Miracle-dz/UniFAR-FTUs huggingface dataset:
Highly active antiretroviral therapy and survival in HIV-infected injection drug users.

CONTEXT Highly active antiretroviral therapy (HAART) is often withheld from injection drug users (IDUs) infected with the human immunodeficiency virus (HIV) based on the belief that their unstable lifestyles may predetermine a markedly inferior outcome with HAART. However, long-term evaluations of HIV treatment outcomes among IDUs in comparison with other risk groups are not available. OBJECTIVE To compare survival rates among HIV-infected patients initiating HAART with and without a history of injection drug use. DESIGN, SETTING, AND PATIENTS Population-based, prospective cohort study (HAART Observational Medical Evaluation and Research [HOMER]) of 3116 antiretroviral-naive HIV-infected patients in a province-wide HIV/AIDS treatment program in British Columbia, Canada. Of the 3116 patients, 915 were IDUs (29.4%), 579 were female (18.6%), and the median age was 39.4 years (interquartile range, 33.3-46.4 years). Treatment with HAART was initiated between August 1, 1996, and June 30, 2006. The median duration of follow-up was 5.3 years (interquartile range, 2.8-8.3 years) for IDUs and 4.3 years (interquartile range, 2.0-7.6 years) for non-IDUs. Patients were followed up until June 30, 2007. Data were analyzed between November 1, 2007, and May 26, 2008. MAIN OUTCOME MEASURE All-cause mortality. RESULTS Overall, 622 individuals died (20.0%) during the study period (232 IDUs and 390 non-IDUs), for a crude mortality rate of 20.0% (95% confidence interval [CI], 18.4%-21.5%). At 84 months after the initiation of HAART, the product limit estimate of the cumulative all-cause mortality rate was similar between the 915 IDUs (26.5%; 95% CI, 23.2%-29.8%) and 2201 non-IDUs (21.6%; 95% CI, 16.9%-26.2%) (Wilcoxon P = .47). In multivariate time-updated Cox regression, the hazard ratio of mortality was similar between IDUs and non-IDUs (1.09; 95% CI, 0.92-1.29). CONCLUSION In this study population, injection drug use was not associated with decreased survival among HIV-infected patients initiating HAART.
Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer.

BACKGROUND The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).
Fragile X related protein 1 (FXR1P) regulates proliferation of adult neural stem cells

Fragile X related protein 1 (FXR1P) is a member of the fragile X family of RNA-binding proteins, which includes FMRP and FXR2P. Both FMRP and FXR2P regulate neurogenesis, a process affected in a number of neurological and neuropsychiatric disorders, including fragile X syndrome. Although FXR1P has been implicated in various developmental processes and neuropsychiatric diseases, its role in neurodevelopment is not well understood. The goal of the present study was to elucidate the function of FXR1P in adult neurogenesis. We used an inducible mouse model that allows us to investigate how FXR1P deficiency in adult neural stem cells (aNSCs) affects proliferation and neuronal differentiation. Deletion of FXR1 in aNSCs resulted in fewer adult-born cells in the dentate gyrus (DG) overall, reducing populations across different stages of neurogenesis, including radial glia-like cells, intermediate progenitors, neuroblasts, immature neurons and neurons. We hypothesized that this reduction in new cell numbers resulted from impaired proliferation, which we confirmed both in vivo and in vitro. We discovered that FXR1P-deficient aNSCs have altered expression of a select number of cell-cycle genes, and we identified the mRNA of cyclin-dependent kinase inhibitor 1A (Cdkn1a, p21) as a direct target of FXR1P. Restoration of p21 mRNA to wild-type levels rescued the proliferation deficit in cells lacking FXR1P, demonstrating that p21 is a mediator of FXR1P in aNSCs. These results indicate that FXR1P plays an important role in regulating aNSC self-renewal and maintenance in the adult brain, which may have implications for a number of neurodevelopmental and psychiatric disorders.
Temporal dynamics of the knowledge‐mediated visual disambiguation process in humans: a magnetoencephalography study

