ResearchPad - 35 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[<i>TGM6</i> L517W is not a pathogenic variant for spinocerebellar ataxia type 35]]> https://www.researchpad.co/article/elastic_article_7785 To investigate the pathogenicity of the TGM6 variant for spinocerebellar ataxia 35 (SCA35), which was previously reported to be caused by pathogenic mutations in the gene TGM6.MethodsNeurologic assessment and brain MRI were performed to provide detailed description of the phenotype. Whole-exome sequencing and dynamic mutation analysis were performed to identify the genotype.ResultsThe proband, presenting with myoclonic epilepsy, cognitive decline, and ataxia, harbored both the TGM6 p.L517W variant and expanded CAG repeats in gene ATN1. Further analysis of the other living family members in this pedigree revealed that the CAG repeat number was expanded in all the patients and within normal range in all the unaffected family members. However, the TGM6 p.L517W variant was absent in 2 affected family members, but present in 3 healthy individuals.ConclusionsThe nonsegregation of the TGM6 variant with phenotype does not support this variant as the disease-causing gene in this pedigree, questioning the pathogenicity of TGM6 in SCA35. ]]> <![CDATA[CLASP2 binding to curved microtubule tips promotes flux and stabilizes kinetochore attachments]]> https://www.researchpad.co/article/N6bf105bd-3502-4ac3-942f-3873dd79be05

Girão et al. use structure-guided functional mutants of CLASP2 to show that recognition of growing microtubule plus-ends through EB–protein interaction and the ability to associate with curved microtubule protofilaments through TOG2 and TOG3 domains promote growth and stabilization of kinetochore–microtubules required for poleward flux.

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<![CDATA[SGEF forms a complex with Scribble and Dlg1 and regulates epithelial junctions and contractility]]> https://www.researchpad.co/article/Nafa1aa93-c090-4a21-b5c1-05b1bdb45d04

Awadia et al. show that SGEF, a RhoG-specific GEF, forms a ternary complex with two members of the Scribble polarity complex, Scribble and Dlg1, and regulates junction formation, apical contractility, E-cadherin stability, and lumen formation in epithelial cells.

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<![CDATA[Spastin joins LDs and peroxisomes in the interorganelle contact ballet]]> https://www.researchpad.co/article/N33b25519-6894-4a7e-9e8a-a9106810022b

W.M. Henne previews work from Chang et al. that demonstrates a role for Spastin in tethering lipid droplets to peroxisomes to facilitate fatty acid exchange.

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<![CDATA[Assembling nuclear domains: Lessons from DNA repair]]> https://www.researchpad.co/article/Nd5296de9-d84a-44e2-a392-db9b4e326f26

Schrank and Gautier discuss the generation and function of nuclear domains during DNA repair with a special focus on nuclear actin polymerization.

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<![CDATA[LTK is an ER-resident receptor tyrosine kinase that regulates secretion]]> https://www.researchpad.co/article/Nb241a4e3-9203-4bab-87dd-85c699f4a230

The endoplasmic reticulum (ER) is a major regulator of cellular proteostasis. However, only little is known about signaling molecules resident to this organelle. Centonze et al. identify LTK as the first ER-resident receptor tyrosine kinase and show that it stimulates secretory trafficking out of the ER.

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<![CDATA[Quantitative glycoproteomics reveals new classes of STT3A- and STT3B-dependent N-glycosylation sites]]> https://www.researchpad.co/article/Na54090d5-3f6e-44e5-8fd5-62c1b475cee5

Cherepanova et al. provide quantitative glycoproteomic analyses of human cells that lack either the STT3A or STT3B oligosaccharyltransferase (OST) complex, revealing new classes of STT3A- and STT3B-dependent glycosylation sites and indicating how cooperation between the OST complexes maximizes acceptor site occupancy in cellular glycoproteins.

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<![CDATA[Synthetic bovine lactoferrin peptide Lfampin kills Entamoeba histolytica trophozoites by necrosis and resolves amoebic intracecal infection in mice]]> https://www.researchpad.co/article/5c4b940fd5eed0c48487dbec

Amoebiasis caused by the protozoan parasite Entamoeba histolytica remains a public health problem in developing countries, making the identification of new anti-amoebic compounds a continuing priority. Previously, we have shown that lactoferrin (Lf) and several Lf-derived peptides exhibit in vitro anti-amoebic activity independently of their iron-binding activity. Here, we evaluated the amoebicidal effect of synthetic Lf-derived peptides Lfcin-B, Lfcin 17-30, and Lfampin, analyzed the mechanism of death induced by the peptides and determined their therapeutic effects on murine intestinal amoebiasis. MTT assays in trophozoite cultures of E. histolytica exposed to each peptide (1–1000 μM) showed that Lfampin is far more amoebicidal than Lfcins. Lfampin killed 80% of trophozoites at doses higher than 100 μM in 24 h, and FACs analysis using Annexin V/propidium iodide showed that death occurred mainly by necrosis. In contrast, Lfcin-B and Lfcin 17-30 appeared to have no significant effect on amoebic viability. FACs and confocal microscopy analysis using FITC-labeled peptides showed that all three peptides are internalized by the amoeba mainly using receptor (PI3K signaling) and actin-dependent pathways but independent of clathrin. Docking studies identified cholesterol in the amoeba’s plasma membrane as a possible target of Lfampin. Oral treatment of intracecally infected mice with the abovementioned peptides at 10 mg/kg for 4 days showed that Lfampin resolved 100% of the cases of intestinal amoebiasis, whereas Lfcin 17-30 and Lfcin-B were effective in resolving infection in 80 and 70% of cases, respectively. These data show that although synthetic bovine Lf-derived peptides exhibit varying amoebicidal potentials in vitro, they do resolve murine intestinal amoebiasis efficiently, suggesting that they may be useful as a therapeutic treatment.

