36 research outputs found
The BED finger domain protein MIG-39 halts migration of distal tip cells in Caenorhabditis elegans
AbstractOrgans are often formed by the extension and branching of epithelial tubes. An appropriate termination of epithelial tube extension is important for generating organs of the proper size and morphology. However, the mechanism by which epithelial tubes terminate their extension is mostly unknown. Here we show that the BED-finger domain protein MIG-39 acts to stop epithelial tube extension in Caenorhabditis elegans. The gonadal leader cells, called distal tip cells (DTCs), migrate in a U-shaped pattern during larval development and stop migrating at the young adult stage, generating a gonad with anterior and posterior U-shaped arms. In mig-39 mutants, however, DTCs overshot their normal stopping position. MIG-39 promoted the deceleration of DTCs, leading to the proper timing and positioning of the cessation of DTC migration. Among three Rac GTPase genes, mutations in ced-10 and rac-2 enhanced the overshoot of anterior DTCs, while they suppressed that of posterior DTCs of mig-39 mutants. On the other hand, the mutation in mig-2 suppressed both the anterior and posterior DTC defects of mig-39. Genetic analyses suggested that MIG-39 acts in parallel with Rac GTPases in stopping DTC migration. We propose a model in which the anterior and posterior DTCs respond in an opposite manner to the levels of Rac activities in the cessation of DTC migration
In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment
Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which has multiple functions such as binding to methylated DNA or interacting with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We investigated the evolution and molecular features of MeCP2, CDKL5, and FOXG1 and their binding partners using phylogenetic profiling to gain a better understanding of their similarities. We also predicted the structural order–disorder propensity and assessed the evolutionary rates per site of MeCP2, CDKL5, and FOXG1 to investigate the relationships between disordered structure and other related properties with RTT. Here, we provide insight to the structural characteristics, evolution and interaction landscapes of those three proteins. We also uncovered the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT
ノウコウソク ノ チリョウ セイセキ ワ ナゼ コウジョウ シナイ ノカ : 10ネンカン ノ ヤマガタケン ノウソッチュウ トウロク データ カラ ノ ヨゴ フリョウ インシ ノ ケントウ
We studied ten years of stroke data registered with the Yamagata Society on Treatment for Cerebral Stroke(YSTCS). The subjects included 16,407 cases of acute-phase cerebral infarction that were registered with the YSTCS during the ten years between 2002 and 2011. The cases were divided into two groups: the early phase group(2002-2006)and the late phase group(2007-2011). The clinical diagnoses included atherothrombotic cerebral infarction(AT)(n=7,196; 43.9%), cardiogenic cerebral embolism(CE)(n=4,011; 24.4%), and lacunar infarction(LI)(n=4,703; 28.7%). The average age of the early phase group was 72.7±11.43 years, while that of the late phase group was 75.0±11.35 years; the difference was statistically significant. The proportion of CE cases increased in the late phase, while that of LI decreased. This phenomenon was more marked in cases involving patients of ≥80 years of age. In both the early and late phase groups, the AT and CE cases showed a significantly high proportion of poor outcomes. However, when age adjustment was implemented in the late phase group, the treatment outcomes improved across all clinical entities. A multiple logistic regression analysis revealed a significant association between old age, female sex, severe symptoms at onset, CE, a previous history of stroke, and a poor prognosis. It is clear that developments in medicine have not kept pace with the advancement in the age at onset. The improvement of the outcomes of treatment for cerebral infarction requires further developments in acute-phase therapies and the primary prevention of cardiogenic cerebral embolism, many cases of which are severe
Mitochondrial dysfunction causes Ca2+ overload and ECM degradation–mediated muscle damage in C. elegans
Mitochondrial dysfunction impairs muscle health and causes subsequent muscle wasting. This study explores the role of mitochondrial dysfunction as an intramuscular signal for the extracellular matrix (ECM)–based proteolysis and, consequentially, muscle cell dystrophy. We found that inhibition of the mitochondrial electron transport chain causes paralysis as well as muscle structural damage in the nematode Caenorhabditis elegans. This was associated with a significant decline in collagen content. Both paralysis and muscle damage could be rescued with collagen IV overexpression, matrix metalloproteinase (MMP), and Furin inhibitors in Antimycin A–treated animal as well as in the C. elegans Duchenne muscular dystrophy model. Additionally, muscle cytosolic calcium increased in the Antimycin A–treated worms, and its down-regulation rescued the muscle damage, suggesting that calcium overload acts as one of the early triggers and activates Furin and MMPs for collagen degradation. In conclusion, we have established ECM degradation as an important pathway of muscle damage
Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials
Aims:
The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials.
Methods and Results:
Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594).
Conclusions:
GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation
Nonstructural proteins NS7b and NS8 are likely to be phylogenetically associated with evolution of 2019-nCoV
The seventh novel human infecting Betacoronavirus that causes pneumonia (2019 novel coronavirus, 2019-nCoV) originated in Wuhan, China. The evolutionary relationship between 2019-nCoV and the other human respiratory illness-causing coronavirus is not closely related. We sought to characterize the relationship of the translated proteins of 2019-nCoV with other species of Orthocoronavirinae. A phylogenetic tree was constructed from the genome sequences. A cluster tree was developed from the profiles retrieved from the presence and absence of homologs of ten 2019-nCoV proteins. The combined data were used to characterize the relationship of the translated proteins of 2019-nCoV to other species of Orthocoronavirinae. Our analysis reliably suggests that 2019-nCoV is most closely related to BatCoV RaTG13 and belongs to subgenus Sarbecovirus of Betacoronavirus, together with SARS coronavirus and Bat-SARS-like coronavirus. The phylogenetic profiling cluster of homolog proteins of one annotated 2019-nCoV protein against other genome sequences revealed two clades of ten 2019-nCoV proteins. Clade 1 consisted of a group of conserved proteins in Orthocoronavirinae comprising Orf1ab polyprotein, Nucleocapsid protein, Spike glycoprotein, and Membrane protein. Clade 2 comprised six proteins exclusive to Sarbecovirus and Hibecovirus. Two of six Clade 2 nonstructural proteins, NS7b and NS8, were exclusively conserved among 2019-nCoV, BetaCoV_RaTG, and BatSARS-like Cov. NS7b and NS8 have previously been shown to affect immune response signaling in the SARS-CoV experimental model. Thus, we speculated that knowledge of the functional changes in the NS7b and NS8 proteins during evolution may provide important information to explore the human infective property of 2019-nCoV
A Fibulin-1 Homolog Interacts with an ADAM Protease that Controls Cell Migration in C. elegans
AbstractADAM (a disintegrin and metalloprotease) family proteins play important roles in animal development and pathogenesis [1]. In C. elegans, a secreted ADAM protein, MIG-17, acts from outside the gonad to control the migration of gonadal distal tip cells (DTCs) that promote gonad morphogenesis [2]. Here, we report that dominant mutations in the fbl-1 gene encoding fibulin-1 spliced isoforms, which are calcium binding extracellular matrix proteins, bypass the requirement for MIG-17 activity in directing DTC migration. Specific amino acid substitutions in the third EGF-like motif of one of the two isoforms, FBL-1C, which corresponds to mammalian fibulin-1C, suppress mig-17 mutations. FBL-1C is synthesized in the gut cells and localizes strongly to the gonadal basement membrane in a MIG-17-dependent manner. Localization of mutant FBL-1C is weaker than that of the wild-type protein and is insensitive to MIG-17 activity, suggesting that it gains a novel function that compensates for its reduced molecular density. We propose that proteolysis by MIG-17 recruits FBL-1C to the gonadal basement membrane, where it is required for the guidance of DTCs, and that mutant FBL-1C acts in a manner that mimics the downstream events of MIG-17-mediated proteolysis