Functional Anatomy: Dynamic States in Basal Ganglia Circuits

The most appealing models of how the basal ganglia function propose distributed patterns of cortical activity selectively interacting with striatal networks to yield the execution of context-dependent movements. If movement is encoded by patterns of activity then these may be disrupted by influences at once more subtle and more devastating than the increase or decrease of neuronal firing that dominate the usual models of the circuit. In the absence of dopamine the compositional capabilities of cell assemblies in the network could be disrupted by the generation of dominant synchronous activity that engages most of the system. Experimental evidence about Parkinson's disease suggests that dopamine loss produces abnormal patterns of activity in different nuclei. For example, increased oscillatory activity arises in the GPe, GPi, and STN and is reflected as increased cortical beta frequency coherence disrupting the ability to produce motor sequences. When the idea of deep brain stimulation was proposed – it was supported by the information that lesions of the subthalamus reversed the effects of damage to the dopamine input to the system. However, it seems increasingly unlikely that the stimulation acts by silencing the nucleus as was at first proposed. Perhaps the increased cortical beta activity caused by the lack of dopamine could have disabled the patterning of network activity. Stimulation of the subthalamic nucleus disrupts the on-going cortical rhythms. Subsequently asynchronous firing is reinstated and striatal cell assemblies and the whole basal ganglia circuit engage in a more normal pattern of activity. We will review the different variables involved in the generation of sequential activity patterns, integrate our data on deep brain stimulation and network population dynamics, and thus provide a novel interpretation of functional aspects of basal ganglia circuitry

The role of diet and other environmental factors in the causation of gastric cancer in Iran—A population based study

Despite a declining trend in the incidence of gastric cancer (GC), it is still a major global public health concern of the 21st century. The rates of GC reported from Ardabil Province, Iran, are among the highest in the world. To investigate risk factors for GC in Ardabil, we undertook a population-based case-control study. The study aimed to recruit all Ardabil residents newly diagnosed with GC in the time period of 2004–2005, and 2 controls per case. Participants were interviewed using a structured questionnaire. Ten milliliters of blood was collected for blood grouping and investigating the presence of IgG antibodies against Helicobacter pylori. During the study period, 217 people with GC and 394 controls were recruited. In multivariate analysis, diet and Helicobacter pylori infection (OR 5 2.41; 95% CI: 1.35–4.32) were found to be the factors that were most strongly related to GC. High intake of Allium vegetables (OR 5 0.35) and fruit, especially citrus fruit (OR 5 0.31) and consumption of fresh fish (OR 5 0.37) were significantly protective. On the other hand, consumption of red meat (OR 5 3.40) and dairy products (OR 5 2.28) were positively associated with the risk of GC. People who had a preference for higher salt intake (OR 5 3.10) and drinking strong and hot tea (OR 5 2.64 and 2.85, respectively) were at higher risk. In conclusion, Helicobacter pylori infection as measured by serum IgG as well as the consumption of red meat and dairy products increases the risk of GC in Ardabil, while the intake of fresh fruit and fresh fish decrease the risk

Repression of ergosterol biosynthesis is essential for stress resistance and is mediated by the Hog1 MAP kinase and the Mot3 and Rox1 transcription factors

