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1.
J Vet Med Sci ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34776468

RESUMO

The present study was undertaken to examine whether oral administration of colostrum to mastitic cows reduced inflammation in the udder. Fifty milliliters of a colostrum whey product was administered orally daily for 3 days to cows suffering from mastitis. Milk was collected on day 0 and 7 of colostrum administration. For Experiment 1, milk from 11 udder quarters with high somatic cell counts (SCC) in four cows was used. SCC in milk decreased significantly after colostrum administration, whereas colostrum administration increased sodium and IgA concentrations significantly compared with those before administration. In Experiment 2, cows with clinical mastitis were divided into two groups, with and without colostrum administration, whereas all cows with subclinical mastitis were administered colostrum. Antibiotics were infused into the mammary gland from the first day of colostrum administration for 2-4 days. There was no significant decrease in SCC after colostrum administration in any group. However, udder firmness in both groups was reduced after administration regardless of colostrum administration. IgA concentration in both clinical mastitis groups was significantly increased after colostrum administration compared to that before administration, although there was no significant difference between them. These results suggest the possibility that oral administration of colostrum attenuates inflammation of the mammary gland. Further studies are required to examine the effect of colostrum more precisely using cows with subclinical and chronic mastitis and longer duration of colostrum administration.

2.
J Vet Med Sci ; 83(11): 1620-1627, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34526421

RESUMO

The aim of this study was to evaluate the microbiota of normal milk in dairy cows and their relationship with host factors, such as the age of the cow (Age), somatic cell counts in milk (SCCs), and days in milk (DIM). We investigated 48 milk samples from 22 cows with no systemic or local clinical signs using MinIONTM nanopore sequencing for a 16S rRNA gene amplicon. Bacterial richness was positively correlated with the DIM (P=0.043), and both the Shannon-Wiener Index and Simpson's Index, which are metrics of alpha-diversity, were also significantly positively correlated with the SCC (P<0.001). The composition ratios of both Actinobacteria at the phylum level and Kocuria spp. at the genus level in the milk microbiota were significantly correlated with the SCC (P<0.001 and P<0.001, respectively). In the beta-diversity test, the one-way analysis of similarities test showed a significant difference (P=0.0051) between the low- and high-SCC groups. This study clarified that the composition of the normal milk microbiota in this herd was related to the SCC. It also raised the possibility of variations in bacterial genera in the normal milk microbiota between the low- and high-SCC groups. However, to clarify the actual condition of the milk microbiota and to elucidate the relationship with the SCC, it is necessary to perform further analyses taking into account not only the relative abundance, but also the absolute abundance of microbes.


Assuntos
Doenças dos Bovinos , Mastite Bovina , Microbiota , Sequenciamento por Nanoporos , Animais , Bovinos , Contagem de Células/veterinária , Feminino , Lactação , Leite , Sequenciamento por Nanoporos/veterinária , RNA Ribossômico 16S/genética
3.
Neuromuscul Disord ; 31(9): 870-876, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34465502

RESUMO

Sporadic inclusion body myositis (sIBM) is a degenerative, intractable, inflammatory myopathy with an immune pathomechanism. We report on a case of a 44-year-old Japanese man who began developing progressive muscle weakness at age 40. Rheumatoid arthritis symptoms manifested at 43 with strongly positive anti-cyclic citrullinated peptide antibodies. Along with typical sIBM pathology, a muscle biopsy revealed dramatic inflammation with prominent perivascular B-cell infiltration forming ectopic lymphoid follicle-like structures (ELFLSs). Exome sequencing identified no causative variants of hereditary myopathy or immune disorders. A combination of immunotherapy slowed the progression of the muscular symptoms. This unusual form of sIBM, including earlier age at onset, a partial response to immunotherapy, and a histopathology presenting B-cell infiltrate with ectopic lymphoid follicle-like structures, indicates a possible association of rheumatoid arthritis and heterogeneity with the autoimmune involvement of sIBM. We review the clinical and pathological features of patients with rheumatoid arthritis associated sIBM in the literature.