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<![CDATA[The state of art of neutrophil extracellular traps in protozoan and helminthic infections]]> https://www.researchpad.co/article/5c4b93edd5eed0c48487d506

Neutrophil extracellular traps (NETs) are DNA fibers associated with histones, enzymes from neutrophil granules and anti-microbial peptides. NETs are released in a process denominated NETosis, which involves sequential steps that culminate with the DNA extrusion. NETosis has been described as a new mechanism of innate immunity related to defense against different pathogens. The initial studies of NETs were carried out with bacteria and fungi, but currently a large variety of microorganisms capable of inducing NETs have been described including protozoan and helminth parasites. Nevertheless, we have little knowledge about how NETosis process is carried out in response to the parasites, and about its implication in the resolution of this kind of disease. In the best case, the NETs entrap and kill parasites in vitro, but in others, immobilize the parasites without affecting their viability. Moreover, insufficient studies on the NETs in animal models of infections that would help to define their role, and the association of NETs with chronic inflammatory pathologies such as those occurring in several parasitic infections have left open the possibility of NETs contributing to pathology instead of protection. In this review, we focus on the reported mechanisms that lead to NET release by protozoan and helminth parasites and the evidence that support the role of NETosis in the resolution or pathogenesis of parasitic diseases.

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<![CDATA[Prolactin as immune cell regulator in Toxocara canis somatic larvae chronic infection]]> https://www.researchpad.co/article/5c0aef0cd5eed0c4845a2450

Toxocariasis is a zoonotic disease produced by ingestion of larval Toxocara spp. eggs. Prolactin (PRL) has been considered to have an important role in Toxocara canis infection. Recent evidence has found that PRL directly can increase parasite growth and differentiation of T. canis. The present study, evaluated the effect of high PRL levels on the immune system’s response and parasites clearance in chronic infection. Our results showed that hyperprolactinemia did not affect the number of larvae recovered from several tissues in rats. Parasite-specific antibody production, showed no difference between the groups. Lung tissue presented eosinophilic granulomas typical of a chronic infection in all the experimental groups. Flow cytometry analysis was made in order to determine changes in the percentage of innate and adaptive immune cell subpopulations in the spleen, peripheric (PLN) and mesenteric (MLN) lymphatic nodes. The results showed a differential effect of PRL and infection on different immune compartments in the percent of total T cells, T helper cells, T cytotoxic cells, B cells, NK cells, and Tγδ cells. To our knowledge, for the first time it is demonstrated that PRL can have an immunomodulatory role during T. canis chronic infection in the murine host.

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<![CDATA[LAMTOR/Ragulator is a negative regulator of Arl8b- and BORC-dependent late endosomal positioning]]> https://www.researchpad.co/article/5c01f906d5eed0c4842bf9af

Functions of lysosomes are tightly associated with their position within the cell. Filipek et al. identify the EGF-dependent LAMTOR/Ragulator-BORC interaction as a negative regulator of Arl8b lysosomal recruitment that triggers plus-end directed lysosome movement.

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<![CDATA[Pulses and waves of contractility]]> https://www.researchpad.co/article/5c01f927d5eed0c4842c04b7

Wu discusses a study by Graessl et al. that describes a Rho GTPase signaling network that combines positive and negative feedback to regulate subcellular contraction patterns.

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<![CDATA[UNC-45a promotes myosin folding and stress fiber assembly]]> https://www.researchpad.co/article/5b5a5d10463d7e0616519a62

How nonmuscle myosin II is recruited to contractile actomyosin bundles or stress fibers and assembled into functional bipolar filaments is unclear. Lehtimäki et al. show that UNC-45a functions as a myosin chaperone that contributes to the assembly of functional stress fibers.

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<![CDATA[Segregation in the Golgi complex precedes export of endolysosomal proteins in distinct transport carriers]]> https://www.researchpad.co/article/5c01f91fd5eed0c4842c01a1

Chen et al. present evidence that two sets of newly synthesized endolysosomal proteins segregate in the Golgi complex before their export in two distinct populations of transport carriers, by mechanisms that are respectively dependent or independent of sorting signal–adaptor interactions.

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<![CDATA[SUMOylation of human septins is critical for septin filament bundling and cytokinesis]]> https://www.researchpad.co/article/5c01f90ad5eed0c4842bfad6

Yeast septins were among the first proteins reported to be SUMOylated, but the impact of this modification on septin function is unclear. Ribet et al. show that septins are SUMOylated in humans and that SUMOylation is critical for septin bundle formation and septin function in cell division.

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<![CDATA[Kinesins relocalize the chromosomal passenger complex to the midzone for spindle disassembly]]> https://www.researchpad.co/article/5c129a79d5eed0c4848c82d4

The chromosomal passenger complex (CPC) is a master mitotic regulator, but its role during mitotic exit is not fully understood. Ibarlucea-Benitez et al. reveal that the kinesins Kip1 and Kip3 recruit the CPC to the spindle midzone in anaphase and show that this relocalization is important for spindle disassembly.

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<![CDATA[Membrane protein recycling from the vacuole/lysosome membrane]]> https://www.researchpad.co/article/5c129a7fd5eed0c4848c839e

How membrane proteins delivered to the vacuole membrane are recycled remains unknown. Suzuki and Emr show that the Snx4 coat complex assembles on the vacuole surface to mediate the vacuole-to-endosome retrograde trafficking of transmembrane proteins.

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