Duganstokholm0618

Mitochondrial disease presenting in childhood is characterised by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but the majority have non-classical multisystemic disease presentations involving virtually any organ in the body. Each child has a unique constellation of clinical features and disease trajectory, leading to enormous challenges in diagnosis and management of these heterogeneous disorders. This review discusses the classical mitochondrial syndromes presenting most frequently in childhood and then presents an organ based perspective including systems less frequently linked to mitochondrial disease, such as skin and hair abnormalities and immune dysfunction. An approach to diagnosis is then presented, encompassing clinical evaluation and biochemical, neuroimaging and genetic investigations, and emphasising the problem of phenocopies. The impact of next generation sequencing is discussed, together with the importance of functional validation of novel genetic variants never previously linked to mitochondrial disease. The review concludes with a brief discussion of currently available and emerging therapies. The field of mitochondrial medicine has made enormous strides in the last 30 years, with approaching 400 different genes across two genomes now linked to primary mitochondrial disease. However many important questions remain unanswered, including the reasons for tissue specificity and variability of clinical presentation of individuals sharing identical gene defects, and a lack of disease-modifying therapies and biomarkers to monitor disease progression and/or response to treatment. This article is protected by copyright. All rights reserved.The structure and properties of two-dimensional phosphoborane sheets were computationally investigated using Density Functional Theory calculations. The calculated phonon spectrum and band structure point to dynamic stability and allowed characterization of the predicted two-dimensional material as a direct-gap semiconductor with a band gap of ~1.5 eV. The calculation of the optical properties showed that the two-dimensional material has a relatively small absorptivity coefficient. The parameters of the mechanical properties characterize the two-dimensional phosphoborane as a relatively soft material, similar to the monolayer of MoS2 . Assessment of thermal stability by the method of molecular dynamics indicates sufficient stability of the predicted material, which makes it possible to observe it experimentally. © 2020 Wiley Periodicals, Inc.Surgery involving the use of cardiopulmonary bypass (CPB) has long been associated with cerebral changes and may also contribute to adverse neurocognitive outcomes. However, there is a debate as to whether bypass itself is responsible for these changes. We conducted a systematic literature review on PubMed, supplementing our work with recent articles from other sources to examine the current evidence on neurocognitive decline associated with CPB. While surgeries involving CPB appear to be associated with cerebral changes and potentially with neurocognitive decline, it is unclear as to whether decline is related to the procedure itself. It is possible that the impacts of CPB can be more readily observed among individuals with preoperative cognitive impairment. It is thus important to screen for subtle and more apparent preoperative cognitive impairment as a risk factor for adverse outcomes. Further research, comparing on-pump and off-pump cohorts and involving intensive screening of preoperative cognitive decline, is indicated to elucidate the true neurocognitive consequences of the heart-lung machine. © 2020 Wiley Periodicals, Inc.Inherited epidermolysis bullosa is a skin fragility disorder typified by blister formation following minor trauma. Four major EB types are distinguished based on the level of cleavage within the skin. Among these, epidermolysis bullosa simplex (EBS) is characterized by blister formation within the basal epidermis. EBS is the most heterogeneous EB type with mutations in seven different genes and a spectrum of clinical manifestations, ranging from widespread life-threatening skin and mucosal involvement to mild localized disease forms. This article is protected by copyright. All rights reserved.Mutations in the mitochondrial genome are the cause of many debilitating neuromuscular disorders. Currently, there is no cure or treatment for these diseases, and symptom management is the only relief doctors can provide. Although supplements and vitamins are commonly used in treatment, they provide little benefit to the patient and are only palliative. This is why gene therapy is a promising research topic to potentially treat and in theory, even cure diseases caused by mutations in the mitochondrial DNA (mtDNA). Mammalian cells contain approximately a thousand copies of mtDNA, which can lead to a phenomenon called heteroplasmy, where both wild-type and mutant mtDNA molecules co-exist within the cell. Disease only manifests once the percent of mutant mtDNA reaches a high threshold (>80%), which causes mitochondrial dysfunction and reduced ATP production. This is a useful feature to take advantage of for gene therapy applications, as not every mutant copy of mtDNA needs to be eliminated, but only enough to shift the heteroplasmic ratio below the disease threshold. Several DNA editing enzymes have been used to shift heteroplasmy in cell culture and mice. This review provides an overview of these enzymes, and discusses roadblocks of applying these to gene therapy in humans. This article is protected by copyright. All rights reserved.The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS-such as the G12C mutation-are found in most pancreatic, half of colorectal, and a third of lung cancer cases and is thus responsible for a substantial proportion of cancer deaths. RGD peptide cell line Consequently, KRAS has been the subject of exhaustive drug targeting efforts over the past 3-4 decades. These efforts have included targeting the KRAS protein itself but also its posttranslational modifications, membrane localization, protein-protein interactions, and downstream signaling pathways. Most of these strategies have failed and no KRAS-specific drugs have yet been approved. However, for one specific mutation, KRASG12C , there is light on the horizon. MRTX849 was recently identified as a potent, selective, and covalent KRASG12C inhibitor that possesses favorable drug-like properties. MRTX849 selectively modifies the mutant cysteine residue in GDP-bound KRASG12C and inhibits GTP-loading and downstream KRAS-dependent signaling.