Type 1 diabetes is an autoimmune-mediated disease that culminates in the targeted destruction of insulin-producing β-cells. CD4 responses in NOD mice are dominated by insulin epitope B:9-23 (InsB_9-23) specificity, and mutation of the key T-cell receptor (TCR) contact residue within the epitope prevents diabetes development. However, it is not clear how insulin self-antigen controls the selection of autoimmune and regulatory T cells (Tregs). Here we demonstrate that mutation of insulin epitope results in escape of highly pathogenic T cells. We observe an increase in antigen reactivity, clonality, and pathogenicity of insulin-specific T cells that develop in the absence of cognate antigen. Using a single TCR system, we demonstrate that Treg development is greatly diminished in mice with the Y16A mutant epitope. Collectively, these results suggest that the tyrosine residue at position 16 is necessary to constrain TCR reactivity for InsB_9-23 by both limiting the development of pathogenic T cells and supporting the selection of Tregs.

Jens J. Holst
May 1, 2011; 34:S251-S257
Diabetes Treatments

Korey K. Hood
Jun 1, 2006; 29:1389-1389
BR Epidemiology/Health Services/Psychosocial Research

OBJECTIVE

Haptoglobin is an acute-phase reactant with pleiotropic functions. We aimed to study whether urine haptoglobin may predict risk of mortality in people with type 2 diabetes.

OBJECTIVE

This study aims to evaluate the association of energy and macronutrient intake at dinner versus breakfast with disease-specific and all-cause mortality in people with diabetes.

In Staphylococcus aureus–caused endocarditis, the pathogen secretes staphylocoagulase (SC), thereby activating human prothrombin (ProT) and evading immune clearance. A previous structural comparison of the SC(1–325) fragment bound to thrombin and its inactive precursor prethrombin 2 has indicated that SC activates ProT by inserting its N-terminal dipeptide Ile1-Val2 into the ProT Ile16 pocket, forming a salt bridge with ProT's Asp194, thereby stabilizing the active conformation. We hypothesized that these N-terminal SC residues modulate ProT binding and activation. Here, we generated labeled SC(1–246) as a probe for competitively defining the affinities of N-terminal SC(1–246) variants preselected by modeling. Using ProT(R155Q,R271Q,R284Q) (ProTQQQ), a variant refractory to prothrombinase- or thrombin-mediated cleavage, we observed variant affinities between ∼1 and 650 nm and activation potencies ranging from 1.8-fold that of WT SC(1–246) to complete loss of function. Substrate binding to ProTQQQ caused allosteric tightening of the affinity of most SC(1–246) variants, consistent with zymogen activation through occupation of the specificity pocket. Conservative changes at positions 1 and 2 were well-tolerated, with Val1-Val2, Ile1-Ala2, and Leu1-Val2 variants exhibiting ProTQQQ affinity and activation potency comparable with WT SC(1–246). Weaker binding variants typically had reduced activation rates, although at near-saturating ProTQQQ levels, several variants exhibited limiting rates similar to or higher than that of WT SC(1–246). The Ile16 pocket in ProTQQQ appears to favor nonpolar, nonaromatic residues at SC positions 1 and 2. Our results suggest that SC variants other than WT Ile1-Val2-Thr3 might emerge with similar ProT-activating efficiency.

London : printed for Knight and Lacey, 1826.

Dani Gamerman.

Source: Brazilian Journal of Probability and Statistics, Volume 33, Number 4, 686--705.

Abstract:
Point processes are one of the most commonly encountered observation processes in Spatial Statistics. Model-based inference for them depends on the likelihood function. In the most standard setting of Poisson processes, the likelihood depends on the intensity function, and can not be computed analytically. A number of approximating techniques have been proposed to handle this difficulty. In this paper, we review recent work on exact solutions that solve this problem without resorting to approximations. The presentation concentrates more heavily on discrete time but also considers continuous time. The solutions are based on model specifications that impose smoothness constraints on the intensity function. We also review approaches to include a regression component and different ways to accommodate it while accounting for additional heterogeneity. Applications are provided to illustrate the results. Finally, we discuss possible extensions to account for discontinuities and/or jumps in the intensity function.