4.
Pain Ther ; 10(2): 1635-1648, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34581982

RESUMO

INTRODUCTION: Tapentadol has analgesic effects comparable to those of conventional opioids and is associated with fewer side effects, including gastrointestinal symptoms, drowsiness, and dizziness, than other opioids. However, the safety of tapentadol in the Japanese population remains unclear; the present multicentre study aimed to examine the safety of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events. METHODS: The safety of tapentadol was assessed retrospectively in patients with any type of cancer treated between August 18, 2014 and October 31, 2019 across nine institutions in Japan. Patients were examined at baseline and at the time of opioid discontinuation. Multivariate analysis was performed to identify factors associated with tapentadol discontinuation owing to adverse events. RESULTS: A total of 906 patients were included in this study, and 685 (75.6%) cases were followed up until tapentadol cessation for any reason. Among patients who discontinued treatment, 119 (17.4%) did so because of adverse events. Among adverse events associated with difficulty in taking medication, nausea was the most common cause of treatment discontinuation (4.7%), followed by drowsiness (1.8%). Multivariate analysis showed that those who were prescribed tapentadol by a palliative care physician (odds ratio [OR] 2.60, 95% confidence interval [CI] 1.36-4.99, p = 0.004), patients switching to tapentadol due to side effects from previous opioids (OR 2.19, 95% CI 1.05-4.56, p = 0.037), and patients who did not use naldemedine (OR 5.06, 95% CI 2.47-10.37, p < 0.0001) had an increased risk of treatment discontinuation owing to adverse events. CONCLUSIONS: This study presents the safety profile of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events in the Japanese population. Prospective controlled trials are required to evaluate the safety of tapentadol and validate the present findings. TRIAL REGISTRATION NUMBER: UMIN 000044282 (University Hospital Medical Information Network).

5.
Int J Med Robot ; 17(6): e2322, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34405536

RESUMO

BACKGROUND: Previously, we developed an image-guided navigation system (IG-NS) incorporating augmented reality technology. Nevertheless, the system could still only aid the operator by presenting imagery and was short of achieving the goal of developing a real navigation system. Therefore, we developed a recognised position-guided navigation system (RP-NS) and herein reported the functionality and usefulness of this system in a phantom model for clinical applications. METHODS: We developed RP-NS which was reconstructed by adding the positional recognition and instruction functions with the cautions by displaying the images on the monitor with a voice to the IG-NS. We evaluated accuracy of positional recognition and instruction functions using phantom model. By utilising the chronological recording of the tip position of the surgical apparatus, the surgical precision of the operators was assessed. Finally, the feasibility of improvements in surgical precision using this system was evaluated. RESULTS: The RP-NS indicated an accuracy of the position recognition functions with an error of 2.7 mm. The surgeons could perform partial hepatectomies within mean value of 7.5% error as compared with calculated volume according to the instruction. Improvements in surgical precision using this system were obtained on the surgeons with different levels. CONCLUSIONS: The RP-NS was highly effective as a navigation system owing to precise positional recognition and adequate instruction functions. Therefore, these results indicate that the use of this system may complement differences in proficiency, and numerically evaluate surgical skills and analyse tendencies of surgeons.


Assuntos
Cirurgia Assistida por Computador , Hepatectomia , Humanos , Tomografia Computadorizada por Raios X
6.
Stem Cell Reports ; 16(6): 1527-1541, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34048688

RESUMO

Amyotrophic lateral sclerosis (ALS) is an adult-onset incurable motor neuron (MN) disease. The reasons for selective MN vulnerability in ALS are unknown. Axonal pathology is among the earliest signs of ALS. We searched for novel modulatory genes in human MN axon shortening affected by TARDBP mutations. In transcriptome analysis of RNA present in the axon compartment of human-derived induced pluripotent stem cell (iPSC)-derived MNs, PHOX2B (paired-like homeobox protein 2B) showed lower expression in TARDBP mutant axons, which was consistent with axon qPCR and in situ hybridization. PHOX2B mRNA stability was reduced in TARDBP mutant MNs. Furthermore, PHOX2B knockdown reduced neurite length in human MNs. Finally, phox2b knockdown in zebrafish induced short spinal axons and impaired escape response. PHOX2B is known to be highly express in other types of neurons maintained after ALS progression. Collectively, TARDBP mutations induced loss of axonal resilience, which is an important ALS-related phenotype mediated by PHOX2B downregulation.

