Healthcare law in the US and the RTE in India: steps towards universal provision of social goods

Earlier this year, the Supreme Court of India upheld the constitutional validity of the Right of Children to Free and Compulsory Education Act 2009 and the Supreme Court of the United States likewise upheld the Patient Protection and Affordable Care Act, 2010. The two pieces of legislation attempt to expand, to a greater or lesser degree, the provision of education and health services, respectively. This article attempts to understand and evaluate the policy debates and legal decisions around the two Acts as attempts by two constitutional liberal democracies to clarify the relationship between the state and private sector, and their respective roles and responsibilities to secure social welfare

Tbr1 instructs laminar patterning of retinal ganglion cell dendrites.

Visual information is delivered to the brain by >40 types of retinal ganglion cells (RGCs). Diversity in this representation arises within the inner plexiform layer (IPL), where dendrites of each RGC type are restricted to specific sublaminae, limiting the interneuronal types that can innervate them. How such dendritic restriction arises is unclear. We show that the transcription factor Tbr1 is expressed by four mouse RGC types with dendrites in the outer IPL and is required for their laminar specification. Loss of Tbr1 results in elaboration of dendrites within the inner IPL, while misexpression in other cells retargets their neurites to the outer IPL. Two transmembrane molecules, Sorcs3 and Cdh8, act as effectors of the Tbr1-controlled lamination program. However, they are expressed in just one Tbr1+ RGC type, supporting a model in which a single transcription factor implements similar laminar choices in distinct cell types by recruiting partially non-overlapping effectors

Politics and society between elections

The problems of India’s development and governance are routinely linked to the logic of India’s electoral democracy. As a result, a great deal is known about elections, but paradoxically our knowledge of politics and society between elections is relatively underdeveloped. As much as anything else, development and governance outcomes are shaped by how the government functions between elections; including how it relates to citizens on a regular basis, how it provides routine public services to them, and how public order is maintained. Further, governance processes are nested in the social and political relationships between citizens and government functionaries

A Spontaneous Mutation in Contactin 1 in the Mouse

Mutations in the gene encoding the immunoglobulin-superfamily member cell adhesion molecule contactin1 (CNTN1) cause lethal congenital myopathy in human patients and neurodevelopmental phenotypes in knockout mice. Whether the mutant mice provide an accurate model of the human disease is unclear; resolving this will require additional functional tests of the neuromuscular system and examination of Cntn1 mutations on different genetic backgrounds that may influence the phenotype. Toward these ends, we have analyzed a new, spontaneous mutation in the mouse Cntn1 gene that arose in a BALB/c genetic background. The overt phenotype is very similar to the knockout of Cntn1, with affected animals having reduced body weight, a failure to thrive, locomotor abnormalities, and a lifespan of 2–3 weeks. Mice homozygous for the new allele have CNTN1 protein undetectable by western blotting, suggesting that it is a null or very severe hypomorph. In an analysis of neuromuscular function, neuromuscular junctions had normal morphology, consistent with previous studies in knockout mice, and the muscles were able to generate appropriate force when normalized for their reduced size in late stage animals. Therefore, the Cntn1 mutant mice do not show evidence for a myopathy, but instead the phenotype is likely to be caused by dysfunction in the nervous system. Given the similarity of CNTN1 to other Ig-superfamily proteins such as DSCAMs, we also characterized the expression and localization of Cntn1 in the retinas of mutant mice for developmental defects. Despite widespread expression, no anomalies in retinal anatomy were detected histologically or using a battery of cell-type specific antibodies. We therefore conclude that the phenotype of the Cntn1 mice arises from dysfunction in the brain, spinal cord or peripheral nervous system, and is similar in either a BALB/c or B6;129;Black Swiss background, raising a possible discordance between the mouse and human phenotypes resulting from Cntn1 mutations

The role of nicotinic receptor function in the development of synapses and in diabetes-induced dysautonomias

Autonomic circuits depend critically on cholinergic synaptic transmission to develop and function normally, and severe dysautonomias emerge if cholinergic transmission is disrupted. Yet, we do not fully understand how synaptic activity helps cholinergic synapses develop on autonomic neurons nor do we understand whether or not disrupted postsynaptic nAChRs render cholinergic synapses non-functional, resulting in dysautonomias. To study these two issues, I investigated sympathetic neurons from mice with a disruption in the 3 nAChR subunit gene (3 KO). I hypothesized that (1) the loss of 3 subunits would remove functional nAChRs from cholinergic synapses and abolish synaptic transmission; (2) the loss of postsynaptic activity would prevent cholinergic nerve terminals from developing normally; and (3) functional 3 nAChRs are inactivated by diabetes-induced reactive oxygen species (ROS) to render cholinergic synapses non-functional and cause dysautonomias. To test these hypotheses I combined electrophysiological, molecular biology and imaging techniques to examine cholinergic synapses on sympathetic neurons in 3 KO mice. I found that the loss of 3 prevents the appearance of functional nAChRs on sympathetic neurons and abolishes synaptic transmission through sympathetic ganglia. In spite of this, morphologically normal cholinergic synapses form and persist for months on sympathetic neurons from 3 KO mice. Surprisingly, in the absence of postsynaptic activity the presynaptic terminals are immature and lack high-affinity choline transporters (CHTs). As a result, they cannot sustain ACh release and become quickly depleted. Moreover, using in vivo gene transfer strategies I demonstrate that CHT expression in nerve terminals is induced and maintained by signals downstream of postsynaptic activity; converting these immature terminals that deplete rapidly to mature terminals capable of sustainingLes circuits autonomes nécessitent la transmission synaptique cholinergique pour un développement et une fonction normale. Le résultat d'une perturbation de cette transmission cholinergique est l'apparition de dysautonomies sévères. Hors, nous ne comprenons pas complètement comment l'activité synaptique aide au développement des synapses cholinergiques sur les neurones autonomes, ni si les dysautonomies sont la conséquence d'une perturbation des nAChRs post-synaptiques ayant comme résultat des synapses cholinergiques non-fonctionnelles. Pour en savoir plus sur ces deux sujets, j'ai étudié des neurones sympatiques provenant de souris qui possèdent une perturbation du gène sous-unité a3 nAChR (a3KO). J'ai formulé l'hypothèse que (1) l'absence d'activité post-synaptique empêcherait le développement normal des terminaisons nerveuses cholinergiques ; et (2) les dérivés réactifs de l'oxygène (DRO) provoqués par le diabète causent l'inactivation des nAChRs fonctionnels produisant des synapses cholinergiques non-fonctionnelles et les dysautonomies qui les accompagnent. J'ai combiné plusieurs méthodes pour tester ces hypothèses en examinant les synapses cholinergiques sur des neurones sympatiques dans des souries a3KO. J'ai trouvé que la perte de a3 empêche l'apparition de nAChRs fonctionnels dans les neurones sympathiques et supprime la transmission synaptique à travers les ganglions sympathiques. Malgré cela, des synapses cholinergiques morphologiquement normales se forment et persistent pendant plusieurs mois dans les neurones de souries a3KO. Étonnement, en l'absence d'activité post-synaptique, les terminaisons pre-synaptiques sont immatures et ne possèdent pas de transporteurs à haute affinité de choline (CHT). L'absence de CHTs à comme résultat l'inhabilité de soutenir le relâchement d'ACh causant son épuisement rapide. De plus, en utilisant des techniques de tran