We study the interplay of two important issues on Bayesian model selection (BMS): censoring and model misspecification. We consider additive accelerated failure time (AAFT), Cox proportional hazards and probit models, and a more general concave log-likelihood structure. A fundamental question is what solution can one hope BMS to provide, when (inevitably) models are misspecified. We show that asymptotically BMS keeps any covariate with predictive power for either the outcome or censoring times, and discards other covariates. Misspecification refers to assuming the wrong model or functional effect on the response, including using a finite basis for a truly non-parametric effect, or omitting truly relevant covariates. We argue for using simple models that are computationally practical yet attain good power to detect potentially complex effects, despite misspecification. Misspecification and censoring both have an asymptotically negligible effect on (suitably-defined) false positives, but their impact on power is exponential. We portray these issues via simple descriptions of early/late censoring and the drop in predictive accuracy due to misspecification. From a methods point of view, we consider local priors and a novel structure that combines local and non-local priors to enforce sparsity. We develop algorithms to capitalize on the AAFT tractability, approximations to AAFT and probit likelihoods giving significant computational gains, a simple augmented Gibbs sampler to hierarchically explore linear and non-linear effects, and an implementation in the R package mombf. We illustrate the proposed methods and others based on likelihood penalties via extensive simulations under misspecification and censoring. We present two applications concerning the effect of gene expression on colon and breast cancer.

Jennifer E. Starling, Jared S. Murray, Carlos M. Carvalho, Radek K. Bukowski, James G. Scott.

Source: The Annals of Applied Statistics, Volume 14, Number 1, 28--50.

Abstract:
This article introduces BART with Targeted Smoothing, or tsBART, a new Bayesian tree-based model for nonparametric regression. The goal of tsBART is to introduce smoothness over a single target covariate $t$ while not necessarily requiring smoothness over other covariates $x$. tsBART is based on the Bayesian Additive Regression Trees (BART) model, an ensemble of regression trees. tsBART extends BART by parameterizing each tree’s terminal nodes with smooth functions of $t$ rather than independent scalars. Like BART, tsBART captures complex nonlinear relationships and interactions among the predictors. But unlike BART, tsBART guarantees that the response surface will be smooth in the target covariate. This improves interpretability and helps to regularize the estimate. After introducing and benchmarking the tsBART model, we apply it to our motivating example—pregnancy outcomes data from the National Center for Health Statistics. Our aim is to provide patient-specific estimates of stillbirth risk across gestational age $(t)$ and based on maternal and fetal risk factors $(x)$. Obstetricians expect stillbirth risk to vary smoothly over gestational age but not necessarily over other covariates, and tsBART has been designed precisely to reflect this structural knowledge. The results of our analysis show the clear superiority of the tsBART model for quantifying stillbirth risk, thereby providing patients and doctors with better information for managing the risk of fetal mortality. All methods described here are implemented in the R package tsbart .

Maxim Rabinovich, Aaditya Ramdas, Michael I. Jordan, Martin J. Wainwright.

Source: Bayesian Analysis, Volume 15, Number 2, 505--532.

Abstract:
Slow mixing is the central hurdle is applications of Markov chains, especially those used for Monte Carlo approximations (MCMC). In the setting of Bayesian inference, it is often only of interest to estimate the stationary expectations of a small set of functions, and so the usual definition of mixing based on total variation convergence may be too conservative. Accordingly, we introduce function-specific analogs of mixing times and spectral gaps, and use them to prove Hoeffding-like function-specific concentration inequalities. These results show that it is possible for empirical expectations of functions to concentrate long before the underlying chain has mixed in the classical sense, and we show that the concentration rates we achieve are optimal up to constants. We use our techniques to derive confidence intervals that are sharper than those implied by both classical Markov-chain Hoeffding bounds and Berry-Esseen-corrected central limit theorem (CLT) bounds. For applications that require testing, rather than point estimation, we show similar improvements over recent sequential testing results for MCMC. We conclude by applying our framework to real-data examples of MCMC, providing evidence that our theory is both accurate and relevant to practice.