7.
J Hum Genet ; 66(10): 965-972, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33744911

RESUMO

Heat shock protein family B member 8, encoded by HSPB8, is an essential component of the chaperone-assisted selective autophagy complex, which maintains muscle function by degrading damaged proteins in the cells. Mutations in HSPB8 have been reported to cause Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy IIa, and rimmed vacuolar myopathies (RVM). In this study, we identified a novel heterozygous frameshift variant c.525_529del in HSPB8 in a large Japanese family with RVM, using whole exome sequencing. Three affected individuals had severe respiratory failure, which has not been addressed by previous studies. Muscle atrophy in the paraspinal muscles was also a clinical feature of the individuals affected with RVM in this study. The frameshift mutation was located in the last coding exon, and the mutated protein was predicted to harbor an isoleucine-leucine-valine (ILV) sequence, which corresponds to the IXI/V (isoleucine, X amino acids, and isoleucine or valine) motif. The IXI/V motif is essential for assembly into larger oligomers in other small heat shock proteins and all frameshift mutants of HSPB8 were predicted to share the ILV sequence in the C-terminal extension. The in silico prediction tools showed low protein solubility and increased aggregation propensity for the region around the ILV sequence. The IXI/V motif might be associated with the pathogenesis of HSPB8-related RVM.

8.
Neurology ; 96(12): e1595-e1607, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33597289

RESUMO

OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Miosite de Corpos de Inclusão/tratamento farmacológico , Acidentes por Quedas , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/efeitos dos fármacos , Miosite de Corpos de Inclusão/complicações , Tempo , Resultado do Tratamento , Teste de Caminhada
9.
Foot Ankle Int ; 42(3): 333-339, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33167681

RESUMO

BACKGROUND: Hypermobility of the first ray has been evaluated using various methods and has conventionally been considered to be involved in the pathology of hallux valgus. We hypothesized that hypermobility of the first ray in hallux valgus could be decreased by simply correcting foot alignment without arthrodesis. This study sought to evaluate first-ray mobility using weightbearing computed tomography (CT) before and after proximal oblique osteotomy and also in healthy volunteer's feet. METHODS: Subjects were 11 feet of 11 patients with primary hallux valgus who underwent surgery with a plantarly applied anatomic precontoured locking plate and 22 feet of 11 matched healthy volunteers. We performed nonweightbearing and weightbearing (using a load equivalent to body weight) CT scans using an original loading device preoperatively and 1-1.5 years postoperatively. Three-dimensional displacement of the distal bone relative to the proximal bone was quantified for each joint of the first ray by comparing nonweightbearing and weightbearing CT images. RESULTS: At baseline, there were significant differences in hallux valgus angle (P < .001) and 1-2 intermetatarsal angle (P < .001) between healthy volunteer's feet and preoperative hallux valgus feet. Hallux valgus angle (P < .001) and 1-2 intermetatarsal angle (P < .001) differed significantly between before and after surgery. All first ray joint displacement under loading decreased postoperatively to within 2° of that in healthy volunteer's feet and showed no significant difference between postoperatively hallux valgus feet and healthy volunteer's feet (P > .05). CONCLUSIONS: We found that first metatarsal osteotomy even without arthrodesis corrected deformity and decreased mobility of the first ray after hallux valgus surgery. LEVEL OF EVIDENCE: Level III, case-control study.

10.
J Cell Physiol ; 236(7): 5293-5305, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33378552

RESUMO

The ubiquitin-proteasome system is a major protein degradation pathway in the cell. Proteasomes produce several peptides that are rapidly degraded to free amino acids by intracellular aminopeptidases. Our previous studies reported that proteolysis via proteasomes and aminopeptidases is required for myoblast proliferation and differentiation. However, the role of intracellular aminopeptidases in myoblast proliferation and differentiation had not been clarified. In this study, we investigated the effects of puromycin-sensitive aminopeptidase (PSA) on C2C12 myoblast proliferation and differentiation by knocking down PSA. Aminopeptidase enzymatic activity was reduced in PSA-knockdown myoblasts. Knockdown of PSA induced impaired cell cycle progression in C2C12 myoblasts and accumulation of cells at the G2/M phase. Additionally, after the induction of myogenic differentiation in PSA-knockdown myoblasts, multinucleated circular-shaped myotubes with impaired cell polarity were frequently identified. Cell division cycle 42 (CDC42) knockdown in myoblasts resulted in a loss of cell polarity and the formation of multinucleated circular-shaped myotubes, which were similar to PSA-knockdown myoblasts. These data suggest that PSA is required for the proliferation of myoblasts in the growth phase and for the determination of cell polarity and elongation of myotubes in the differentiation phase.


