The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model

Copyright @ 2012 Elsevier. The article can be accessed from the link below.This article has been made available through the Brunel Open Access Publishing Fund.Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a dynamic GAA repeat expansion mutation within intron 1 of the FXN gene. Studies of mouse models for other trinucleotide repeat (TNR) disorders have revealed an important role of mismatch repair (MMR) proteins in TNR instability. To explore the potential role of MMR proteins on intergenerational GAA repeat instability in FRDA, we have analyzed the transmission of unstable GAA repeat expansions from FXN transgenic mice which have been crossed with mice that are deficient for Msh2, Msh3, Msh6 or Pms2. We find in all cases that absence of parental MMR protein not only maintains transmission of GAA expansions and contractions, but also increases GAA repeat mutability (expansions and/or contractions) in the offspring. This indicates that Msh2, Msh3, Msh6 and Pms2 proteins are not the cause of intergenerational GAA expansions or contractions, but act in their canonical MMR capacity to protect against GAA repeat instability. We further identified differential modes of action for the four MMR proteins. Thus, Msh2 and Msh3 protect against GAA repeat contractions, while Msh6 protects against both GAA repeat expansions and contractions, and Pms2 protects against GAA repeat expansions and also promotes contractions. Furthermore, we detected enhanced occupancy of Msh2 and Msh3 proteins downstream of the FXN expanded GAA repeat, suggesting a model in which Msh2/3 dimers are recruited to this region to repair mismatches that would otherwise produce intergenerational GAA contractions. These findings reveal substantial differences in the intergenerational dynamics of expanded GAA repeat sequences compared with expanded CAG/CTG repeats, where Msh2 and Msh3 are thought to actively promote repeat expansions.This study is funded under European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242193/EFACTS. This article is made available through the Brunel Open Access Publishing Fund

Connect the Dots: Using Evaluations of Teacher Effectiveness to Inform Policy and Practice

The National Council on Teacher Quality (NCTQ) has long advocated that any meaningful understanding of "effective" teaching must be rooted in results for kids. Whatever else they accomplish in the classroom, effective teachers improve student achievement. It seems like commonsense. Yet, until recently, it has been an exceptional way of thinking about teacher quality, totally out of step with teacher policy across the states. As part of the annual State Teacher Policy Yearbook, NCTQ has systematically collected and analyzed state policies on teacher preparation, training, retention, compensation and other personnel policies. In this paper we provide: 1. A detailed and up-to-date lay of the land on teacher evaluation policies across the 50 states and the District of Columbia Public Schools; 2. An in-depth look at policy in states promising ambitious teacher evaluation systems (states requiring student growth and achievement to be a significant or the most significant factor in teacher ratings), including states' efforts to "connect the dots" and use teacher evaluation results in meaningful ways to inform policy and practice; 3. A compilation of some of the important lessons learned, pitfalls and successes states have experienced on the road to improving teacher evaluation systems

The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues

Friedreich ataxia (FRDA) is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, leading to reduced expression of frataxin protein. Evidence suggests that the mutation may induce epigenetic changes and heterochromatin formation, thereby impeding gene transcription. In particular, studies using FRDA patient blood and lymphoblastoid cell lines have detected increased DNA methylation of specific CpG sites upstream of the GAA repeat and histone modifications in regions flanking the GAA repeat. In this report we show that such epigenetic changes are also present in FRDA patient brain, cerebellum and heart tissues, the primary affected systems of the disorder. Bisulfite sequence analysis of the FXN flanking GAA regions reveals a shift in the FRDA DNA methylation profile, with upstream CpG sites becoming consistently hypermethylated and downstream CpG sites becoming consistently hypomethylated. We also identify differential DNA methylation at three specific CpG sites within the FXN promoter and one CpG site within exon 1. Furthermore, we show by chromatin immunoprecipitation (ChIP) analysis that there is overall decreased histone H3K9 acetylation together with increased H3K9 methylation of FRDA brain tissue. Further studies of brain, cerebellum and heart tissues from our GAA repeat expansion-containing FRDA YAC transgenic mice reveal comparable epigenetic changes to those detected in FRDA patient tissue. We have thus developed a mouse model that will be a valuable resource for future therapeutic studies targeting epigenetic modifications of the FXN gene to increase frataxin expression

Stress and Memory: Behavioral Effects and Neurobiological Mechanisms

Stress is a potent modulator of learning and memory processes. Although there have been a few attempts in the literature to explain the diversity of effects (including facilitating, impairing, and lack of effects) described for the impact of stress on memory function according to single classification criterion, they have proved insufficient to explain the whole complexity of effects. Here, we review the literature in the field of stress and memory interactions according to five selected classifying factors (source of stress, stressor duration, stressor intensity, stressor timing with regard to memory phase, and learning type) in an attempt to develop an integrative model to understand how stress affects memory function. Summarizing on those conditions in which there was enough information, we conclude that high stress levels, whether intrinsic (triggered by the cognitive challenge) or extrinsic (induced by conditions completely unrelated to the cognitive task), tend to facilitate Pavlovian conditioning (in a linear-asymptotic manner), while being deleterious for spatial/explicit information processing (which with regard to intrinsic stress levels follows an inverted U-shape effect). Moreover, after reviewing the literature, we conclude that all selected factors are essential to develop an integrative model that defines the outcome of stress effects in memory processes. In parallel, we provide a brief review of the main neurobiological mechanisms proposed to account for the different effects of stress in memory function. Glucocorticoids were found as a common mediating mechanism for both the facilitating and impairing actions of stress in different memory processes and phases. Among the brain regions implicated, the hippocampus, amygdala, and prefrontal cortex were highlighted as critical for the mediation of stress effects