Steps towards universal provision of social goods healthcare law in the US and the RTE in India

Earlier this year, the Supreme Court of India upheld the constitutional validity of the Right of Children to Free and Compulsory Education Act 2009 and the Supreme Court of the United States likewise upheld the Patient Protection and Affordable Care Act, 2010. The two pieces of legislation attempt to expand, to a greater or lesser degree, the provision of education and health services, respectively. This article attempts to understand and evaluate the policy debates and legal decisions around the two Acts as attempts by two constitutional liberal democracies to clarify the relationship between the state and private sector, and their respective roles and responsibilities to secure social welfare

SIDEKICK 2 DIRECTS FORMATION OF A RETINAL CIRCUIT THAT DETECTS DIFFERENTIAL MOTION

In the mammalian retina, processes of ~70 types of interneurons form specific synapses on ~30 types of retinal ganglion cells (RGCs) in a neuropil called the inner plexiform layer (IPL). Each RGC type extracts salient features from visual input, which are sent deeper into the brain for further processing 1-4. The specificity and stereotypy of synapses formed in the IPL account for the feature-detecting ability of the RGCs. Here, we analyze the development and function of synapses on one RGC type, the W3B-RGC5,6. These cells have the remarkable property of responding when the timing of a small object's movement differs from that of the background, but not when they coincide6. Such cells, called “local edge detectors” or “object motion sensors”, can distinguish moving objects from a visual scene that is also moving6-12. We show that W3B-RGCs receive strong and selective input from an unusual excitatory amacrine cell type called VG3-AC. Both W3B-RGCs and VG3-ACs express the immunoglobulin superfamily recognition molecule Sidekick-2 (Sdk2)13,14, and both loss- and gain-of function studies indicate that Sdk2-dependent homophilic interactions are necessary for the selectivity of the connection. The Sdk2-specified synapse is essential for visual responses of W3B-RGCs: whereas bipolar cells relay visual input directly to most RGCs, the W3B-RGCs receive much of their input indirectly, via the VG3-ACs. This non-canonical circuit introduces a delay into the pathway from photoreceptors in the center of the receptive field to W3B-RGCs, which could improve their ability to judge the synchrony of local and global motion

Cadherin Combinations Recruit Dendrites of Distinct Retinal Neurons to a Shared Interneuronal Scaffold

Distinct neuronal types connect in complex ways to generate functional neural circuits. The molecular diversity required to specify this connectivity could be supplied by multigene families of synaptic recognition molecules, but most studies to date have assessed just one or a few members at a time. Here, we analyze roles of cadherins (Cdhs) in formation of retinal circuits comprising eight neuronal types that inform the brain about motion in four directions. We show that at least 15 classical Cdhs are expressed by neurons in these circuits and at least 6 (Cdh6-10 and 18) act individually or in combinations to promote specific connectivity among the cells. They act in part by directing the processes of output neurons and excitatory interneurons to a cellular scaffold formed by inhibitory interneurons. Because Cdhs are expressed combinatorially by many central neurons, similar interactions could be involved in patterning circuits throughout the brain

Tbr1 instructs laminar patterning of retinal ganglion cell dendrites.

Visual information is delivered to the brain by >40 types of retinal ganglion cells (RGCs). Diversity in this representation arises within the inner plexiform layer (IPL), where dendrites of each RGC type are restricted to specific sublaminae, limiting the interneuronal types that can innervate them. How such dendritic restriction arises is unclear. We show that the transcription factor Tbr1 is expressed by four mouse RGC types with dendrites in the outer IPL and is required for their laminar specification. Loss of Tbr1 results in elaboration of dendrites within the inner IPL, while misexpression in other cells retargets their neurites to the outer IPL. Two transmembrane molecules, Sorcs3 and Cdh8, act as effectors of the Tbr1-controlled lamination program. However, they are expressed in just one Tbr1+ RGC type, supporting a model in which a single transcription factor implements similar laminar choices in distinct cell types by recruiting partially non-overlapping effectors