Triplet Proteins Research Articles

Borderline concentrations of a cerebrospinal fluid triplet of tau proteins and beta-amyloid 42 in the diagnosis of Alzheimer‘s disease and other neurodegenerative dementias

Borderline concentrations of a cerebrospinal fluid triplet of tau proteins and beta-amyloid 42 in the diagnosis of Alzheimer‘s disease and other neurodegenerative dementias

Proteolytic activation of human-specific Olduvai domains by the furin protease

Olduvai protein domains (formerly DUF1220) show the greatest human-specific increase in copy number of any coding region in the genome and are highly correlated with human brain evolution and cognitive disease. The majority of human copies are found within four NBPF genes organized in a variable number of a tandemly arranged three-domain blocks called Olduvai triplets. Here we show that these human-specific Olduvai domains are posttranslationally processed by the furin protease, with a cleavage site occurring once at each triplet. These findings suggest that all expanded human-specific NBPF genes encode proproteins consisting of many independent Olduvai triplet proteins which are activated by furin processing. The exceptional correlation of Olduvai copy number and brain size taken together with our new furin data, indicates the ultimate target of selection was a rapid increase in dosage of autonomously functioning Olduvai triplet proteins, and that these proteins are the primary active agent underlying Olduvai's role in human brain expansion.

Role of the Triplet State and Protein Dynamics in the Formation and Stability of the Tryptophan Radical in an Apoazurin Mutant.

The protein, azurin, has enabled the study of the tryptophan radical. Upon UV excitation of tyrosine-deficient apoazurin and in the presence of a Co(III) electron acceptor, the neutral radical (W48•) is formed. The lifetime of W48• in apoazurin is 41 s, which is shorter than the lifetime of several hours in Zn-substituted azurin. Molecular dynamics simulations revealed enhanced fluctuations of apoazurin which likely destabilize W48•. The photophysics of W48 was investigated to probe the precursor state for ET. The phosphorescence intensity was eliminated in the presence of an electron acceptor while the fluorescence was unchanged; this quenching of the phosphorescence is attributed to ET. The kinetics associated with W48• were examined with a model that incorporates intersystem crossing, ET, deprotonation, and decay of the cation radical. The estimated rate constants for ET (6 × 106 s–1) and deprotonation (3 × 105 s–1) are in agreement with a photoinduced mechanism where W48• is derived from the triplet state. The triplet as the precursor state for ET was supported by photolysis of apoazurin with 280 nm in the absence and presence of triplet-absorbing 405 nm light. Absorption bands from the neutral radical were observed only in the presence of blue light.

Insights on Rigidity and Flexibility at the Global and Local Levels of Protein Structures and Their Roles in Homologous Psychrophilic, Mesophilic, and Thermophilic Proteins: A Computational Study.

The rigidity and flexibility of homologous psychrophilic (P), mesophilic (M), and thermophilic (T) proteins have been investigated at the global and local levels in terms of "packing factors" and "atomic fluctuations" obtained from B-factors. For comparison of atomic fluctuations, correction of errors by considering errors in B-factors from all sources in a consolidated manner and conversion of the fluctuations to the same temperature have been suggested and validated. The results indicate no differences in the global values like the average packing factor among the three classes of protein homologues, but at local levels there are differences. A comparison of homologous protein triplets show that the average atomic fluctuations at a given temperature mainly obey the order P > M > T. Packing factors and the atomic fluctuations are anti-correlated, suggesting that altering the rigidity of the active site might be a potential strategy to make tailor-made psychrophilic or thermophilic proteins from their mesophilic homologues. The computer codes developed and used in this work are available at the link https://github.com/Munna-Sarkar/proteins-rigidity-flexibility.git.

The Effect of Short-Term Exposure to Cadmium on the Expression of Vascular Endothelial Barrier Antigen in the Developing Rat Forebrain and Cerebellum: A Computerized Quantitative Immunofluorescent Study.