Assuntos
Aminopeptidases/metabolismo , Desenvolvimento Muscular/fisiologia , Mioblastos/enzimologia , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Proliferação de Células/fisiologia , Camundongos
11.
J Vet Med Sci ; 83(2): 338-343, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33342970

RESUMO

The occurrence of multiple metabolic and inflammatory diseases in dairy cows is higher during the periparturient period, which may be triggered by bacterial components, but not a viable bacterium. This study aimed to determine the association of endometritis and ovarian follicular cyst (OFC) with mastitis in dairy cows. Ninety-eight Holstein dairy cows were clinically examined for endometritis and OFC approximately 30-50 days after calving. Blood and milk samples were collected for the determination of milk somatic cell count (SCC); milk interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNFα), and interleukin-8 (IL-8) concentrations; and plasma haptoglobin (Hp) and lipopolysaccharide-binding protein (LBP) concentrations. Of the 98 dairy cows included in this study, 12 were diagnosed with endometritis and 37 cows were identified as OFC-positive, whereas the remaining 49 cows were healthy (without endometritis or OFC). The average and maximum SCCs and plasma Hp and LBP concentrations were not significantly different between the healthy cows and those with endometritis or OFC. However, when the maximum SCC was classified as <300, 300-1,000, or >1,000 × 103 cells/ml, the percentage of cows with the maximum SCC <300 × 103 cells/ml was significantly lower in the endometritis and OFC-positive groups than in the healthy group. These results suggested that cows with endometritis and OFC during the postpartum period exhibit high SCC, indicating that some bacterial components can be transferred between organs.


Assuntos
Doenças dos Bovinos , Endometrite , Cisto Folicular , Mastite , Animais , Bovinos , Endometrite/veterinária , Feminino , Cisto Folicular/veterinária , Lactação , Mastite/veterinária , Leite , Período Pós-Parto
12.
PLoS One ; 15(12): e0231064, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33264289

RESUMO

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.


Assuntos
Ácidos Indolacéticos/uso terapêutico , Mitocôndrias Musculares/metabolismo , Miosite de Corpos de Inclusão/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Trifosfato de Adenosina/biossíntese , Idoso , Idoso de 80 Anos ou mais , Butionina Sulfoximina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , DNA Mitocondrial/genética , Avaliação Pré-Clínica de Medicamentos , Dinaminas/biossíntese , Dinaminas/genética , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Fibroblastos/efeitos dos fármacos , GTP Fosfo-Hidrolases/biossíntese , GTP Fosfo-Hidrolases/genética , Fator 15 de Diferenciação de Crescimento/biossíntese , Fator 15 de Diferenciação de Crescimento/sangue , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Ácidos Indolacéticos/farmacologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/patologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Mioblastos/ultraestrutura , Miosite de Corpos de Inclusão/metabolismo , Miosite de Corpos de Inclusão/patologia , Consumo de Oxigênio , Fenilbutiratos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Estudos Retrospectivos
13.
J Clin Neurosci ; 81: 92-94, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33222978

RESUMO

We evaluated the efficacy of rehabilitation therapy with Hybrid Assistive Limb® (HAL; hereafter HAL therapy) in three patients diagnosed with sporadic inclusion body myositis (sIBM) who were hospitalized to undergo HAL therapy. Among them, one patient participated in eight courses and the other two in two courses of HAL therapy between 2017 and 2020. We determined the mean rate of improvement in two-minute walking distance and 6 m walking speed at the time of hospital discharge. After HAL therapy, we confirmed the patients' desire to continue the use of HAL. In one patient, we observed improvements of 146.0% and 120.0% in two-minute walk and 6 m walking speed, respectively, after the first course of HAL therapy; these values are 133.7% and 130% after the eighth course of HAL therapy. These values exceeded 90% in the other two patients after the second course of HAL therapy. HAL therapy maintained both quantity and quality of ambulation and showed positive psychological effects on patient conditions because it reduces exercise load and facilitates safety. While HAL therapy might be effective in maintaining and improving ambulation in patients with sIBM, we should consider to discontinue HAL therapy as it increased risk of falling.


Assuntos
Terapia por Exercício/métodos , Exoesqueleto Energizado , Miosite de Corpos de Inclusão/reabilitação , Robótica/métodos , Idoso , Terapia por Exercício/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miosite de Corpos de Inclusão/diagnóstico , Robótica/instrumentação , Caminhada/fisiologia
14.
Exp Cell Res ; 397(1): 112337, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33091420

RESUMO

A large number of intracellular proteins are degraded by the ubiquitin-proteasome system, one of the major protein degradation pathways. It produces peptides of several different sizes through protein degradation, and these peptides are rapidly degraded into free amino acids by various intracellular aminopeptidases. Previously, we reported that the activity of proteasomes and aminopeptidases in the proteolysis pathway are necessary for myoblast proliferation and differentiation. However, the detailed function of intracellular aminopeptidases in myoblast proliferation and differentiation has not yet been elucidated. In this study, we focused on alanine aminopeptidase (APN) and investigated the function of APN in C2C12 myoblast proliferation and differentiation. In myoblasts and myotubes, APN was mainly localized in the cell membrane as well as expressed at low levels in the cytoplasm and nucleus. The reduction of the APN enzymatic activity impaired the cell cycle progression in C2C12 myoblasts. In addition, apoptosis was induced after APN-knockdown. Finally, myogenic differentiation was also delayed in the APN-suppressed myoblasts. These findings indicate that APN is required for myoblast proliferation and differentiation.


Assuntos
Antígenos CD13/antagonistas & inibidores , Diferenciação Celular , Proliferação de Células , Mioblastos/patologia , RNA Interferente Pequeno/genética , Animais , Apoptose , Antígenos CD13/genética , Antígenos CD13/metabolismo , Camundongos , Mioblastos/enzimologia
15.
Anim Sci J ; 91(1): e13452, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32902031

RESUMO

The aim of this study was to examine whether ultrasonography can be used to predict the outcome of clinical mastitis in dairy cows. Forty-seven mastitic quarters of Holstein-Friesian cows were examined using ultrasonography at the time of the first examination. In mastitic mammary tissue, three sonographic signs indicating tissue abnormality were found: a hyperechoic spot in the parenchyma area, structural changes to the milk duct, and non-homogeneous parenchyma. Logistic regression was used to evaluate whether the abnormal findings in the sonographic images can be used to predict the outcome of clinical mastitis. The outcomes of clinical mastitis were defined by the return, or failure to return, to marketable milk production. The sonogram finding of non-homogeneous parenchyma in the first examination did predict the outcome of clinical mastitis, whereas the type of systemic symptoms (severe or moderate) was not a predictor in this regression model. Therefore, ultrasound examinations of mammary glands in the first examination could be a useful method for predicting outcome of clinical mastitis. There is an economic benefit if ultrasound examination in first examination helps in the decision of whether or not to treat the mastitic cows.


Assuntos
Indústria de Laticínios , Glândulas Mamárias Humanas/diagnóstico por imagem , Mastite Bovina/diagnóstico por imagem , Ultrassonografia/veterinária , Animais , Bovinos , Feminino , Humanos , Modelos Logísticos , Tecido Parenquimatoso/diagnóstico por imagem , Valor Preditivo dos Testes , Prognóstico , Ultrassonografia/métodos
16.
Front Cell Dev Biol ; 8: 859, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32984340

RESUMO

The ubiquitin-proteasome system has the capacity to degrade polyubiquitinated proteins and plays an important role in many cellular processes. However, the role of Rpt3, a crucial proteasomal gene, has not been investigated in adult muscles in vivo. Herein, we generated skeletal-muscle-specific Rpt3 knockout mice, in which genetic inactivation of Rpt3 could be induced by doxycycline administration. The Rpt3-knockout mice showed a significant reduction by more than 90% in the expression of Rpt3 in adult muscles. Using this model, we found that proteasome dysfunction in adult muscles resulted in muscle wasting and a decrease in the myofiber size. Immunoblotting analysis showed that the amounts of ubiquitinated proteins were markedly higher in muscles of Rpt3-deficient mice than in those of the control mice. Analysis of the autophagy pathway in the Rpt3-deficient mice showed that the upregulation of LC3II, p62, Atg5, Atg7, and Beclin-1 in protein levels, which supposed to be compensatory proteolysis activation. Our results suggest that the proteasome inhibition in adult muscle severely deteriorates myofiber integrity and results in muscle atrophy.

17.
iScience ; 23(9): 101491, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32891887

RESUMO

C21ORF2 and NEK1 have been identified as amyotrophic lateral sclerosis (ALS)-associated genes. Both genes are also mutated in certain ciliopathies, suggesting that they might contribute to the same signaling pathways. Here we show that FBXO3, the substrate receptor of an SCF ubiquitin ligase complex, binds and ubiquitylates C21ORF2, thereby targeting it for proteasomal degradation. C21ORF2 stabilizes the kinase NEK1, with the result that loss of FBXO3 stabilizes not only C21ORF2 but also NEK1. Conversely, NEK1-mediated phosphorylation stabilizes C21ORF2 by attenuating its interaction with FBXO3. We found that the ALS-associated V58L mutant of C21ORF2 is more susceptible to phosphorylation by NEK1, with the result that it is not ubiquitylated by FBXO3 and therefore accumulates together with NEK1. Expression of C21ORF2(V58L) in motor neurons induced from mouse embryonic stem cells impaired neurite outgrowth. We suggest that inhibition of NEK1 activity is a potential therapeutic approach to ALS associated with C21ORF2 mutation.

18.
Commun Biol ; 3(1): 526, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968195

RESUMO

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Coenzima A Ligases/genética , Genes/genética , Predisposição Genética para Doença/genética , Esclerose Amiotrófica Lateral/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Coenzima A Ligases/fisiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Japão , Masculino , Polimorfismo de Nucleotídeo Único/genética
19.
J Physiol Sci ; 70(1): 40, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938372

RESUMO

Skeletal muscle is one of the most abundant and highly plastic tissues. The ubiquitin-proteasome system (UPS) is recognised as a major intracellular protein degradation system, and its function is important for muscle homeostasis and health. Although UPS plays an essential role in protein degradation during muscle atrophy, leading to the loss of muscle mass and strength, its deficit negatively impacts muscle homeostasis and leads to the occurrence of several pathological phenotypes. A growing number of studies have linked UPS impairment not only to matured muscle fibre degeneration and weakness, but also to muscle stem cells and deficiency in regeneration. Emerging evidence suggests possible links between abnormal UPS regulation and several types of muscle diseases. Therefore, understanding of the role of UPS in skeletal muscle may provide novel therapeutic insights to counteract muscle wasting, and various muscle diseases. In this review, we focussed on the role of proteasomes in skeletal muscle and its regeneration, including a brief explanation of the structure of proteasomes. In addition, we summarised the recent findings on several diseases and elaborated on how the UPS is related to their pathological states.


Assuntos
Proteínas Musculares/metabolismo , Músculo Esquelético/enzimologia , Atrofia Muscular/enzimologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Animais , Homeostase , Humanos , Desenvolvimento Muscular , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Proteólise , Regeneração , Células Satélites de Músculo Esquelético/metabolismo , Células Satélites de Músculo Esquelético/patologia , Ubiquitinação
20.
Brain ; 143(8): 2398-2405, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32770214

RESUMO

Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, or Pick's disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer's disease or Pick's disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Neurônios/metabolismo , Fator de Processamento Associado a PTB/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Proteinopatias TDP-43/metabolismo , Idoso , Esclerose Amiotrófica Lateral/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Degeneração Lobar Frontotemporal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Proteinopatias TDP-43/patologia , Proteínas tau/metabolismo
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