scholarly journals Translation from the Ribosome to the Clinic: Implication in Neurological Disorders and New Perspectives from Recent Advances

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 680 ◽  
Author(s):  
Hui ◽  
Chen ◽  
Endo ◽  
Tanaka

De novo protein synthesis by the ribosome and its multitude of co-factors must occur in a tightly regulated manner to ensure that the correct proteins are produced accurately at the right time and, in some cases, also in the proper location. With novel techniques such as ribosome profiling and cryogenic electron microscopy, our understanding of this basic biological process is better than ever and continues to grow. Concurrently, increasing attention is focused on how translational regulation in the brain may be disrupted during the progression of various neurological disorders. In fact, translational dysregulation is now recognized as the de facto pathogenic cause for some disorders. Novel mechanisms including ribosome stalling, ribosome-associated quality control, and liquid-liquid phase separation are closely linked to translational regulation, and may thus be involved in the pathogenic process. The relationships between translational dysregulation and neurological disorders, as well as the ways through which we may be able to reverse those detrimental effects, will be examined in this review.

2020 ◽  
Vol 21 (19) ◽  
pp. 7335 ◽  
Author(s):  
Marta Berrocal-Lobo ◽  
René Toribio ◽  
M. Mar Castellano

Translation plays an important role in plant adaptation to different abiotic and biotic stresses; however, the mechanisms involved in translational regulation during each specific response and their effect in translation are poorly understood in plants. In this work, we show that GCN2 promotes eIF2α phosphorylation upon contact with Botrytis cinerea spores, and that this phosphorylation is required for the proper establishment of plant defense against the fungus. In fact, independent gcn2 mutants display an enhanced susceptibility to B. cinerea infection, which is highlighted by an increased cell death and reduced expression of ethylene- and jasmonic-related genes in the gcn2 mutants. eIF2α phosphorylation is not only triggered in the presence of the fungus, but interestingly, is also achieved in the sole presence of the microbe-associated molecular pattern (MAMP) chitin. Moreover, analysis of de novo protein synthesis by 35SMet–35SCys incorporation indicates that chitin treatment promotes a global inhibition of translation. Taken together, these results suggest that eIF2α phosphorylation by GCN2 is promoted in the presence of chitin and plays an important role in plant defense against B. cinerea infection.


Neurosurgery ◽  
2002 ◽  
Vol 50 (3) ◽  
pp. 646-650 ◽  
Author(s):  
Wolf Lüdemann ◽  
Verena Ellerkamp ◽  
Alexandru C. Stan ◽  
Sami Hussein

Abstract OBJECTIVE AND IMPORTANCE: De novo development of cavernous malformations is poorly documented in the literature. CLINICAL PRESENTATION: We report the case of a 37-year old woman with de novo growth of a cavernous malformation of the brain. The patient presented with a 12-month history of nonspecific headaches and paresthesias after two pregnancies. After computed tomographic scanning of the cranium, a cavernous malformation located parieto-occipitally within the right brain hemisphere was diagnosed. Control magnetic resonance imaging scans obtained 12 years earlier did not reveal a similar lesion. INTERVENTION: Surgery was performed, and the specimen was analyzed histopathologically. CONCLUSION: Immunohistochemistry demonstrated lack of expression of pituitary hormones as well as of androgen, estrogen, and progesterone hormone receptors. However, strong expression of both basic fibroblast growth factor and CD44 was detected in surrounding tissue, and expression of CD44 was noted within the matrix of the cavernous malformation.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jasper Linthorst ◽  
Wim Meert ◽  
Matthew S. Hestand ◽  
Jonas Korlach ◽  
Joris Robert Vermeesch ◽  
...  

Abstract The human genome harbors numerous structural variants (SVs) which, due to their repetitive nature, are currently underexplored in short-read whole-genome sequencing approaches. Using single-molecule, real-time (SMRT) long-read sequencing technology in combination with FALCON-Unzip, we generated a de novo assembly of the diploid genome of a 115-year-old Dutch cognitively healthy woman. We combined this assembly with two previously published haploid assemblies (CHM1 and CHM13) and the GRCh38 reference genome to create a compendium of SVs that occur across five independent human haplotypes using the graph-based multi-genome aligner REVEAL. Across these five haplotypes, we detected 31,680 euchromatic SVs (>50 bp). Of these, ~62% were comprised of repetitive sequences with ‘variable number tandem repeats’ (VNTRs), ~10% were mobile elements (Alu, L1, and SVA), while the remaining variants were inversions and indels. We observed that VNTRs with GC-content >60% and repeat patterns longer than 15 bp were 21-fold enriched in the subtelomeric regions (within 5 Mb of the ends of chromosome arms). VNTR lengths can expand to exceed a critical length which is associated with impaired gene transcription. The genes that contained most VNTRs, of which PTPRN2 and DLGAP2 are the most prominent examples, were found to be predominantly expressed in the brain and associated with a wide variety of neurological disorders. Repeat-induced variation represents a sizeable fraction of the genetic variation in human genomes and should be included in investigations of genetic factors associated with phenotypic traits, specifically those associated with neurological disorders. We make available the long and short-read sequence data of the supercentenarian genome, and a compendium of SVs as identified across 5 human haplotypes.


2018 ◽  
Vol 79 (3-4) ◽  
pp. 187-191 ◽  
Author(s):  
Alfonsa Claudia Taiello ◽  
Rossella Spataro ◽  
Vincenzo La Bella

Background and Purpose: The palmomental reflex (PMR) is a primitive reflex that might be released due to inhibition in adulthood. It has been associated with several neurodegenerative conditions. The aim of the present study was to evaluate the frequency of PMR in amyotrophic lateral sclerosis (ALS). Patients and Methods: Non-demented ALS patients (n = 179) were recruited. Two groups of disease controls were enrolled: (a) non-demented patients with other neurological disorders (NC; n = 86, mean age 60 ± 14 years); (b) healthy subjects, healthy controls (HC; n = 175, mean age 61 ± 12 years). PMR was elicited by a brisk stroke along the thenar eminence of the right hand with a key or a pen. Results: The PMR could be elicited in 46% of the ALS patients, compared to 29% of NC and 16% of HC (p < 0.001). A multivariate analysis showed that bulbar-onset and female gender are associated with an increased risk of PMR. Conclusion: We demonstrate a higher frequency of the PMR in ALS patients compared to NC or HC. Its expression increases with age, being higher in bulbar-onset patients. Given that the reflex circuit is located in the brain stem, its release due to inhibition might be associated to the presence of a cortico-bulbar tract dysfunction in ALS.


Author(s):  
D. Cherns

The use of high resolution electron microscopy (HREM) to determine the atomic structure of grain boundaries and interfaces is a topic of great current interest. Grain boundary structure has been considered for many years as central to an understanding of the mechanical and transport properties of materials. Some more recent attention has focussed on the atomic structures of metalsemiconductor interfaces which are believed to control electrical properties of contacts. The atomic structures of interfaces in semiconductor or metal multilayers is an area of growing interest for understanding the unusual electrical or mechanical properties which these new materials possess. However, although the point-to-point resolutions of currently available HREMs, ∼2-3Å, appear sufficient to solve many of these problems, few atomic models of grain boundaries and interfaces have been derived. Moreover, with a new generation of 300-400kV instruments promising resolutions in the 1.6-2.0 Å range, and resolutions better than 1.5Å expected from specialist instruments, it is an appropriate time to consider the usefulness of HREM for interface studies.


Author(s):  
M. Sato ◽  
Y. Ogawa ◽  
M. Sasaki ◽  
T. Matsuo

A virgin female of the noctuid moth, a kind of noctuidae that eats cucumis, etc. performs calling at a fixed time of each day, depending on the length of a day. The photoreceptors that induce this calling are located around the neurosecretory cells (NSC) in the central portion of the protocerebrum. Besides, it is considered that the female’s biological clock is located also in the cerebral lobe. In order to elucidate the calling and the function of the biological clock, it is necessary to clarify the basic structure of the brain. The observation results of 12 or 30 day-old noctuid moths showed that their brains are basically composed of an outer and an inner portion-neural lamella (about 2.5 μm) of collagen fibril and perineurium cells. Furthermore, nerve cells surround the cerebral lobes, in which NSCs, mushroom bodies, and central nerve cells, etc. are observed. The NSCs are large-sized (20 to 30 μm dia.) cells, which are located in the pons intercerebralis of the head section and at the rear of the mushroom body (two each on the right and left). Furthermore, the cells were classified into two types: one having many free ribosoms 15 to 20 nm in dia. and the other having granules 150 to 350 nm in dia. (Fig. 1).


Author(s):  
Peter R. Breggin

BACKGROUND: The vaccine/autism controversy has caused vast scientific and public confusion, and it has set back research and education into genuine vaccine-induced neurological disorders. The great strawman of autism has been so emphasized by the vaccine industry that it, and it alone, often appears in authoritative discussions of adverse effects of the MMR and other vaccines. By dismissing the chimerical vaccine/autism controversy, vaccine defenders often dismiss all genuinely neurological aftereffects of the MMR (measles, mumps, and rubella) and other vaccines, including well-documented events, such as relatively rare cases of encephalopathy and encephalitis. OBJECTIVE: This report explains that autism is not a physical or neurological disorder. It is not caused by injury or disease of the brain. It is a developmental disorder that has no physical origins and no physical symptoms. It is extremely unlikely that vaccines are causing autism; but it is extremely likely that they are causing more neurological damage than currently appreciated, some of it resulting in psychosocial disabilities that can be confused with autism and other psychosocial disorders. This confusion between a developmental, psychosocial disorder and a physical neurological disease has played into the hands of interest groups who want to deny that vaccines have any neurological and associated neuropsychiatric effects. METHODS: A review of the scientific literature, textbooks, and related media commentary is integrated with basic clinical knowledge. RESULTS: This report shows how scientific sources have used the vaccine/autism controversy to avoid dealing with genuine neurological risks associated with vaccines and summarizes evidence that vaccines, including the MMR, can cause serious neurological disorders. Manufacturers have been allowed by the US Food and Drug Administration (FDA) to gain vaccine approval without placebo-controlled clinical trials. CONCLUSIONS: The misleading vaccine autism controversy must be set aside in favor of examining actual neurological harms associated with vaccines, including building on existing research that has been ignored. Manufacturers of vaccines must be required to conduct placebo-controlled clinical studies for existing vaccines and for government approval of new vaccines. Many probable or confirmed neurological adverse events occur within a few days or weeks after immunization and could be detected if the trials were sufficiently large. Contrary to current opinion, large, long-term placebo-controlled trials of existing and new vaccines would be relatively easy and safe to conduct.


2009 ◽  
Vol 4 (1) ◽  
pp. 48 ◽  
Author(s):  
Patrick Serruys ◽  
Scot Garg ◽  
◽  

Recent years have seen an ongoing debate as to whether coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) is the most appropriate revascularisation strategy for patients with coronary heart disease (CAD). The Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) study was conducted with the intention of defining the specific roles of each therapy in the management of de novo three-vessel disease or left main CAD. Interim results after 12 months show that PCI leads to significantly higher rates of major adverse cardiac or cerebrovascular events compared with CABG (17.8 versus 12.4; p=0.002), largely owing to increased rates of repeat revascularisation. However, CABG was much more likely to lead to stroke. Interestingly, categorisation of patients by severity of CAD complexity according to the SYNTAX score has shown that there are certain patients in whom PCI can yield results that are comparable to, if not better than, those achieved with CABG. Careful clinical evaluation and comprehensive assessment of CAD severity, alongside application of the SYNTAX score, can aid practitioners in selecting the most suitable therapy for each individual CAD patient.


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