Clinical and laboratory studies have shown that environmental exposure to cadmium produces damage to several organs, including bones, lungs, and kidneys. The involvement of cadmium in central nervous system (CNS) disorders has also been widely reported, but the precise pathophysiological mechanism is not yet fully understood. Children who were exposed to cadmium during pregnancy are known to suffer from developmental delays, learning difficulties, attention deficit hyperactivity disorder (ADHD), and other cognitive and neurobehavioral deficits. Results from numerous studies suggest that dysfunction of the blood-brain barrier (BBB) structures is an important step in the neurotoxicity of cadmium. A rat-specific BBB marker protein, the endothelial barrier antigen (EBA), has been previously isolated and classified by Sternberger and others. The mouse IgG1 clone, anti-endothelial barrier antigen (anti-EBA), detects a protein triplet (23.5kDa, 25 kDa, and 30kDa) localized to the luminal surface of central and peripheral nervous system (CNS and PNS) vascular endothelial cells with selective permeability barrier functions. This marker has been widely used for characterizing BBB alterations under demyelinating, inflammatory, and other CNS pathologies. Many studies have been published using the rat model system for studying the neurotoxic effect of acute and chronic exposure to cadmium.We applied the indirect immunofluorescent techniques using the anti-EBA antibody in conjunction with the Olympus cellSens computerized image analysis to detect and quantify the surface areas of BBB-competent microvessel profiles in paraformaldehyde-fixed, paraffin-embedded brains of term-delivered young rats after intraperitoneal injection of a single dose of cadmium chloride. We detected a statistically significant reduction in EBA-positive microvessel surface areas in the forebrain (t = 5.86, df = 1789, p-value < 0.001) and cerebellum (t=73.40, df=1337, p < 0.001) of cadmium-treated rats compared to the normal controls. Thus, this study supports the hypothesis that the EBA is a sensitive and measurable indicator for quantitative assessment of the impact of cadmium exposure in the developing rat brain.

Serum protein triplet TGF-\u03b21, TIMP-1, and YKL-40 serve as diagnostic and prognostic profile for astrocytoma

Astrocytoma is the most common glial tumour of the CNS. The most malignant form is grade IV Astrocytoma, also called Glioblastoma. Due to its heterogeneity, aggressiveness and lethal nature scientists are trying to find less invasive methods for early prediction of tumour onset, recurrence, response to therapy and patients’ survival. Here, applying decision tree classification algorithm we performed astrocytoma specific protein profile analysis on serum proteins TIMP-1, active and latent form of TGF-β1, IP-10, ANGPT-1, OPN, and YKL-40 using enzyme-linked immunosorbent detection assay (ELISA). Results have demonstrated that astrocytoma specific profile consisted of three proteins—active form of TGF-β1, TIMP-1 and YKL-40 and was able to correctly classify 78.0% (103/132) of sample and 83.3% (60/72) of astrocytoma sample. Calculating decision tree algorithm associated with astrocytoma patient survival, prediction model reached an accuracy of 83.3% (60/72). All together these results indicate that glioma detection and prediction from patient serum using glioma associated proteins and applying mathematical classification tools could be achieved, and applying more comprehensive research further could be implemented in clinic.

Novel Approach for Detecting the Neurological or Behavioral Impact of Physiological Episodes (PEs) in Military Aircraft Crews.