Brian Zingg
Apr 15, 2020; 40:3250-3267
Systems/Circuits

Amanda Avona
May 29, 2019; 39:4323-4331
Systems/Circuits

EL Bienenstock
Jan 1, 1982; 2:32-48
Articles

Revealing the organization and function of neural circuits is greatly facilitated by viral tools that spread transsynaptically. Adeno-associated virus (AAV) exhibits anterograde transneuronal transport, however, the synaptic specificity of this spread and its broad application within a diverse set of circuits remains to be explored. Here, using anatomic, functional, and molecular approaches, we provide evidence for the preferential transport of AAV1 to postsynaptically connected neurons and reveal its spread is strongly dependent on synaptic transmitter release. In addition to glutamatergic pathways, AAV1 also spreads through GABAergic synapses to both excitatory and inhibitory cell types. We observed little or no transport, however, through neuromodulatory projections (e.g., serotonergic, cholinergic, and noradrenergic). In addition, we found that AAV1 can be transported through long-distance descending projections from various brain regions to effectively transduce spinal cord neurons. Combined with newly designed intersectional and sparse labeling strategies, AAV1 can be applied within a wide variety of pathways to categorize neurons according to their input sources, morphology, and molecular identities. These properties make AAV1 a promising anterograde transsynaptic tool for establishing a comprehensive cell-atlas of the brain, although its capacity for retrograde transport currently limits its use to unidirectional circuits.

SIGNIFICANCE STATEMENT The discovery of anterograde transneuronal spread of AAV1 generates great promise for its application as a unique tool for manipulating input-defined cell populations and mapping their outputs. However, several outstanding questions remain for anterograde transsynaptic approaches in the field: (1) whether AAV1 spreads exclusively or specifically to synaptically connected neurons, and (2) how broad its application could be in various types of neural circuits in the brain. This study provides several lines of evidence in terms of anatomy, functional innervation, and underlying mechanisms, to strongly support that AAV1 anterograde transneuronal spread is highly synapse specific. In addition, several potentially important applications of transsynaptic AAV1 in probing neural circuits are described.

Neonatal stroke is as frequent as stroke in the elderly, but many pathophysiological injury aspects are distinct in neonates, including immune signaling. While myeloid cells can traffic into the brain via multiple routes, the choroid plexus (CP) has been identified as a uniquely educated gate for immune cell traffic during health and disease. To understand the mechanisms of myeloid cell trafficking via the CP and their influence on neonatal stroke, we characterized the phenotypes of CP-infiltrating myeloid cells after transient middle cerebral artery occlusion (tMCAO) in neonatal mice of both sexes in relation to blood-brain barrier permeability, injury, microglial activation, and CX3CR1-CCR2 signaling, focusing on the dynamics early after reperfusion. We demonstrate rapid recruitment of multiple myeloid phenotypes in the CP ipsilateral to the injury, including inflammatory CD45⁺CD11b⁺Ly6c^highCD86⁺, beneficial CD45⁺CD11b⁺Ly6c^lowCD206⁺, and CD45⁺CD11b⁺Ly6c^lowLy6g^high cells, but only minor leukocyte infiltration into acutely ischemic-reperfused cortex and negligible vascular albumin leakage. We report that CX3CR1-CCR2-mediated myeloid cell recruitment contributes to stroke injury. Considering the complexity of inflammatory cascades triggered by stroke and a role for TLR2 in injury, we also used direct TLR2 stimulation as an independent injury model. TLR2 agonist rapidly recruited myeloid cells to the CP, increased leukocytosis in the CSF and blood, but infiltration into the cortex remained low over time. While the magnitude and the phenotypes of myeloid cells diverged between tMCAO and TLR2 stimulation, in both models, disruption of CX3CR1-CCR2 signaling attenuated both monocyte and neutrophil trafficking to the CP and cortex.

SIGNIFICANCE STATEMENT Stroke during the neonatal period leads to long-term disabilities. The mechanisms of ischemic injury and inflammatory response differ greatly between the immature and adult brain. We examined leukocyte trafficking via the choroid plexus (CP) following neonatal stroke in relation to blood-brain barrier integrity, injury, microglial activation, and signaling via CX3CR1 and CCR2 receptors, or following direct TLR2 stimulation. Ischemia-reperfusion triggered marked unilateral CX3CR1-CCR2 dependent accumulation of diverse leukocyte subpopulations in the CP without inducing extravascular albumin leakage or major leukocyte infiltration into the brain. Disrupted CX3CR1-CCR2 signaling was neuroprotective in part by attenuating monocyte and neutrophil trafficking. Understanding the migratory patterns of CP-infiltrating myeloid cells with intact and disrupted CX3CR1-CCR2 signaling could identify novel therapeutic targets to protect the neonatal brain.