A Brand-New, Area - Efficient Architecture for the FFT Algorithm Designed for Implementation of FPGAs

Elliptic curve cryptography, which is more commonly referred to by its acronym ECC, is widely regarded as one of the most effective new forms of cryptography developed in recent times. This is primarily due to the fact that elliptic curve cryptography utilises excellent performance across a wide range of hardware configurations in addition to having shorter key lengths. A High Throughput Multiplier design was described for Elliptic Cryptographic applications that are dependent on concurrent computations. A Proposed (Carry-Select) Division Architecture is explained and proposed throughout the whole of this work. Because of the carry-select architecture that was discussed in this article, the functionality of the divider has been significantly enhanced. The adder carry chain is reduced in length by this design by a factor of two, however this comes at the expense of additional adders and control. When it comes to designs for high throughput FFT, the total number of butterfly units that are implemented is what determines the amount of space that is needed by an FFT processor. In addition to blocks that may either add or subtract numbers, each butterfly unit also features blocks that can multiply numbers. The size of the region that is covered by these dual mathematical blocks is decided by the bit resolution of the models. When the bit resolution is increased, the area will also increase. The standard FFT approach requires that each stage contain  times as many butterfly units as the stage before it. This requirement must be met before moving on to the next stage

Design and Implementation of High QoS 3D-NoC using Modified Double Particle Swarm Optimization on FPGA

One technique to overcome the exponential growth bottleneck is to increase the number of cores on a processor, although having too many cores might cause issues including chip overheating and communication blockage. The problem of the communication bottleneck on the chip is presently effectively resolved by networks-on-chip (NoC). A 3D stack of chips is now possible, thanks to recent developments in IC manufacturing techniques, enabling to reduce of chip area while increasing chip throughput and reducing power consumption. The automated process associated with mapping applications to form three-dimensional NoC architectures is a significant new path in 3D NoC research. This work proposes a 3D NoC partitioning approach that can identify the 3D NoC region that has to be mapped. A double particle swarm optimization (DPSO) inspired algorithmic technique, which may combine the characteristics having neighbourhood search and genetic architectures, also addresses the challenge of a particle swarm algorithm descending into local optimal solutions. Experimental evidence supports the claim that this hybrid optimization algorithm based on Double Particle Swarm Optimisation outperforms the conventional heuristic technique in terms of output rate and loss in energy. The findings demonstrate that in a network of the same size, the newly introduced router delivers the lowest loss on the longest path.  Three factors, namely energy, latency or delay, and throughput, are compared between the suggested 3D mesh ONoC and its 2D version. When comparing power consumption between 3D ONoC and its electronic and 2D equivalents, which both have 512 IP cores, it may save roughly 79.9% of the energy used by the electronic counterpart and 24.3% of the energy used by the latter. The network efficiency of the 3D mesh ONoC is simulated by DPSO in a variety of configurations. The outcomes also demonstrate an increase in performance over the 2D ONoC. As a flexible communication solution, Network-On-Chips (NoCs) have been frequently employed in the development of multiprocessor system-on-chips (MPSoCs). By outsourcing their communication activities, NoCs permit on-chip Intellectual Property (IP) cores to communicate with one another and function at a better level. The important components in assigning application duties, distributing the work to the IPs, and coordinating communication among them are mapping and scheduling methods. This study aims to present an entirely advanced form of research in the area of 3D NoC mapping and scheduling applications, grouping the results according to various parameters and offering several suggestions for further research

No One Benefits: How Teacher Pension Systems Are Failing Both Teachers And Taxpayers

A 50-state look at the funding crisis in the pension systems that serve teachers, including features that make them so costly and elements that aren't fair, advantageous or beneficial to all teachers

Legality of Appointment of Village Apparatus according to Article 49 Paragraph (2) of Law Number 6 of 2014 concerning Villages in Ujung Padang Village, Alas Maras Subdistrict, Seluma Regency

The purpose of this study was to determine the procedures for the appointment of old village officials and new village officials in the village of Ujung Padang and to find out the validity of the appointment of old and new village officials in the village of Ujung Padang in terms of Law Number 6 of 2014. The research method in this paper is the method Qualitative research is research that refers to the legal norms contained in legislation and court decisions as well as norms that live and develop in society. Based on the results of an interview with the Ujung Padang Village Head on July 5, 2022, he explained that, "If we talk about the mechanism for the appointment of village officials, of course the appointment of new and old Village officials is based on the law (Law number 6 of 2014 concerning Villages). ). Only the appointment of the Lamo Village Apparatus used to be filled with direct appointments by the Village Head and in consultation with the Camat, for the appointment of the New Village Apparatus I carried out the Undnag-Undnag Mandate Number 6 of 2014 and the Seluma Regional Government Number 7 of 2016 regarding Village Apparatus. Fill it out through a screening and screening mechanism, selection of prospective candidates, and a written test. After getting the results of the selection then communicated with the Camat on behalf of the Regent. If we talk about the legal legitimacy of the official Village apparatus, both the old and the new, it is certainly not our domain to determine the legal person, and the one who is nedo is legal. That is the realm of the State Administrative Court, which can determine you.