Military and civil aviation have documented physiological episodes among aircrews. Therefore, continued efforts are being made to improve the internal environment. Studies have shown that exposures to many organic compounds present in emissions are known to cause a variety of physiological symptoms. We hypothesize that these compounds may reversibly inhibit acetylcholinesterase, which may disrupt synaptic signaling. As a result, neural proteins leak through the damaged blood-brain barrier into the blood and in some, elicit an autoimmune response. Neural-specific autoantibodies of immunoglobulin-G (IgG) class were estimated by the Western blotting technique in the sera of 26 aircrew members and compared with the sera of 19 normal healthy nonaircrew members, used as controls. We found significantly elevated levels of circulating IgG-class autoantibodies to neurofilament triplet proteins, tubulin, microtubule-associated tau proteins (Tau), microtubule-associated protein-2, myelin basic protein, and glial fibrillary acidic protein, but not S100 calcium-binding protein B compared to healthy controls. Repetitive physiological episodes may initiate cellular injury, leading to neuronal degeneration in selected individuals. Diagnosis and intervention should occur at early postinjury periods. Use of blood-based biomarkers to assess subclinical brain injury would help in both diagnosis and treatment.

Learning signaling networks from combinatorial perturbations by exploiting siRNA off-target effects.

MotivationPerturbation experiments constitute the central means to study cellular networks. Several confounding factors complicate computational modeling of signaling networks from this data. First, the technique of RNA interference (RNAi), designed and commonly used to knock-down specific genes, suffers from off-target effects. As a result, each experiment is a combinatorial perturbation of multiple genes. Second, the perturbations propagate along unknown connections in the signaling network. Once the signal is blocked by perturbation, proteins downstream of the targeted proteins also become inactivated. Finally, all perturbed network members, either directly targeted by the experiment, or by propagation in the network, contribute to the observed effect, either in a positive or negative manner. One of the key questions of computational inference of signaling networks from such data are, how many and what combinations of perturbations are required to uniquely and accurately infer the model?ResultsHere, we introduce an enhanced version of linear effects models (LEMs), which extends the original by accounting for both negative and positive contributions of the perturbed network proteins to the observed phenotype. We prove that the enhanced LEMs are identified from data measured under perturbations of all single, pairs and triplets of network proteins. For small networks of up to five nodes, only perturbations of single and pairs of proteins are required for identifiability. Extensive simulations demonstrate that enhanced LEMs achieve excellent accuracy of parameter estimation and network structure learning, outperforming the previous version on realistic data. LEMs applied to Bartonella henselae infection RNAi screening data identified known interactions between eight nodes of the infection network, confirming high specificity of our model and suggested one new interaction.Availability and implementation https://github.com/EwaSzczurek/LEM Supplementary information Supplementary data are available at Bioinformatics online.

De novo Blood Biomarkers in Autism: Autoantibodies against Neuronal and Glial Proteins.

Autism spectrum disorders (ASDs) are the most common neurodevelopmental disorders with unidentified etiology. The behavioral manifestations of ASD may be a consequence of genetic and/or environmental pathology in neurodevelopmental processes. In this limited study, we assayed autoantibodies to a panel of vital neuronal and glial proteins in the sera of 40 subjects (10 children with ASD and their mothers along with 10 healthy controls, age-matched children and their mothers). Serum samples were screened using Western Blot analysis to measure immunoglobulin (IgG) reactivity against a panel of 9 neuronal proteins commonly associated with neuronal degeneration: neurofilament triplet proteins (NFP), tubulin, microtubule-associated proteins (tau), microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), α-synuclein (SNCA) and astrocytes proteins such as glial fibrillary acidic protein (GFAP) and S100B protein. Our data show that the levels of circulating IgG class autoantibodies against the nine proteins were significantly elevated in ASD children. Mothers of ASD children exhibited increased levels of autoantibodies against all panel of tested proteins except for S100B and tubulin compared to age-matched healthy control children and their mothers. Control children and their mothers showed low and insignificant levels of autoantibodies to neuronal and glial proteins. These results strongly support the importance of anti-neuronal and glial protein autoantibodies biomarker in screening for ASD children and further confirm the importance of the involvement of the maternal immune system as an index that should be considered in fetal in utero environmental exposures. More studies are needed using larger cohort to verify these results and understand the importance of the presence of such autoantibodies in children with autism and their mothers, both as biomarkers and their role in the mechanism of action of autism and perhaps in its treatment.

A Systematic Review of the Use of Biochemical Markers in the Assessment of Spinal Cord Ischemia in Thoracoabdominal Aortic Aneurysm Repair.

Despite advances in perioperative critical care and surgical technique, spinal cord ischemia remains a devastating complication of thoracic and thoracoabdominal aortic aneurysm repair. Biochemical markers present in peripheral blood and cerebrospinal fluid (CSF) may be useful in assessing spinal cord injury. We systematically analyze and report the role of all reported biochemical markers that have been used in assessing and diagnosing spinal cord ischemia in thoracic and thoracoabdominal aortic aneurysm repair. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used for this review. Published literature was searched to identify all studies reporting on the use of biochemical markers in thoracoabdominal aortic aneurysm repair in the assessment of spinal cord ischemia. Marker-specific and patient-specific data were extracted from all studies and where possible, subgroup analysis was performed on marker-specific data sets. Fourteen studies of 321 patients undergoing thoracic and thoracoabdominal aortic aneurysm repair were eligible for further analysis. Seven distinct biochemical markers were used in both CSF and blood samples: S100B proteins (S100B), neurone-specific enolase, lactate dehydrogenase, glial fibrillary acidic protein (GFAp), neurofilament triplet protein (NFL) and Tau protein, and glucose. There was substantial evidence demonstrating the heightened levels of S100, NFL, and GFAp in CSF in patients with spinal cord ischemia. There is however, wide variability in the correlation of the same 6 biochemical markers in peripheral blood and spinal cord ischemia. In patients with spinal cord injury, dramatic rises occur with S100B, NFL, and GFAp in CSF. However, further work is needed if biochemical markers are to impact on the future of thoracoabdominal aortic aneurysm repair.

Anti-α-galactoside and Anti-β-glucoside Antibodies are Partially Occupied by Either of Two Albumin-bound O-glycoproteins and Circulate as Ligand-binding Triplets

ABSTRACTTwo heavily O-glycosylated proteins and albumin co-purified with anti-α-galactoside (anti-Gal), the chief xenograft-rejecting antibody and anti-β-glucan (ABG) antibody isolated from human plasma by affinity chromatography on respective ligand-bearing matrices. Both antibodies and O-glycoproteins co-purified with plasma albumin eluted from albumin-specific matrix. Using components of affinity-purified antibody samples separated by electrophoresis binding of either albumin or antibody to the affinity matrix of the other or binding of O-glycoprotein to either matrix was ruled out. Enzyme-linked immunoassay and ligand-induced fluorescence enhancement of fluorolabeled antibody showed that O-glycoproteins occupied sugar-binding sites of anti-Gal and ABG. Neither antibody recognized albumin. O-Glycoprotein-albumin complexes free in plasma, or released from antibodies by specific sugars, were captured on microwell-coated O-glycan-specific lectin jacalin and detected using labeled anti-albumin. We conclude that circulating anti-Gal and ABG form protein triplets in which either O-glycoprotein bridges between antibody and albumin by binding simultaneously to both. Bound albumin restricted O-glycoprotein occupation on antibodies enabling triplets to bind other ligands using spared binding sites. Free anti-Gal and ABG were undetectable in plasma. Jacalin treatment, but not de-O-glycosylation of O-glycoproteins abolished their recognition by anti-Gal or ABG indicating that antibodies recognized serine- and threonine-rich peptide sequences that underlie the O-glycans and are reported surrogate ligands for anti-Gal. The albumin- and antibody-binding O-glycoproteins AOP1 and AOP2 were single polypeptide proteins of size 107 kDa and 98 kDa, containing 54% and 51% carbohydrate respectively and conformed to no known plasma protein in properties. Prospects of triplet-mediated modulations in autologous tissues expressing antibody ligands are discussed.

Evolution of the shut-off steps of vertebrate phototransduction.