NEIL Mackay (“Johnson? Sturgeon? When it comes to coronavirus they are both the same”, The Herald, May 5) lambasts Nicola Sturgeon and Boris Johnson for both taking an almost identical approach in their fight against Covid-19, somehow implying that this is in itself a fault.

Children with specific language impairment are at risk for social difficulties. However, whether this occurs adaptively as a result of language impairment or occurs as a result of an underlying deficit in social cognition remains unclear.

We used eye tracking to explore how children with specific language impairment view social scenes. The overall gaze behavior resembled that of typically developing children. Significant attention to the speaker’s mouth may result in receiving less social-emotional information from the eyes. (Read the full article)

Ideal empirical antibiotic choices are based on local susceptibility data. These choices are important for ensuring positive patient outcomes, but pediatric-specific data may not be available.

Antibiotic susceptibilities differ by age group within a tertiary-care hospital. Knowing these differences, pediatricians chose empirical antibiotic therapy more likely to be successful. Children with infectious diseases would benefit from reporting of pediatric-specific susceptibility results. (Read the full article)

For newborn infants, extreme hyperbilirubinemia (≥24.5 mg/dL) is associated with risk for severe bilirubin encephalopathy. The causal factor of extreme hyperbilirubinemia is often not established. The genotype of Gilbert syndrome, the UGT1A1*28 allele, is considered a potential risk factor.

The UGT1A1*28 allele was not associated with risk for developing extreme hyperbilirubinemia. (Read the full article)

Preparticipation physical evaluations (PPEs) are considered necessary for a high standard of care for US scholastic athletes. However, important questions remain regarding consistency of implementation and content of cardiovascular screening practices among states.

Our results show that PPE policies are variable among US states, and adoption of current PPE-4 best practices is slow, demonstrating the need for nationwide PPE standardization. (Read the full article)

Vinod K. Bhutani
Jan 1, 1999; 103:6-14
ARTICLES

Wilmington, Del. (October 25, 2017) – Owing to Circumstances is a participatory site specific installation that will be on view in the Mezzanine Gallery from November 3-22, 2017. An opening reception to meet the artist will be held on Friday, November 3 from 5-7 p.m. Borders received a 2017 Emerging Fellowship in Sculpture. Borders designed […]

Xiaomi Mi 10 and last year's OnePlus 7T, both boast impressive specifications like octa-core processors and 8GB of RAM. So, let's compare the two phones to see how similar or different they...

However, if someone wants to buy a comprehensive health cover, it would cost them Rs 8,000-11,000 for Rs 10 lakh sum insured.

Banks are offering Covid-19 personal loans only to existing borrowers and pension and salary account holders

The US is operating on making the process of visa application shorter for Indian citizens and starting 1 September 2019, certain candidates can appeal for a waiver from the compulsory interview. In a statement to the associations of the travel agents,…

All states have been requested to give a complete waiver on all fixed electricity and other utility charges as well as excise duties without any penalties to the tourism and hospitality industry, FAITH said in a statement.

The European Commission has revised the thresholds relating to the award procedures of public contracts and concession agreements by means of four separate Commission Delegated Regulations, adopted on 30 October 2019, which entered into force on 1 J...

The Government Equalities Office (GEO) is proposing to make significant changes to the planned specific equality duties that will apply to certain public bodies in England, as well as some operating across Great Britain. The Welsh Assembly Governme...

TBD (Owen Holland) Ltd v Simons & Ors [2020] EWHC 30 (Ch) Background A search order is one of the most draconian orders that the English courts can make, allowing an applicant – where there is a real possibility that a respondent may destroy o...

What happens when you find yourself in circumstances that God’s Word doesn’t speak to? If Scripture is truly sufficient, what do you do when facing issues of modern life that the Bible does not directly address?

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