expansion of autoreactive T cell responses to other beta cell antigens (i.e., determinant spreading). Finally, GAD65 peptide treatment reduced insulitis and long-term IDDM incidence. Collectively, these data suggest that the nasal administration of GAD65 peptides induces a Th2 cell response that inhibits the spontaneous development of autoreactive Th1 responses and the progression of beta cell autoimmunity in NOD mice

Are goal states represented during kinematic imitation?

A number of studies have shown that observation of another person's actions can modulate one's own actions, such as when 2 individuals cooperate in order to complete a joint task. However, little is known about whether or not direct matching of specific movements is modulated by the goals of the actions observed. In a series of 7 experiments, we employed an action observation paradigm in which 2 coactors sat opposite each other and took turns to reach out to targets presented on a shared workspace. Importantly, coactors performed either the same goal at the reached-to location or a different goal. Although results consistently showed that the reaching action of 1 individual slows the observer's reaching action to the same spatial location, the effect was not modulated according to the adopted goals of coactors. These findings challenge the notion that the processes involved in the imitation of specific movements code for the action goals of those movements

Hierarchy and Feedback in the Evolution of the E. coli Transcription Network

The E.coli transcription network has an essentially feedforward structure, with, however, abundant feedback at the level of self-regulations. Here, we investigate how these properties emerged during evolution. An assessment of the role of gene duplication based on protein domain architecture shows that (i) transcriptional autoregulators have mostly arisen through duplication, while (ii) the expected feedback loops stemming from their initial cross-regulation are strongly selected against. This requires a divergent coevolution of the transcription factor DNA-binding sites and their respective DNA cis-regulatory regions. Moreover, we find that the network tends to grow by expansion of the existing hierarchical layers of computation, rather than by addition of new layers. We also argue that rewiring of regulatory links due to mutation/selection of novel transcription factor/DNA binding interactions appears not to significantly affect the network global hierarchy, and that horizontally transferred genes are mainly added at the bottom, as new target nodes. These findings highlight the important evolutionary roles of both duplication and selective deletion of crosstalks between autoregulators in the emergence of the hierarchical transcription network of E.coli.Comment: to appear in PNA

Combining semi-automated image analysis techniques with machine learning algorithms to accelerate large scale genetic studies

Background: Genetic analyses of plant root system development require large datasets of extracted architectural traits. To quantify such traits from images of root systems, researchers often have to choose between automated tools (that are prone to error and extract only a limited number of architectural traits) or semi-automated ones (that are highly time consuming). Findings: We trained a Random Forest algorithm to infer architectural traits from automatically-extracted image descriptors. The training was performed on a subset of the dataset, then applied to its entirety. This strategy allowed us to (i) decrease the image analysis time by 73% and (ii) extract meaningful architectural traits based on image descriptors. We also show that these traits are sufficient to identify Quantitative Trait Loci that had previously been discovered using a semi-automated method. Conclusions: We have shown that combining semi-automated image analysis with machine learning algorithms has the power to increase the throughput in large scale root studies. We expect that such an approach will enable the quantification of more complex root systems for genetic studies. We also believe that our approach could be extended to other area of plant phenotyping

Computational Modelling of Cardiac Electrophysiological Changes in Malarial Fever

Cardiac function is impaired in severe malarial fever, and ECGs show changes associated with repolarization. These could contribute to mortality via ventricular arrhythmia. The cardiac effects could be due to the malarial parasite load in the heart, specific cardio-toxic effects of the parasite or cardio-toxic effects of antimalarial agents. We construct a simple 1-dimensional electrophysiological model for the physico-chemical changes clinically observed during malarial fever: with temperature, pH and [ionic]plasma changes. The model can quantitatively reproduce the tachycardia and QTc prolongation seen in the adult, and shortening seen in the child during malarial fever

Home Health “Start of Care” Policy Change: Examining Occupational Therapist Engagement in New Responsibilities

A 2022 federal policy change allowed occupational therapists (OTs) to open home health cases in a process known as the Start of Care or SOC, a responsibility previously limited to nurses, physical therapists, and speech-language pathologists. The American Occupational Therapy Association (AOTA) recognizes the opportunity for increased professional value and service utilization and called upon practitioners to advocate such and to educate home health agencies about the change. Since clinicians’ practice patterns are directly impacted by such policy changes, because current OT participation in and perspective on new responsibilities were unknown, it was important to hear directly from these therapists. Study outcomes and methods were grounded in the Dynamic Capabilities Transformation Process (Uhl-Bien & Arena, 2017), a framework suited for studying responses to change that originates externally: We sought to describe home health occupational therapist participation in data collection and reporting processes before and after the policy change, to identify resources and barriers that impacted engagement in new responsibilities, and to describe perceptions of the policy change as an opportunity. Occupational therapists who have worked U.S.-based home health in the last three years were invited via convenience and snowball sampling to participate in an online survey. A total of 247 U.S.-based occupational therapists from 45 states completed the survey, with 72.1% reporting that they worked in home health for at least six years. Though 80.2% knew about the policy change and 90% have performed non-SOC Medicare-mandated assessments, only 42.5% have performed the SOC. Of those who have performed the SOC (n = 105), 60% reported confidence in their ability to perform the SOC. Barriers to accessing SOC training or education were reported by 78.5% of all participants, of whom 59.3% reported agency resistance to occupational therapists performing the SOC. Despite reported challenges, 79.3% viewed the policy change as an opportunity for the occupational therapy profession, and 63.4% as an opportunity for occupational therapists. We see a strong foundation on behalf of occupational therapists to adapt positively to externally driven change. But fewer than half had performed a single SOC. Respondent comments express frustration attached to added responsibility without respective autonomy, adequate time or compensation. Results suggest that additional resources and processes are needed to integrate policy into everyday processes, especially when occupational therapists are not the drivers of change, nor in positions of power to enact or oversee such change. Uhl-Bien, M. & Arena, M. (2018). Leadership for organizational adaptability: A theoretical synthesis and integrative framework. The Leadership Quarterly, 29(1), 89-104 https://doi.org/10.1016/j.leaqua.2017.12.009 Synopsis: After Medicare changed its policy to allow occupational therapists (OTs) to open home health cases, we wanted to learn from OTs whether they knew about the policy change, if they were now opening cases, what may have inhibited or helped their participation, and whether they viewed the change positively. The study used an online survey by which OTs reported frustrations and challenges associated with the change; however, OTs generally believe that the change is beneficial to the profession and to providers. Results suggest that additional resources and processes are needed to integrate policy into everyday processes

A diffusion-based quantification technique for assessment of sacroiliitis in adolescents with enthesitis-related arthritis

OBJECTIVE: To investigate the use of a quantitative diffusion-weighted imaging (DWI) tool for measuring inflammation of the sacroiliac joints (SIJs) in enthesitis-related arthritis (ERA). METHODS: A retrospective study was performed with institutional review board approval. Subjects were adolescents who had undergone MRI of the SIJs since January 2010. 10 patients with a clinical diagnosis of ERA and 10 controls with a clinical diagnosis of mechanical back pain were assessed. Axial T1 weighted, short tau inversion recovery (STIR) and DWI (b-values 0, 50, 100, 300 and 600 mm(2) s(-1)) images were acquired. Apparent diffusion coefficient (ADC) maps were generated using a monoexponential fit. On each of four slices, two to three linear regions-of-interest were placed on each joint. Normalized ADC (nADC) values were defined as joint ADC divided by a reference ADC derived from normal sacral bone. STIR images were scored using a modification of an established technique. The correlation between nADC values and STIR scores was evaluated using Spearman's rank correlation. RESULTS: Mean nADC values were significantly higher in cases than in controls (p = 0.0015). There was a strong correlation between STIR scores and nADC values (R = 0.85). CONCLUSION: ADC values are significantly increased in inflamed SIJs compared with controls. There is a good correlation between this diffusion-based method and STIR scores of inflammation. ADVANCES IN KNOWLEDGE: We have described and provisionally validated a method for quantifying the severity of inflammation in the SIJs in ERA using ADC measurements. This method is quick, is reproducible and could potentially be automated

Application of a genetic risk score to racially diverse type 1 diabetes populations demonstrates the need for diversity in risk-modeling

This is the final version of the article. Available from the publisher via the DOI in this record.Prior studies identified HLA class-II and 57 additional loci as contributors to genetic susceptibility for type 1 diabetes (T1D). We hypothesized that race and/or ethnicity would be contextually important for evaluating genetic risk markers previously identified from Caucasian/European cohorts. We determined the capacity for a combined genetic risk score (GRS) to discriminate disease-risk subgroups in a racially and ethnically diverse cohort from the southeastern U.S. including 637 T1D patients, 46 at-risk relatives having two or more T1D-related autoantibodies (≥2AAb+), 790 first-degree relatives (≤1AAb+), 68 second-degree relatives (≤1 AAb+), and 405 controls. GRS was higher among Caucasian T1D and at-risk subjects versus ≤ 1AAb+ relatives or controls (P < 0.001). GRS receiver operating characteristic AUC (AUROC) for T1D versus controls was 0.86 (P < 0.001, specificity = 73.9%, sensitivity = 83.3%) among all Caucasian subjects and 0.90 for Hispanic Caucasians (P < 0.001, specificity = 86.5%, sensitivity = 84.4%). Age-at-diagnosis negatively correlated with GRS (P < 0.001) and associated with HLA-DR3/DR4 diplotype. Conversely, GRS was less robust (AUROC = 0.75) and did not correlate with age-of-diagnosis for African Americans. Our findings confirm GRS should be further used in Caucasian populations to assign T1D risk for clinical trials designed for biomarker identification and development of personalized treatment strategies. We also highlight the need to develop a GRS model that accommodates racial diversity.Supported by grants from the National Institutes of Health P01 AI42288 (MAA), R01 DK106191 (TMB), UC4 DK104194 (CEM), and from the JDRF Career Development Award (2–2012–280 to TMB). RAO is supported by a Diabetes UK Harry Keen Fellowship. DJP is supported by the JDRF Postdoctoral Fellowship Award (2-PDF-2016-207-A-N)