Different isoforms of the genes involved in phototransduction are expressed in vertebrate rod and cone photoreceptors, providing a unique example of parallel evolution via gene duplication. In this study, we determine the molecular phylogeny of the proteins underlying the shut-off steps of phototransduction in the agnathan and jawed vertebrate lineages. For the G-protein receptor kinases (GRKs), the GRK1 and GRK7 divisions arose prior to the divergence of tunicates, with further expansion during the two rounds of whole-genome duplication (2R); subsequently, jawed and agnathan vertebrates retained different subsets of three isoforms of GRK. For the arrestins, gene expansion occurred during 2R. Importantly, both for GRKs and arrestins, the respective rod isoforms did not emerge until the second round of 2R, just prior to the separation of jawed and agnathan vertebrates. For the triplet of proteins mediating shut-off of the G-protein transducin, RGS9 diverged from RGS11, probably at the second round of 2R, whereas Gβ5 and R9AP appear not to have undergone 2R expansion. Overall, our analysis provides a description of the duplications and losses of phototransduction shut-off genes that occurred during the transition from a chordate with only cone-like photoreceptors to an ancestral vertebrate with both cone- and rod-like photoreceptors.

A Panel of Autoantibodies Against Neural Proteins as Peripheral Biomarker for Pesticide-Induced Neurotoxicity.

In the present study, we screened the sera of subjects chronically exposed to mixtures of pesticides (composed mainly of organophosphorus compounds (OPs) and others) and developed neurological symptoms for the presence of autoantibodies against cytoskeletal neural proteins. OPs have a well-characterized clinical profile resulting from acute cholinergic crisis. However, some of these compounds cause neuronal degeneration and demyelination known as organophosphorus compound-induced delayed neurotoxicity (OPIDN) and/or organophosphorus compound-induced chronic neurotoxicity (OPICN). Studies from our group have demonstrated the presence of autoantibodies to essential neuronal and glial proteins against cytoskeletal neural proteins in patients with chemical-induced brain injury. In this study, we screened the serum of 50 pesticide-exposed subjects and 25 non-exposed controls, using Western blot analysis against the following proteins: neurofilament triplet proteins (NFPs), tubulin, microtubule-associated tau proteins (Tau), microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), glial fibrillary acidic protein (GFAP), calcium-calmodulin kinase II (CaMKII), glial S100-B protein, and alpha-synuclein (SNCA). Serum reactivity was measured as arbitrary chemiluminescence units. As a group, exposed subjects had significantly higher levels of autoantibody reactivity in all cases examined. The folds of increase in of autoantibodies against neural proteins of the subjects compared to healthy humans in descending order were as follows: MBP, 7.67, MAG 5.89, CaMKII 5.50, GFAP 5.1, TAU 4.96, MAP2 4.83, SNCA 4.55, NFP 4.55, S-100B 2.43, and tubulin 1.78. This study has demonstrated the presence of serum autoantibodies to central nervous system-specific proteins in a group of farmers chronically exposed to pesticides who developed neurological signs and symptoms of neural injury. These autoantibodies can be used as future diagnostic/therapeutic target for OP-induced neurotoxicity.

The third wave: Intermediate filaments in the maturing nervous system.

Intermediate filaments are critical for the extreme structural specialisations of neurons, providing integrity in dynamic environments and efficient communication along axons a metre or more in length. As neurons mature, an initial expression of nestin and vimentin gives way to the neurofilament triplet proteins and α-internexin, substituted by peripherin in axons outside the CNS, which physically consolidate axons as they elongate and find their targets. Once connection is established, these proteins are transported, assembled, stabilised and modified, structurally transforming axons and dendrites as they acquire their full function. The interaction between these neurons and myelinating glial cells optimises the structure of axons for peak functional efficiency, a property retained across their lifespan. This finely calibrated structural regulation allows the nervous system to maintain timing precision and efficient control across large distances throughout somatic growth and, in maturity, as a plasticity mechanism allowing functional adaptation.

Screening for novel central nervous system biomarkers in veterans with Gulf War Illness

Gulf War illness (GWI) is primarily diagnosed by symptom report; objective biomarkers are needed that distinguish those with GWI. Prior chemical exposures during deployment have been associated in epidemiologic studies with altered central nervous system functioning in veterans with GWI. Previous studies from our group have demonstrated the presence of autoantibodies to essential neuronal and glial proteins in patients with brain injury and autoantibodies have been identified as candidate objective markers that may distinguish GWI. Here, we screened the serum of 20 veterans with GWI and 10 non-veteran symptomatic (low back pain) controls for the presence of such autoantibodies using Western blot analysis against the following proteins: neurofilament triplet proteins (NFP), tubulin, microtubule associated tau proteins (Tau), microtubule associated protein-2 (MAP-2), myelin basic protein (MBP), myelin associated glycoprotein (MAG), glial fibrillary acidic protein (GFAP), calcium-calmodulin kinase II (CaMKII) and glial S-100B protein. Serum reactivity was measured as arbitrary chemiluminescence units. As a group, veterans with GWI had statistically significantly higher levels of autoantibody reactivity in all proteins examined except S-100B. Fold increase of the cases relative to controls in descending order were: CaMKII 9.27, GFAP 6.60, Tau 4.83, Tubulin 4.41, MAG 3.60, MBP 2.50, NFP 2.45, MAP-2 2.30, S-100B 1.03. These results confirm the continuing presence of neuronal injury/gliosis in these veterans and are in agreement with the recent reports indicating that 25years after the war, the health of veterans with GWI is not improving and may be getting worse. Such serum autoantibodies may prove useful as biomarkers of GWI, upon validation of the findings using larger cohorts.

Developmental pattern of the neuronal intermediate filament inaa in the zebrafish retina.

α-Internexin is a member of the neuronal intermediate filament (nIF) protein family, which also includes peripherin and neurofilament (NF) triplet proteins. Previous studies found that expression of α-internexin precedes that of the NF triplet proteins in mammals and suggested that α-internexin plays a key role in the neuronal cytoskeleton network during development. In this study, we aimed to analyze the expression patterns and function of internexin neuronal intermediate filament protein-alpha a (inaa), the encoding gene of which is a homolog of the mammalian α-internexin, during retinal development in zebrafish. Via in vitro and in vivo studies, we demonstrated that zebrafish inaa is an α-internexin homolog that shares characteristics with nIFs. An immunohistochemical analysis of zebrafish revealed that inaa was distributed dynamically in the developing retina. It was widely localized in retinal neuroepithelial cells at 1 day postfertilization (dpf), and was mainly found in the ganglion cell layer (GCL) and inner part of the inner nuclear layer (INL) from 3-9 dpf; after 14 dpf, it was restricted to the outer nuclear layer (ONL). Moreover, we demonstrated for the first time that inaa acted distinctively from the cytoskeletal scaffold of zebrafish cone photoreceptors during development. In conclusion, we demonstrated the morphological features of a novel nIF, inaa, and illustrated its developmental expression pattern in the zebrafish retina. J. Comp. Neurol. 524:3810-3826, 2016. © 2016 Wiley Periodicals, Inc.

α-Internexin and Peripherin: Expression, Assembly, Functions, and Roles in Disease.