Disambiguation of a noisy visual scene with prior knowledge is an indispensable task of the visual system. To adequately adapt to a dynamically changing visual environment full of noisy visual scenes, the implementation of knowledge‐mediated disambiguation in the brain is imperative and essential for proceeding as fast as possible under the limited capacity of visual image processing. However, the temporal profile of the disambiguation process has not yet been fully elucidated in the brain. The present study attempted to determine how quickly knowledge‐mediated disambiguation began to proceed along visual areas after the onset of a two‐tone ambiguous image using magnetoencephalography with high temporal resolution. Using the predictive coding framework, we focused on activity reduction for the two‐tone ambiguous image as an index of the implementation of disambiguation. Source analysis revealed that a significant activity reduction was observed in the lateral occipital area at approximately 120 ms after the onset of the ambiguous image, but not in preceding activity (about 115 ms) in the cuneus when participants perceptually disambiguated the ambiguous image with prior knowledge. These results suggested that knowledge‐mediated disambiguation may be implemented as early as approximately 120 ms following an ambiguous visual scene, at least in the lateral occipital area, and provided an insight into the temporal profile of the disambiguation process of a noisy visual scene with prior knowledge.
Legal power and legal rights--isolation and quarantine in the case of drug-resistant tuberculosis.

The recent case of Andrew Speaker has focused attention on the role of compulsory isolation and quarantine in tuberculosis control. Wendy Parmet writes that lost in the debate was the recognition of legal checks on the use of compulsory isolation and quarantine as well as the importance of such checks. Wendy Parmet discusses the case of Andrew Speaker and the appropriate use of legal and public health tools to interrupt transmission of drug-resistant tuberculosis and other infectious diseases. Wendy Parmet is a professor of law at Northeastern University School of Law, Boston.
Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia

Abstract Dystonia is a neurological movement disorder that forces the body into twisting, repetitive movements or sometimes painful abnormal postures. With the advent of next‐generation sequencing technologies, the homozygous mutations T71N and A190T in the neuronal calcium sensor (NCS) hippocalcin were identified as the genetic cause of primary isolated dystonia (DYT2 dystonia). However, the effect of these mutations on the physiological role of hippocalcin has not yet been elucidated. Using a multidisciplinary approach, we demonstrated that hippocalcin oligomerises in a calcium‐dependent manner and binds to voltage‐gated calcium channels. Mutations T71N and A190T in hippocalcin did not affect stability, calcium‐binding affinity or translocation to cellular membranes (Ca2+/myristoyl switch). We obtained the first crystal structure of hippocalcin and alignment with other NCS proteins showed significant variability in the orientation of the C‐terminal part of the molecule, the region expected to be important for target binding. We demonstrated that the disease‐causing mutations did not affect the structure of the protein, however both mutants showed a defect in oligomerisation. In addition, we observed an increased calcium influx in KCl‐depolarised cells expressing mutated hippocalcin, mostly driven by N‐type voltage‐gated calcium channels. Our data demonstrate that the dystonia‐causing mutations strongly affect hippocalcin cellular functions which suggest a central role for perturbed calcium signalling in DYT2 dystonia.
Incidência de lesão musculoesquelética em jogadores de futebol

INTRODUCTION: Due to soccer worldwide popularity, especially in Brazil, several studies try to outline a profile of injuries and players more prone to it; however, this kind of study is rare in the northern region of our country. OBJETIVE: To analyze the incidence of musculoskeletal injuries on professional soccer players of Remo Club. METHODS: We analyzed 27 professional soccer players of Remo Club were analyzed during the Soccer Championship from Para State, 2010. Data were collected through verification of records and application of a semi-coded questionnaire to the athletes; subsequently, statistical analysis was conducted. RESULTS: By analyzing the sample, it was found that most of the injuries were contractures and contusions (bruises), the body parts most affected were the thigh and the knee and the athletes who suffered the most damage were midfielders. CONCLUSION: Several muscular injuries were observed; therefore, a follow-up of the multidisciplinary staff is needed, since this kind of injuries does not occur due to trauma, but rather due to the movements imposed to the players during games and practice. Thus, adequate physical preparation can reduce the incidence of this type of injuries.
Communicating with adolescents about AIDS : experience from Eastern and Southern Africa