[EN] Hyperosmotic stress triggers a complex adaptive response that is dominantly regulated by the Hog1 MAP kinase in yeast. Here we characterize a novel physiological determinant of osmostress tolerance, which involves the Hog1-dependent transcriptional downregulation of ergosterol biosynthesis genes (ERG). Yeast cells considerably lower their sterol content in response to high osmolarity. The transcriptional repressors Mot3 and Rox1 are essential for this response. Both factors together with Hog1 are required to rapidly and transiently shut down transcription of ERG2 and ERG11 upon osmoshock. Mot3 abundance and its binding to the ERG2 promoter is stimulated by osmostress in a Hog1-dependent manner. As an additional layer of control, the expression of the main transcriptional activator of ERG gene expression, Ecm22, is negatively regulated by Hog1 and Mot3/Rox1 upon salt shock. Oxidative stress also triggers repression of ERG2, 11 transcription and a profound decrease in total sterol levels. However, this response was only partially dependent on Mot3/Rox1 and Hog1. Finally, we show that the upc2-1 mutation confers stress insensitive hyperaccumulation of ergosterol, overexpression of ERG2, 11 and severe sensitivity to salt and oxidative stress. Our results indicate that transcriptional control of ergosterol biosynthesis is an important physiological target of stress signalling.We thank J.M. Mulet for his help with the quantification of intracellular ion concentrations, W.A. Prinz (NIH, Bethesda, MD) and A.K. Menon (Weill Cornell Medical College, New York) for the kind gift of the upc2-1 strain, F. Winston (Harvard Medical School, Boston) for the kind gift of the MOT3-18myc strain, and Avelino Corma (Instituto de Tecnologia Quimica, Valencia, Spain) for making available an ICP optical emission spectrometer for ion content determination. This work was supported by grants from Ministerio de Educacion y Ciencia (BFU2005-01714), from Ministerio de Ciencia e Innovacion (BFU2008-00271) and from Consejo Superior de Investigaciones Cientificas (200820I019). F.M. is recipient of an FPI predoctoral fellowship from Ministerio de Educacion y Ciencia.Martínez Montañés, FV.; Pascual-Ahuir Giner, MD.; Proft ., MH. (2010). Repression of ergosterol biosynthesis is essential for stress resistance and is mediated by the Hog1 MAP kinase and the Mot3 and Rox1 transcription factors. Molecular Microbiology. 79(4):1008-1023. https://doi.org/10.1111/j.1365-2958.2010.07502.xS1008102379

Muscle molecular adaptations to endurance exercise training are conditioned by glycogen availability: a proteomics-based analysis in the McArdle mouse model

KEY POINTS: Although they are unable to utilize muscle glycogen, McArdle mice adapt favourably to an individualized moderate-intensity endurance exercise training regime. Yet, they fail to reach the performance capacity of healthy mice with normal glycogen availability. There is a remarkable difference in the protein networks involved in muscle tissue adaptations to endurance exercise training in mice with and without glycogen availability. Indeed, endurance exercise training promoted the expression of only three proteins common to both McArdle and wild-type mice: LIMCH1, PARP1 and TIGD4. In turn, trained McArdle mice presented strong expression of mitogen-activated protein kinase 12 (MAPK12). ABSTRACT: McArdle's disease is an inborn disorder of skeletal muscle glycogen metabolism that results in blockade of glycogen breakdown due to mutations in the myophosphorylase gene. We recently developed a mouse model carrying the homozygous p.R50X common human mutation (McArdle mouse), facilitating the study of how glycogen availability affects muscle molecular adaptations to endurance exercise training. Using quantitative differential analysis by liquid chromatography with tandem mass spectrometry, we analysed the quadriceps muscle proteome of 16-week-old McArdle (n = 5) and wild-type (WT) (n = 4) mice previously subjected to 8 weeks' moderate-intensity treadmill training or to an equivalent control (no training) period. Protein networks enriched within the differentially expressed proteins with training in WT and McArdle mice were assessed by hypergeometric enrichment analysis. Whereas endurance exercise training improved the estimated maximal aerobic capacity of both WT and McArdle mice as compared with controls, it was ∼50% lower than normal in McArdle mice before and after training. We found a remarkable difference in the protein networks involved in muscle tissue adaptations induced by endurance exercise training with and without glycogen availability, and training induced the expression of only three proteins common to McArdle and WT mice: LIM and calponin homology domains-containing protein 1 (LIMCH1), poly (ADP-ribose) polymerase 1 (PARP1 - although the training effect was more marked in McArdle mice), and tigger transposable element derived 4 (TIGD4). Trained McArdle mice presented strong expression of mitogen-activated protein kinase 12 (MAPK12). Through an in-depth proteomic analysis, we provide mechanistic insight into how glycogen availability affects muscle protein signalling adaptations to endurance exercise training.The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro CNIC Foundation, and is a Severo Ochoa Centre of Excellence (SEV-2015-0505). This study was funded by grants from Fondo de Investigaciones Sanitarias (PI15/01756, PI15/00558, PI12/00914, and PI14/00903), cofinanced by FEDER. G.N.G. is supported by a Miguel Servet research contract (ISCIII CD14/00032 and FEDER) and C.F.L. by a Sara Borrell post doc contract (CD14/00005). Miguel A. Mart´ın is supported by Fondo de Investigaciones Sanitarias (FIS 15/00432). Tomˆas Pin ´os is supported by Fondo de Investigaciones Sanitarias (FIS PI16/01492).S