α-Internexin and peripherin are neuronal-specific intermediate filament (IF) proteins. α-Internexin is a type IV IF protein like the neurofilament triplet proteins (NFTPs, which include neurofilament light chain, neurofilament medium chain, and neurofilament high chain) that are generally considered to be the primary components of the neuronal IFs. However, α-internexin is often expressed together with the NFTPs and has been proposed as the fourth subunit of the neurofilaments in the central nervous system. α-Internexin is also expressed earlier in the development than the NFTPs and is a maker for neuronal IF inclusion disease. α-Internexin can self-polymerize in vitro and in transfected cells and it is present in the absence of the NFTP in development and in granule cells in the cerebellum. In contrast, peripherin is a type III IF protein. Like α-internexin, peripherin is specific to the nervous system, but it is expressed predominantly in the peripheral nervous system (PNS). Peripherin can also self-assemble both in vitro and in transfected cells. It is as abundant as the NFTPs in the sciatic nerve and can be considered a fourth subunit of the neurofilaments in the PNS. Peripherin has multiple isoforms that arise from intron retention, cryptic intron receptor site or alternative translation initiation. The functional significance of these isoforms is not clear. Peripherin is a major component found in inclusions of patients with amyotrophic lateral sclerosis (ALS) and peripherin expression is upregulated in ALS patients.

Tumors displaying hybrid schwannoma and neurofibroma features in patients with neurofibromatosis type 2.

Although schwannoma and neurofibroma tumors are generally reported as distinct pathologic diagnoses, sporadic schwannoma/neurofibroma hybrid nerve sheath tumors have been reported in the general population with components of both entities. We report the clinicopathological features of these hybrid nerve sheath tumors in patients with neurofibromatosis type 2 (NF2). A retrospective review of nerve sheath tumor surgical specimens from patients with NF2 enrolled at the National Institutes of Health was performed. Those specimens reported to have schwannoma-like and neurofibroma-like features were selected for further characterization by morphology, immunohistochemical panel (CD34, S100, neurofilament triplet protein (immunostain) (NFTP), epithelial membrane antigen (EMA)), and confirmation as hybrid tumors. Of 43 total NF2 patients undergoing resection of nerve sheath tumors, 11 specimens from 11 (26%) patients were found to be benign nerve sheath tumors exhibiting hybrid features of both neurofibroma and schwannoma. Immunohistochemical studies showed the schwannoma component to be S100+, CD 34- while the neurofibroma component was CD34+, variable S100+. Our experience emphasizes the importance of including this distinct tumor subtype, the schwannoma/neurofibroma hybrid tumor, in the differential diagnosis of nerve sheath tumors in NF2 patients and suggests that the relationship between neurofibroma and schwannoma tumors is closer than previously suspected.

Free Triplet Conjecture and Equivalence Classes Derived Using Group Theory

All proteins are made up of 20 different amino acids which contain 4 kinds of nucleotides . Three consecutive nucleotides on the gene, called triplet codons, are used to code an amino acid, and 64 triplet codons comprise the genetic code table. Central dogma (DNA-RNA-protein) has been acknowledged, but the process and mechanism of mRNA passing through the nuclear membrane still require further investigation. For these two problems mentioned above, this paper proposed a conjecture of nucleotide free triplet and obtained 20 equivalence classes of mapping from free triplet vertex set to nucleotide set using group theory. Whether the four numbers 3, 4, 20 and 64 have relevance are taken into consideration here. Subsequently, the numbers 3, 4, 20 and 64 were connected together which was important for the analysis of triplet code and protein composition.

Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite, and synaptic pathology in the APP/PS1 transgenic model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with the loss of cognitive function. Neurofilament (NF) triplet proteins, the major structural (intermediate filament) proteins of neurons, are expressed in a subset of pyramidal cells that show a high degree of vulnerability to degeneration in AD. Alterations in the NF triplet proteins in amyloid-beta (Aβ) plaque-associated dystrophic neurites (DNs) represent the first cytoskeletal aberration to occur in the neocortex in the earliest stages of AD. We generated transgenic APP/PS1 (APPswe/PSEN1dE9) mice on the neurofilament light knockout (NFL KO) background to explore the role of NFL deletion in the context of DN formation, synaptic changes, and other neuropathologic features. Our analysis demonstrated that NFL deficiency significantly increased neocortical DN pathology, Aβ deposition, synapse vulnerability, and microgliosis in APP/PS1 mice. Thus, NFs may have a role in protecting neurites from dystrophy and in regulating cellular pathways related to the generation of Aβ plaques.