This publication reviews HIV/AIDS prevention programs in Malawi Zambia Uganda and Kenya specifically targeted at adolescents. After an overview of the current status of the AIDS epidemic in the region and its impact on youth the report presents results of a rapid assessment of specific programs in the four countries and suggests guidelines for evaluating youth-oriented HIV/AIDS prevention programs. Study methodologies included interviews with program managers a review of published and unpublished literature and perusal of IEC materials developed for youth. The majority of programs reviewed were using a combination of behavior modification techniques and media initiatives. Since the key message to adolescents in Eastern and Southern Africa has been abstinence programs tended to fail to offer explicit information on condoms and safer sex negotiating skills. Nearly all programs failed to conduct needs assessments audience analyses and pretesting of interventions and process or impact evaluations. Factors identified as key to a successful program included use of social learning theory as a foundation for program development an emphasis on reducing sexual risk-taking behaviors active learning methods opportunities to practice communication and negotiation skills developmentally appropriate and culturally relevant curricula use of peer educators as change agents and systems for reinforcing the program message and reinforcing positive behavior. Further research is needed to identify factors that influence the sexual behavior of African adolescents define the most effective communication strategies and assess adolescents response to current AIDS prevention messages.
Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin

Abstract Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the gene SACS, encoding the 520 kDa protein sacsin. Although sacsin’s physiological role is largely unknown, its sequence domains suggest a molecular chaperone or protein quality control function. Consequences of its loss include neurofilament network abnormalities, specifically accumulation and bundling of perikaryal and dendritic neurofilaments. To investigate if loss of sacsin affects intermediate filaments more generally, the distribution of vimentin was analysed in ARSACS patient fibroblasts and in cells where sacsin expression was reduced. Abnormal perinuclear accumulation of vimentin filaments, which sometimes had a cage-like appearance, occurred in sacsin-deficient cells. Mitochondria and other organelles were displaced to the periphery of vimentin accumulations. Reorganization of the vimentin network occurs in vitro under stress conditions, including when misfolded proteins accumulate. In ARSACS patient fibroblasts HSP70, ubiquitin and the autophagy-lysosome pathway proteins Lamp2 and p62 relocalized to the area of the vimentin accumulation. There was no overall increase in ubiquitinated proteins, suggesting the ubiquitin–proteasome system was not impaired. There was evidence for alterations in the autophagy–lysosome pathway. Specifically, in ARSACS HDFs cellular levels of Lamp2 were elevated while levels of p62, which is degraded in autophagy, were decreased. Moreover, autophagic flux was increased in ARSACS HDFs under starvation conditions. These data show that loss of sacsin effects the organization of intermediate filaments in multiple cell types, which impacts the cellular distribution of other organelles and influences autophagic activity.
Effects of attention and distractor contrast on the responses of middle temporal area neurons to transient motion direction changes

The ability of primates to detect transient changes in a visual scene can be influenced by the allocation of attention, as well as by the presence of distractors. We investigated the neural substrates of these effects by recording the responses of neurons in the middle temporal area (MT) of two monkeys while they detected a transient motion direction change in a moving target. We found that positioning a distractor near the target impaired the change‐detection performance of the animals. This impairment monotonically decreased as the distractor's contrast decreased. A neural correlate of this effect was a decrease in the ability of MT neurons to signal the direction change (detection sensitivity or DS) when a distractor was near the target, both located inside the neuron's receptive field. Moreover, decreasing distractor contrast increased neuronal DS. On the other hand, directing attention away from the target decreased neuronal DS. At the level of individual neurons, we found a negative correlation between the degree of response normalization and the DS. Finally, the intensity of a neuron's response to the change was predictive of the animal's reaction time, suggesting that the activity of our recorded neurons was linked to the animal's detection performance. Our results suggest that the ability of an MT neuron to signal a transient direction change is regulated by the degree of inhibitory drive into the cell. The presence of distractors, their contrast and the allocation of attention influence such inhibitory drive, therefore modulating the ability of the neurons to signal transient changes in stimulus features and consequently behavioral performance.
High performance AC drives using passivity based controllers

The energy-based approach, also known as "passivity based", is becoming a popular nonlinear control method allowing precise and stable control of the induction motor and more in general of AC motors. Its main features are: simple formulation; the actual possibility of the use of inexpensive microprocessors for its implementation; its global stability in the whole operating range including zero speed region; satisfactory tracking capabilities of position, speed, torque and flux; and high robustness in case of parameter variations. This paper, after a short theoretical background presents and discusses several experimental results.
The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes

Insulin resistance is a major predictor of the development of metabolic disorders. Sirtuins (SIRTs) have emerged as potential targets that can be manipulated to counteract age-related diseases, including type 2 diabetes. SIRT2 has been recently shown to exert important metabolic effects, but whether SIRT2 regulates insulin sensitivity in hepatocytes is currently unknown. The aim of this study is to investigate this possibility and to elucidate underlying molecular mechanisms. Here, we show that SIRT2 is downregulated in insulin-resistant hepatocytes and livers, and this was accompanied by increased generation of reactive oxygen species, activation of stress-sensitive ERK1/2 kinase, and mitochondrial dysfunction. Conversely, SIRT2 overexpression in insulin-resistant hepatocytes improved insulin sensitivity, mitigated reactive oxygen species production and ameliorated mitochondrial dysfunction. Further analysis revealed a reestablishment of mitochondrial morphology, with a higher number of elongated mitochondria rather than fragmented mitochondria instigated by insulin resistance. Mechanistically, SIRT2 was able to increase fusion-related protein Mfn2 and decrease mitochondrial-associated Drp1. SIRT2 also attenuated the downregulation of TFAM, a key mtDNA-associated protein, contributing to the increase in mitochondrial mass. Importantly, we found that SIRT2 expression in PBMCs of human subjects was negatively correlated with obesity and insulin resistance. These results suggest a novel function for hepatic SIRT2 in the regulation of insulin sensitivity and raise the possibility that SIRT2 activators may offer novel opportunities for preventing or treating insulin resistance and type 2 diabetes.
Induction of hypertension blunts baroreflex inhibition of vasopressin neurons in the rat

Vasopressin secretion from the posterior pituitary gland is determined by action potential discharge of hypothalamic magnocellular neurosecretory cells. Vasopressin is a potent vasoconstrictor, but vasopressin levels are paradoxically elevated in some patients with established hypertension. To determine whether vasopressin neurons are excited in hypertension, extracellular single‐unit recordings of vasopressin neurons from urethane‐anaesthetized Cyp1a1‐Ren2 rats with inducible angiotensin‐dependent hypertension were made. The basal firing rate of vasopressin neurons was higher in hypertensive Cyp1a1‐Ren2 rats than in non‐hypertensive Cyp1a1‐Ren2 rats. The increase in firing rate was specific to vasopressin neurons because oxytocin neuron firing rate was unaffected by the induction of hypertension. Intravenous injection of the α1‐adrenoreceptor agonist, phenylephrine (2.5 μg/kg), transiently increased mean arterial blood pressure to cause a baroreflex‐induced inhibition of heart rate and vasopressin neuron firing rate (by 52 ± 9%) in non‐hypertensive rats. By contrast, intravenous phenylephrine did not inhibit vasopressin neurons in hypertensive rats, despite a similar increase in mean arterial blood pressure and inhibition of heart rate. Circulating angiotensin II can excite vasopressin neurons via activation of afferent inputs from the subfornical organ. However, the increase in vasopressin neuron firing rate and the loss of inhibition by intravenous phenylephrine were not blocked by intra‐subfornical organ infusion of the angiotensin AT1 receptor antagonist, losartan. It can be concluded that increased vasopressin neuron activity at the onset of hypertension is driven, at least in part, by reduced baroreflex inhibition of vasopressin neurons and that this might exacerbate the increase in blood pressure at the onset of hypertension.
Structural and functional connectivity between the lateral posterior–pulvinar complex and primary visual cortex in the ferret

The role of higher‐order thalamic structures in sensory processing remains poorly understood. Here, we used the ferret (Mustela putorius furo) as a novel model species for the study of the lateral posterior (LP)–pulvinar complex and its structural and functional connectivity with area 17 [primary visual cortex (V1)]. We found reciprocal anatomical connections between the lateral part of the LP nucleus of the LP–pulvinar complex (LPl) and V1. In order to investigate the role of this feedback loop between LPl and V1 in shaping network activity, we determined the functional interactions between LPl and the supragranular, granular and infragranular layers of V1 by recording multiunit activity and local field potentials. Coherence was strongest between LPl and the supragranular V1, with the most distinct peaks in the delta and alpha frequency bands. Inter‐area interaction measured by spike‐phase coupling identified the delta frequency band being dominated by the infragranular V1 and multiple frequency bands that were most pronounced in the supragranular V1. This inter‐area coupling was differentially modulated by full‐field synthetic and naturalistic visual stimulation. We also found that visual responses in LPl were distinct from those in V1 in terms of their reliability. Together, our data support a model of multiple communication channels between LPl and the layers of V1 that are enabled by oscillations in different frequency bands. This demonstration of anatomical and functional connectivity between LPl and V1 in ferrets provides a roadmap for studying the interaction dynamics during behaviour, and a template for identifying the activity dynamics of other thalamo‐cortical feedback loops.