Efficacy and safety of sensor-augmented pump therapy (SAPT) with predictive low-glucose management in patients diagnosed with type 1 diabetes mellitus previously treated with SAPT and low glucose suspend

Introducción La terapia con bomba de insulina integrada a sistema de monitoreo continuo con suspensión en hipoglucemia (SAPT-LGS) es una alternativa efectiva y segura para el tratamiento en pacientes con diabetes tipo 1 (DM1). La función de suspensión antes del límite bajo (PLGM) reduce la gravedad y la duración de los eventos hipoglucémicos. Sin embargo, la evidencia del beneficio en pacientes tratados previamente con SAPT-LGS es limitada. Métodos Se realizó un estudio longitudinal antes y después con pacientes DM1 tratados con SAPT-LGS que se cambiaron al sistema Minimed® 640G con SmartGuard®, con el fin de evaluar el impacto en los niveles de A1c, hipoglucemia severa (HS), hipoglucemia asintomática (HA) y área bajo la curva (AUC) <70mg/dl después de tres meses de seguimiento. Resultados Se incluyeron 55 pacientes con DM1, de 37.9 (IQR 6, 79) años, A1c basal de 7.52±1.11%. A los 3 meses bajo PLGM, la A1c se redujo significativamente a 7.18%±0.91% (p=0.004). La tasa de HS se redujo de 2.47 (CI 0.44,4.90) a 0.87 (CI 0.22,1.52) eventos/año del paciente (índice de incidencia 0.353 IC 95%, 0.178, 0.637), el AUC <70mg/dl se redujo de 0,59±0,76 a 0,35±0,65mg/dl x minuto (p = 0,030). HA determinado por el cuestionario Clarke resolvió en 23 de 30 pacientes (p=0,002) Conclusiones Este estudio sugiere que PLGM reduce la frecuencia de HS, HA, la exposición a niveles de glucosa por debajo de 70mg/dl y A1c. Con base a estos resultados, esta terapia debería considerarse en pacientes con DM1 tratados previamente con SAPT-LGS que persisten con HS e HA. Se requieren ensayos clínicos adicionales que comparen la eficacia y la seguridad de estas características.Q4Q3Artículo original451-457Background Sensor-augmented insulin pump therapy (SAPT) with low-glucose suspend (LGS) is an effective and safe alternative for treating patients with type 1 diabetes mellitus (T1DM). New predictive low-glucose management (PLGM) systems decrease the severity and duration of hypoglycemic events. However, evidence of benefits in patients previously treated with SAPT-LGS is limited. Methods A prospective before-after study was conducted in patients with T1DM treated with SAPT-LGS, who were switched to the Minimed® 640G system with SmartGuard® to assess the impact on A1c levels, severe hypoglycemia (SH), hypoglycemia unawareness (HU), and area under the curve (AUC) <70mg/dL after three months of follow-up. Results Fifty-five patients with T1DM with a mean age of 37.9 (IQR 6, 79) years and a mean baseline A1c level of 7.52±1.11% were enrolled. After three months under PLGM, A1c levels significantly decreased to 7.18±0.91% (p=0.004). SH rate decreased from 2.47 (CI 0.44, 4.90) to 0.87 (CI 0.22, 1.52) events/patient-year (Incidence rate ratio 0.353, 95% CI 0.178, 0.637), AUC <70mg/dL decreased from 0.59±0.76 to 0.35±0.65mg/dL x minute (p=0.030). HU determined by Clarke questionnaire resolved in 23 out of 30 patients (p=0.002). Conclusions This study suggests that SAPT with PLGM decreases the frequency of SH, HU, exposure to glucose levels below 70mg/dL, and A1c levels. Based on these results, this therapy should be considered in T1DM patients previously treated with SAPT-LGS with persistent SH and HU. Further clinical trials comparing the efficacy and safety of these features are required

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE