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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two age-dependent multifactorial neurodegenerative disorders, which are typically characterized by the selective death of motor neurons and cerebral cortex neurons, respectively. These two diseases share many clinical, genetic and pathological aspects. During the past decade, cell reprogramming technologies enabled researchers to generate human induced pluripotent stem cells (iPSCs) from somatic cells. This resulted in the unique opportunity to obtain specific neuronal and non-neuronal cell types from patients which could be used for basic research. Moreover, these models can mimic not only the familial forms of ALS/FTD, but also sporadic cases without known genetic cause. At present, there have been extensive technical advances in the generation of iPSCs, as well as in the differentiation procedures to obtain iPSC-derived motor neurons, cortical neurons and non-neuronal cells. The major challenge at this moment is to determine whether these iPSC-derived cells show relevant phenotypes that recapitulate complex diseases. In this review, we will summarize the work related to iPSC models of ALS and FTD. In addition, we will discuss potential drawbacks and solutions for establishing more trustworthy iPSC models for both ALS and FTD.

Inherited peripheral neuropathies (IPNs) are a group of diseases associated with mutations in various genes with fundamental roles in the development and function of peripheral nerves. Over the past 10 years, significant advances in identifying molecular disease mechanisms underlying axonal and myelin degeneration, acquired from cellular biology studies and transgenic fly and rodent models, have facilitated the development of promising treatment strategies. However, no clinical treatment has emerged to date. This lack of treatment highlights the urgent need for more biologically and clinically relevant models recapitulating IPNs. For both neurodevelopmental and neurodegenerative diseases, patient-specific induced pluripotent stem cells (iPSCs) are a particularly powerful platform for disease modeling and preclinical studies. In this review, we provide an update on different in vitro human cellular IPN models, including traditional two-dimensional monoculture iPSC derivatives, and recent advances in more complex human iPSC-based systems using microfluidic chips, organoids, and assembloids. Unveiling progress in modeling inherited peripheral neuropathies Inherited peripheral neuropathies are diseases that cause damage to the motor and sensory nervous system. Despite progress in understanding these diseases, effective treatments are still hard to find. This study looks at using induced pluripotent stem cells (iPSCs - cells that can turn into any type of cell in the body) to mimic the disease and find possible drug targets. The scientists used iPSCs to create different nerve cells and Schwann cells (cells that support nerve function). They studied these cells to see how the disease affects them. The study found that models made from iPSCs can accurately copy key aspects of the disease, providing valuable insights that add to findings from animal models. This research could lead to new treatments for inherited peripheral neuropathies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Charcot-Marie-Tooth disease (CMT) is a group of inherited neurological disorders of the peripheral nervous system. CMT is subdivided into two main types: a demyelinating form, known as CMT1, and an axonal form, known as CMT2. Nearly 30 genes have been identified as a cause of CMT2. One of these is the ‘dehydrogenase E1 and transketolase domain containing 1’ ( DHTKD1 ) gene. We previously demonstrated that a nonsense mutation [c.1455 T > G (p.Y485*)] in exon 8 of DHTKD1 is one of the disease-causing mutations in CMT2Q (MIM 615025). The aim of the current study was to investigate whether human disease-causing mutations in the Dhtkd1 gene cause CMT2Q phenotypes in a mouse model in order to investigate the physiological function and pathogenic mechanisms associated with mutations in the Dhtkd1 gene in vivo. Therefore, we generated a knock-in mouse model with the Dhtkd1 Y486* point mutation. We observed that the Dhtkd1 expression level in sciatic nerve of knock-in mice was significantly lower than in wild-type mice. Moreover, a histopathological phenotype was observed, reminiscent of a peripheral neuropathy, including reduced large axon diameter and abnormal myelination in peripheral nerves. The knock-in mice also displayed clear sensory defects, while no abnormalities in the motor performance were observed. In addition, accumulation of mitochondria and an elevated energy metabolic state was observed in the knock-in mice. Taken together, our study indicates that the Dhtkd1 Y486* knock-in mice partially recapitulate the clinical phenotypes of CMT2Q patients and we hypothesize that there might be a compensatory effect from the elevated metabolic state in the knock-in mice that enables them to maintain their normal locomotor function.

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy, with currently no effective treatment or cure. CMT1A is caused by a duplication of the PMP22 gene, which leads to Schwann cell differentiation defects and dysmyelination of the peripheral nerves. The epigenetic regulator histone deacetylase 3 (HDAC3) has been shown to negatively regulate myelination as well as its associated signaling pathways, PI3K-AKT and MAPK-ERK. We showed that these signaling pathways are indeed downregulated in the C3-PMP22 mouse model, similar to what has been shown in the CMT1A rat model. We confirmed that early postnatal defects are present in the peripheral nerves of the C3-PMP22 mouse model, which led to a progressive reduction in axon caliber size and myelination. The aim of this study was to investigate whether pharmacological HDAC3 inhibition could be a valuable therapeutic approach for this CMT1A mouse model. We demonstrated that early treatment of CMT1A mice with the selective HDAC3 inhibitor RGFP966 increased myelination and myelin g-ratios, which was associated with improved electrophysiological recordings. However, a high dose of RGFP966 caused a decline in rotarod performance and a decline in overall grip strength. Additionally, macrophage presence in peripheral nerves was increased in RGFP966 treated CMT1A mice. We conclude that HDAC3 does not only play a role in regulating myelination but is also important in the neuroimmune modulation. Overall, our results indicate that correct dosing of HDAC3 inhibitors is of crucial importance if translated to a clinical setting for demyelinating forms of CMT or other neurological disorders.

Study Design Retrospective Cohort Study. Objective Restoration of lumbar lordosis (LL) is a principal objective during spinal fusion procedures, traditionally focusing on achieving an LL within 10° of the pelvic incidence (PI). Recent studies have demonstrated a relatively constant L4-S1 alignment of 35-40° at L4-S1 and at least 15° at L4-5, regardless of PI. Based on these results, this study was created to examine the success rate of achieving a minimum of 15° at L4-5 through two differing prone-based techniques: Prone Lateral (pLLIF) and Trans Foraminal Interbody Fusion (TLIF). Methods One hundred patients with a primary single-level L4-5 interbody fusion (50 pLLIF and 50 TLIF) were retrospectively analyzed. Pre and post-operative radiographs were measured to examine the segmental change at each level in the lumbar spine and calculate the success rate for achieving a minimum L4-5 segmental lordosis of 15° at the final follow-up. Results The overall success rate of achieving an L4-5 segmental alignment >15° at the final follow-up was 70%. Prone LLIF was significantly more likely than TLIF to achieve this goal, achieving L4-5 > 15° 84% of the time vs TLIFs 56% (P = 0.002). Prone LLIF demonstrated an average L4-5 increase of 5.6 ± 5.9° which was larger than the mean increase for TLIF 0.4 ± 3.8° (P < 0.001). In both techniques, there was an inverse correlation between pre-operative L4-5 angle and L4-5 angle change. Conclusion Prone lateral lumbar interbody fusion demonstrates a high success rate for achieving a post-operative L4-5 angle >15° and achieves this at a higher rate than TLIF.

Laboratory and field investigations were carried out to investigate the nature and role of the male pheromone emitted by the Dynast beetle Scapanes australis and to develop a mass trapping technique against this major coconut pest in Papua New Guinea. We report the biological data obtained from natural and synthetic pheromone, previously described as an 84:12:4 (w/w) mixture of 2-butanol (1), 3-hydoxy-2-butanone (2), and 2,3-butanediol (3). EAG recordings from natural and synthetic pheromone and a pitfall olfactometer were poorly informative. In contrast, extensive field trapping trials with various synthetic pheromone mixtures and doses showed that 1 and 2 (formulated in polyethylene sachets in 90:5 v/v ratio) were necessary and sufficient for optimum long-range attraction. Beetles were captured in traps baited with racemic 1 plus 2, with or without a stereoisomer mixture of 3 (2.5- to 2500-mg/day doses). Plant pieces, either sugarcane or coconut, enhanced captures by the synthetic pheromone, which was active alone. Traps with the pheromone caught both sexes in a 3:2 female-male ratio. A pheromone-based mass trapping led to the capture of 2173 beetles in 14 traps surrounding 40 ha of a cocoa-coconut plantation. The captures followed a log-linear decrease during the 125-week trapping program. The role of the male pheromone and its potential for crop protection are discussed.

We have developed a highly scalable application, called Shoal, for tracking and utilizing a distributed set of HTTP web caches. Our application uses the Squid HTTP cache. Squid servers advertise their existence to the Shoal server via AMQP messaging by running Shoal Agent. The Shoal server provides a simple REST interface that allows clients to determine their closest Squid cache. Our goal is to dynamically instantiate Squid caches on IaaS clouds in response to client demand. Shoal provides the VMs on IaaS clouds with the location of the nearest dynamically instantiated Squid Cache.

David Mamet's book of essays True and False: Heresy and Common Sense for the Actor boldly claims that formal training, particularly of the academic variety, is of no use to aspiring theater artists. This thesis argues for the importance and validity of such training. It is a defense of both formal training and ofStanislavski--the father of almost all contemporary training systems and a figure particularly irksome to Mamet. The thesis is supported by examples gleaned from my own formal education in theater and from insights gained directing student actors on my final project for my MFA, Kira Obelensky's play Lobster Alice.

Since 2000, Menlo Worldwide Forwarding (formerly Emery Worldwide) has faced a particularly challenging business environment that has been exacerbated by a weakened economy, the events of September 11, and a decreasing demand for airfreight. To meet these challenges, the company and Menlo Worldwide Technologies developed a network-routing-optimization model to optimize Menlo Worldwide Forwarding$s North American transportation network. The project team and senior managers have repeatedly identified and applied low cost solutions to meet the changing and complex network-routing requirements. By maximizing its use of network capacity, the company has increased profitability and reduced operating costs while maintaining high service levels. In 2002 alone, Menlo Worldwide Forwarding reduced operating costs by 21 percent, increased operating margin by 41 percent, and improved financial results by $80 million in the North American aircraft transportation operation. Moreover, management used the optimization model to facilitate Menlo$s transition from a heavily asset-based, integrated airfreight company to an asset-light, freight-forwarding business. This created a flexible operating environment and a competitive advantage for future operations.