Targeting mGlu5 metabotropic glutamate receptors in the treatment of cognitive dysfunction in a mouse model of phenylketonuria

We studied group-I metabotropic glutamate (mGlu) receptors in Pah(enu2) (ENU2) mice, which mimic the genetics and neurobiology of human phenylketonuria (PKU), a metabolic disorder characterized, if untreated, by autism, and intellectual disability (ID). Male ENU2 mice showed increased mGlu5 receptor protein levels in the hippocampus and corpus striatum (but not in the prefrontal cortex) whereas the transcript of the mGlu5 receptor was unchanged. No changes in mGlu1 receptor mRNA and protein levels were found in any of the three brain regions of ENU2 mice. We extended the analysis to Homer proteins, which act as scaffolds by linking mGlu1 and mGlu5 receptors to effector proteins. Expression of the long isoforms of Homer was significantly reduced in the hippocampus of ENU2 mice, whereas levels of the short Homer isoform (Homer 1a) were unchanged. mGlu5 receptors were less associated to immunoprecipitated Homer in the hippocampus of ENU2 mice. The lack of mGlu5 receptor-mediated long-term depression (LTD) in wild-type mice (of BTBR strain) precluded the analysis of hippocampal synaptic plasticity in ENU2 mice. We therefore performed a behavioral analysis to examine whether pharmacological blockade of mGlu5 receptors could correct behavioral abnormalities in ENU2 mice. Using the same apparatus we sequentially assessed locomotor activity, object exploration, and spatial object recognition (spatial novelty test) after displacing some of the objects from their original position in the arena. Systemic treatment with the mGlu5 receptor antagonist, MPEP (20 mg/kg, i.p.), had a striking effect in the spatial novelty test by substantially increasing the time spent in exploring the displaced objects in ENU2 mice (but not in wild-type mice). These suggest a role for mGlu5 receptors in the pathophysiology of ID in PKU and suggest that, also in adult untreated animals, cognitive dysfunction may be improved by targeting these receptors with an appropriate therapy

Analysis and Detection of Electrical Aging Effects on High-Speed Motor Insulation

© 1972-2012 IEEE. The use of fast wide-bandgap devices in high-speed electrical drives with steep pulsewidth modulation voltage waveforms is the main cause of increased stress on the electric machine insulation system and consequently, of reduced reliability of the whole system. This represents a major concern in safety-critical applications, such as in the aerospace and electric transportation fields. The novel contribution of this work is to assess the effects of electrical aging on complex insulation systems (i.e., a whole stator winding) by analyzing easily measurable macroscopic quantities. To this purpose, an electrical aging procedure is defined, and the effects produced on three tested motors are presented. Three different analysis methods are adopted with the aim of assessing the damage caused to an ac motor winding by such steep voltage waveforms and hence to evaluate the state of aging of the insulation system

Disciplinary problems among high achiever students: the types and the causes

This qualitative study has been done to 24 teachers and 72 students from various secondary schools in Penang, Malaysia, in order to investigate the effect of between class ability grouping (BCAG) on high achiever secondary school students. Studies reported that BCAG triggered correspondence bias among teachers, which eventually affect them to show different perception and expectations towards high achiever classes (HAC) and low achiever classes (LAC) students. Symbolic interaction theories explained that individuals tend to be affected by others’ expectation, and therefore behave in a way they were expected to. Therefore, according to the previous studies on BCAG, it was assumed that HAC students would achieve better and would not be significantly involved in disciplinary problems. After semi-structured interview had been conducted in order to collect the data, and two-cycled analyses method, namely In-Vivo and Thematic Analyses had been operated in order to analyze the massive amount of qualitative data, the it was discovered that HAC students were involved with disciplinary problems, such as being disrespectful to teachers, paying less attention in the classroom, neglecting assignments and doing external work during classes. Other findings of this study showed that the disciplinary problems among HAC are related to their self-esteem types due to locus of control difference, as well as bigger issues apart from the competition among themselves. School management system, BCAG itself, reciprocal envy between HAC and LAC students, as well as their inclination towards tuition centers contributed to disciplinary problems among HAC students

Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers

To ensure the completion of DNA replication and maintenance of genome integrity, DNA repair factors protect stalled replication forks upon replication stress. Previous studies have identified a critical role for the tumor suppressors BRCA1 and BRCA2 in preventing the degradation of nascent DNA by the MRE11 nuclease after replication stress. Here we show that depletion of SMARCAL1, a SNF2-family DNA translocase that remodels stalled forks, restores replication fork stability and reduces the formation of replication stress-induced DNA breaks and chromosomal aberrations in BRCA1/2-deficient cells. In addition to SMARCAL1, other SNF2-family fork remodelers, including ZRANB3 and HLTF, cause nascent DNA degradation and genomic instability in BRCA1/2-deficient cells upon replication stress. Our observations indicate that nascent DNA degradation in BRCA1/2-deficient cells occurs as a consequence of MRE11-dependent nucleolytic processing of reversed forks generated by fork remodelers. These studies provide mechanistic insights into the processes that cause genome instability in BRCA1/2- deficient cells

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Addome acuto da perforazione di metastasi digiunale di carcinoma polmonare operato

Lung cancer metastases of small bowel are rare (1,1%), often with few or not symptoms. This aspecific onset and the difficult physical-instrumental approach to small bowel, led often to diagnosis at autopsy. This is not true for intestinal metastases that cause complications (haemorrhage, obstruction, perforation); in this cases emergency surgery leds to the diagnosis. Case report. We describe a case of a male 56 years old patient with acute abdomen due to perforation (X-ray and CT). He refers, about 6 months before, an upper right lobectomy for lung cancer, followed by adjuvant chemo-radiotherapy, because the presence of brain and bone metastases. During the emergency surgery we found out a perforation of the Treitz tract, treated with intestinal resection and immediate end-to-end anastomosis with manual suture. Histological examination shows the perforation of the intestinal wall tract with lung cancer metastases. Conclusions. Our case shows that any acute abdomen in patient with lung cancer can be considered as expression of intestinal metastases. Negative prognosis of this complication imposes to surgeons only a local treatmen

Design Procedure for High-Speed PM Motors Aided by Optimization Algorithms

This paper considers the electromagnetic and structural co-design of superficial permanent magnet synchronous machines for high-speed applications, with the aid of a Pareto optimization procedure. The aim of this work is to present a design procedure for the afore-mentioned machines that relies on the combined used of optimization algorithms and finite element analysis. The proposed approach allows easy analysis of the results and a lowering of the computational burden. The proposed design method is presented through a practical example starting from the specifications of an aeronautical actuator. The design procedure is based on static finite element simulations for electromagnetic analysis and on analytical formulas for structural design. The final results are validated through detailed transient finite element analysis to verify both electromagnetic and structural performance. The step-by-step presentation of the proposed design methodology allows the reader to easily adapt it to different specifications. Finally, a comparison between a distributed-winding (24 slots) and a concentrated-winding (6 slots) machine is presented demonstrating the advantages of the former winding arrangement for high-speed applications