Reconstitution of T cell receptor signaling in ZAP-70-deficient cells by retroviral transduction of the ZAP-70 gene.

A variant of severe combined immunodeficiency syndrome (SCID) with a selective inability to produce CD8 single positive T cells and a signal transduction defect in peripheral CD4+ cells has recently been shown to be the result of mutations in the ZAP-70 gene. T cell receptor (TCR) signaling requires the association of the ZAP-70 protein tyrosine kinase with the TCR complex. Human T cell leukemia virus type I-transformed CD4+ T cell lines were established from ZAP-70-deficient patients and normal controls. ZAP-70 was expressed and appropriately phosphorylated in normal T cell lines after TCR engagement, but was not detected in T cell lines from ZAP-70-deficient patients. To determine whether signaling could be reconstituted, wild-type ZAP-70 was introduced into deficient cells with a ZAP-70 retroviral vector. High titer producer clones expressing ZAP-70 were generated in the Gibbon ape leukemia virus packaging line PG13. After transduction, ZAP-70 was detected at levels equivalent to those observed in normal cells, and was appropriately phosphorylated on tyrosine after receptor engagement. The kinase activity of ZAP-70 in the reconstituted cells was also appropriately upregulated by receptor aggregation. Moreover, normal and transduced cells, but not ZAP-70-deficient cells, were able to mobilize calcium after receptor ligation, indicating that proximal TCR signaling was reconstituted. These results indicate that this form of SCID may be corrected by gene therapy

Prenatal healthcare after sentencing reform: heterogeneous effects for prenatal healthcare access and equity

BACKGROUND: High rates of imprisonment in the U.S. have significant health, social, and economic consequences, particularly for marginalized communities. This study examines imprisonment as a contextual driver of receiving prenatal care by evaluating whether early and adequate prenatal care improved after Pennsylvania’s criminal sentencing reform reduced prison admissions. METHODS: We linked individual-level birth certificate microdata on births (n = 999,503) in Pennsylvania (2009–2015), to monthly county-level rates of prison admissions. We apply an interrupted time series approach that contrasts post-policy changes in early and adequate prenatal care across counties where prison admissions were effectively reduced or continued to rise. We then tested whether prenatal care improvements were stronger among Black birthing people and those with lower levels of educational attainment. RESULTS: In counties where prison admissions declined the most after the policy, early prenatal care increased from 69.0% to 73.2%, and inadequate prenatal care decreased from 18.1% to 15.9%. By comparison, improvements in early prenatal care were smaller in counties where prison admissions increased the most post-policy (73.5 to 76.4%) and there was no change to prenatal care inadequacy (14.4% pre and post). We find this pattern of improvements to be particularly strong among Black birthing people and those with lower levels of educational attainment. CONCLUSIONS: Pennsylvania’s sentencing reforms were associated with small advancements in racial and socioeconomic equity in prenatal care.1(PG012452-02) - Trustees Of Columbia University In The City Of New York; Trustees Of Columbia University In The City Of New YorkPublished versio

k-strings and baryon vertices in SU(N) gauge theories

It is pointed out that the sine law for the k-string tension emerges as the critical threshold below which the spatial Z_N symmetry of the static baryon potential is spontaneously broken. This result applies not only to SU(N) gauge theories, but to any gauge system with stable k-strings admitting a baryon vertex made with N sources in the fundamental representation. Some simple examples are worked out.Comment: 4 pages, 4 figures, v2: reference added, v3: comments and references adde

Microscopic modelling of doped manganites

Colossal magneto-resistance manganites are characterised by a complex interplay of charge, spin, orbital and lattice degrees of freedom. Formulating microscopic models for these compounds aims at meeting to conflicting objectives: sufficient simplification without excessive restrictions on the phase space. We give a detailed introduction to the electronic structure of manganites and derive a microscopic model for their low energy physics. Focussing on short range electron-lattice and spin-orbital correlations we supplement the modelling with numerical simulations.Comment: 20 pages, 10 figs, accepted for publ. in New J. Phys., Focus issue on Orbital Physic

Canonical Formulation of the Light-Front Gluodynamics and Quantization of the Non-Abelian Plane Waves

Without a gauge fixing, canonical variables for the light-front SU(2) gluodynamics are determined. The Gauss law is written in terms of the canonical variables. The system is qualified as a generalized dynamical system with first class constraints. Abeliazation is a specific feature of the formulation (most of the canonical variables transform nontrivially only under the action of an Abelian subgroup of the gauge transformations). At finite volume, a discrete spectrum of the light-front Hamiltonian $P_+$ is obtained in the sector of vanishing $P_-$. We obtain, therefore, a quantized form of the classical solutions previously known as non-Abelian plane waves. Then, considering the infinite volume limit, we find that the presence of the mass gap depends on the way the infinite volume limit is taken, which may suggest the presence of different ``phases'' of the infinite volume theory. We also check that the formulation obtained is in accord with the standard perturbation theory if the latter is taken in the covariant gauges.Comment: REVTEX, 18 pages, version to appear in Phys. Rev.

Molecular Aspects of Secretory Granule Exocytosis by Neurons and Endocrine Cells

Neuronal communication and endocrine signaling are fundamental for integrating the function of tissues and cells in the body. Hormones released by endocrine cells are transported to the target cells through the circulation. By contrast, transmitter release from neurons occurs at specialized intercellular junctions, the synapses. Nevertheless, the mechanisms by which signal molecules are synthesized, stored, and eventually secreted by neurons and endocrine cells are very similar. Neurons and endocrine cells have in common two different types of secretory organelles, indicating the presence of two distinct secretory pathways. The synaptic vesicles of neurons contain excitatory or inhibitory neurotransmitters, whereas the secretory granules (also referred to as dense core vesicles, because of their electron dense content) are filled with neuropeptides and amines. In endocrine cells, peptide hormones and amines predominate in secretory granules. The function and content of vesicles, which share antigens with synaptic vesicles, are unknown for most endocrine cells. However, in B cells of the pancreatic islet, these vesicles contain GABA, which may be involved in intrainsular signaling.' Exocytosis of both synaptic vesicles and secretory granules is controlled by cytoplasmic calcium. However, the precise mechanisms of the subsequent steps, such as docking of vesicles and fusion of their membranes with the plasma membrane, are still incompletely understood. This contribution summarizes recent observations that elucidate components in neurons and endocrine cells involved in exocytosis. Emphasis is put on the intracellular aspects of the release of secretory granules that recently have been analyzed in detail

Ketogenic diet uncovers differential metabolic plasticity of brain cells

To maintain homeostasis, the body, including the brain, reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major central nervous system (CNS) cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation. Under steady-state conditions, CNS cell types prefer distinct modes of energy metabolism. Unexpectedly, the comparison with KD revealed distinct cell type–specific strategies to manage the altered availability of energy metabolites. Astrocytes and neurons but not oligodendrocytes demonstrated metabolic plasticity. Moreover, inflammatory demyelinating disease changed the neuronal metabolic signature in a similar direction as KD. Together, these findings highlight the importance of the metabolic cross-talk between CNS cells and between the periphery and the brain to manage altered nutrition and neurological disease

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA