An inhibitory pull-push circuit in frontal cortex.

Push-pull is a canonical computation of excitatory cortical circuits. By contrast, we identify a pull-push inhibitory circuit in frontal cortex that originates in vasoactive intestinal polypeptide (VIP)-expressing interneurons. During arousal, VIP cells rapidly and directly inhibit pyramidal neurons; VIP cells also indirectly excite these pyramidal neurons via parallel disinhibition. Thus, arousal exerts a feedback pull-push influence on excitatory neurons-an inversion of the canonical push-pull of feedforward input

Crítica a la teoría económica burguesa

La crítica marxista de las distintas posiciones burguesas es una expresión de la lucha de clases en el terreno de las ideas. Convencida de la importancia de dicha crítica, la Editorial Nuestro Tiempo ofrece este volumen que contiene artículos y fragmentos de libros de autores que, desde distintas perspectivas, han analizado la economía burguesa. Se observará que se ha dado preferencia a la inclusión de autores latinoamericanos, profesores e investigadores que en Chile, Venezuela, Colombia y México han puesto su grano de arena en el difícil y aún descuidado terreno de la lucha teórica e ideológica

16(th) IHIW: population global distribution of killer immunoglobulin-like receptor (KIR) and ligands.

In the last fifteen years, published reports have described KIR gene-content frequency distributions in more than 120 populations worldwide. However, there have been limited studies examining these data in aggregate to detect overall patterns of variation at regional and global levels. Here, we present a summary of the collection of KIR gene-content data for 105 worldwide populations collected as part of the 15th and 16th International Histocompatibility and Immunogenetics Workshops, and preliminary results for data analysis

A tale of two capitalisms: preliminary spatial and historical comparisons of homicide rates in Western Europe and the USA

This article examines comparative homicide rates in the United States and Western Europe in an era of increasingly globalized neoliberal economics. The main finding of this preliminary analysis is that historical and spatial correlations between distinct forms of political economy and homicide rates are consistent enough to suggest that social democratic regimes are more successful at fostering the socio-cultural conditions necessary for reduced homicide rates. Thus Western Europe and all continents and nations should approach the importation of American neo-liberal economic policies with extreme caution. The article concludes by suggesting that the indirect but crucial causal connection between political economy and homicide rates, prematurely pushed into the background of criminological thought during the ‘cultural turn’, should be returned to the foreground

Measuring patient-perceived continuity of care for patients with long-term conditions in primary care

Background: Continuity of care is widely acknowledged as important for patients with multi-morbidity but simple, service-orientated indices cannot capture the full impact of continuity in complex care delivery systems. The patient's perspective is important to assess outcomes fully and this is challenging because generic measures of patient-perceived continuity are lacking. We investigate the Chao Perception of Continuity (Chao PC) scale to determine its suitability as a measure of continuity of care for patients with a long-term condition (stroke), and co-morbidity, in a primary care setting. Methods: Design and Setting: A questionnaire study embedded in a prospective observational cohort study of outcomes for patients following acute stroke. Participants: 168 community dwelling patients (58% male) mean age 68 years a minimum one year post-stroke. Functional status: Barthel Index mean =16. Intervention: A 23-item questionnaire, the Chao Perception of Continuity (Chao PC) scale, sent by post to their place of residence or administered face to face as part of the final cohort study assessment. Results: 310 patients were invited to participate; 168 (54%) completed a questionnaire. All 23 questionnaire items were entered into a Principal Component Analysis. Emergent factors from the exploratory analysis were (1) inter-personal trust (relational continuity); (2) interpersonal knowledge and information (informational and relational continuity) and (3) the process of care (managerial continuity). The strongest of these was inter-personal trust. Conclusion: The context-specific items in the Chao PC scale are difficult for respondents to interpret in a United Kingdom Primary Care setting resulting in missing data and low response rates. The Chao-PC therefore cannot be recommended for wider application as a general measure of continuity of care without significant modification. Our findings reflect the acknowledged dimensions of continuity and support the concept of continuity of care as a multi-dimensional construct. We demonstrate the overlapping boundaries across the dimensions in the factor structure derived. Trust and interpersonal knowledge are clearly identified as valuable components of any patient-perceived measure of continuity of care

Focal therapy for prostate cancer: revolution or evolution?

The face of prostate cancer has been dramatically changed since the late 1980s when PSA was introduced as a clinical screening tool. More men are diagnosed with small foci of cancers instead of the advanced disease evident prior to PSA screening. Treatment options for these smaller tumors consist of expectant management, radiation therapy (brachytherapy and external beam radiotherapy) and surgery (cryosurgical ablation and radical prostatectomy). In the highly select patient, cancer specific survival employing any of these treatment options is excellent, however morbidity from these interventions are significant. Thus, the idea of treating only the cancer within the prostate and sparing the non-cancerous tissue in the prostate is quite appealing, yet controversial. Moving forward if we are to embrace the focal treatment of prostate cancer we must: be able to accurately identify index lesions within the prostate, image cancers within the prostate and methodically study the litany of focal therapeutic options available

The R403Q Myosin Mutation Implicated in Familial Hypertrophic Cardiomyopathy Causes Disorder at the Actomyosin Interface

Mutations in virtually all of the proteins comprising the cardiac muscle sarcomere have been implicated in causing Familial Hypertrophic Cardiomyopathy (FHC). Mutations in the beta-myosin heavy chain (MHC) remain among the most common causes of FHC, with the widely studied R403Q mutation resulting in an especially severe clinical prognosis. In vitro functional studies of cardiac myosin containing the R403Q mutation have revealed significant changes in enzymatic and mechanical properties compared to wild-type myosin. It has been proposed that these molecular changes must trigger events that ultimately lead to the clinical phenotype.Here we examine the structural consequences of the R403Q mutation in a recombinant smooth muscle myosin subfragment (S1), whose kinetic features have much in common with slow beta-MHC. We obtained three-dimensional reconstructions of wild-type and R403Q smooth muscle S1 bound to actin filaments in the presence (ADP) and absence (apo) of nucleotide by electron cryomicroscopy and image analysis. We observed that the mutant S1 was attached to actin at highly variable angles compared to wild-type reconstructions, suggesting a severe disruption of the actin-myosin interaction at the interface.These results provide structural evidence that disarray at the molecular level may be linked to the histopathological myocyte disarray characteristic of the diseased state

Unconventional Transcriptional Response to Environmental Enrichment in a Mouse Model of Rett Syndrome

Background: Rett syndrome (RTT) is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE) on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2 2/y). Principal Findings: We found that EE delayed and attenuated some neurological alterations presented by Mecp2 2/y mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models. Conclusions/Significance: We found that EE induced downregulation of several synaptic markers, suggesting that th

PRKCA Polymorphism Changes the Neural Basis of Episodic Remembering in Healthy Individuals

Everyday functioning relies on episodic memory, the conscious retrieval of past experiences, but this crucial cognitive ability declines severely with aging and disease. Vulnerability to memory decline varies across individuals however, producing differences in the time course and severity of memory problems that complicate attempts at diagnosis and treatment. Here we identify a key source of variability, by examining gene dependent changes in the neural basis of episodic remembering in healthy adults, targeting seven polymorphisms previously linked to memory. Scalp recorded Event-Related Potentials (ERPs) were measured while participants remembered words, using an item recognition task that requires discrimination between studied and unstudied stimuli. Significant differences were found as a consequence of a Single Nucleotide Polymorphism (SNP) in just one of the tested genes, PRKCA (rs8074995). Participants with the common G/G variant exhibited left parietal old/new effects, which are typically seen in word recognition studies, reflecting recollection-based remembering. During the same stage of memory retrieval participants carrying a rarer A variant exhibited an atypical pattern of brain activity, a topographically dissociable frontally-distributed old/new effect, even though behavioural performance did not differ between groups. Results replicated in a second independent sample of participants. These findings demonstrate that the PRKCA genotype is important in determining how episodic memories are retrieved, opening a new route towards understanding individual differences in memory

Evidence of HIV-1 adaptation to host HLA alleles following chimp-to-human transmission

<p>Abstract</p> <p>Background</p> <p>The cytotoxic T-lymphocyte immune response is important in controlling HIV-1 replication in infected humans. In this immune pathway, viral peptides within infected cells are presented to T-lymphocytes by the polymorphic human leukocyte antigens (HLA). HLA alleles exert selective pressure on the peptide regions and immune escape mutations that occur at some of the targeted sites can enable the virus to adapt to the infected host. The pattern of ongoing immune escape and reversion associated with several human HLA alleles has been studied extensively. Such mutations revert upon transmission to a host without the HLA allele because the escape mutation incurs a fitness cost. However, to-date there has been little attempt to study permanent loss of CTL epitopes due to escape mutations without an effect on fitness.</p> <p>Results</p> <p>Here, we set out to determine the extent of adaptation of HIV-1 to three well-characterized HLA alleles during the initial exposure of the virus to the human cytotoxic immune responses following transmission from chimpanzee. We generated a chimpanzee consensus sequence to approximate the virus sequence that was initially transmitted to the human host and used a method based on peptide binding affinity to HLA crystal structures to predict peptides that were potentially targeted by the HLA alleles on this sequence. Next, we used codon-based phylogenetic models to quantify the average selective pressure that acted on these regions during the period immediately following the zoonosis event, corresponding to the branch of the phylogenetic tree leading to the common ancestor of all of the HIV-1 sequences. Evidence for adaptive evolution during this period was observed at regions recognised by HLA A*6801 and A*0201, both of which are common in African populations. No evidence of adaptive evolution was observed at sites targeted by HLA-B*2705, which is a rare allele in African populations.</p> <p>Conclusion</p> <p>Our results suggest that the ancestral HIV-1 virus experienced a period of positive selective pressure due to immune responses associated with HLA alleles that were common in the infected human population. We propose that this resulted in permanent escape from immune responses targeting unconstrained regions of the virus.</p