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1.
BMJ Open ; 14(1): e071967, 2024 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-38191256

RESUMO

INTRODUCTION: Long head of biceps brachii tendinopathy (LHBT) is characterised by persistent pain and disability of shoulder joint, impairing patients' quality of life. Extracorporeal shock wave therapy (ESWT) is a non-invasive treatment, which promotes tissue regeneration and repair. However, ESWT has a side effect that often causes short-term pain and swelling in the treatment area. It is known that the effects of Kinesio taping (KT) on relieving swelling and pain. Due to insufficient clinical evidence from current limited studies, this randomised controlled study aims to explore the effects of ESWT combined with KT on upper limb function during individuals with LHBT. METHODS AND ANALYSIS: A 2×2 factorial design, double-blind, randomised controlled trial will be conducted. A total of 144 participants will be randomly allocated into one of four groups (KT+ESWT, KT+sham ESWT, sham KT+ESWT or sham KT+sham ESWT) to participate in a 4-week treatment programme. Measurements will be taken at pretreatment (baseline), immediately after treatment and 6 weeks after treatment. The primary endpoint will be the Constant-Murley score (CMS), the secondary endpoints will include the pain Numerical Rating Scale, range of motion, pressure pain threshold and soft tissue hardness of biceps, speed test and global rating of change. Repeated measures analysis of variance will be used to compare differences among the effects of different interventions. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. In addition to international conference reports, findings will be disseminated through international publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2100051324.


Assuntos
Doenças Musculoesqueléticas , Qualidade de Vida , Humanos , China , Extremidade Superior , Método Duplo-Cego , Dor , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
Food Chem X ; 20: 100927, 2023 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-38144810

RESUMO

The effects of freeze-thawed cycles (FTs) and a new antifreeze protein from Sabina chinensis (Linn.) Ant. cv. Kaizuca leaves (ScAFP) on the structure and physicochemical characteristics of wheat starch were studied. The mechanical breaking exerted by ice crystals on starch granules during FTs gradually deepened, sequentially squeezing the surface (2-6 FTs), amorphous region (8 FTs) and crystalline region (10 FTs) of starch granules. These changes led to reduced thermal stability, increased retrogradation tendency, and weakened gel network structure. The addition of ScAFP retarded the damage of ice crystals on starch granule structure and crystal structure during FTs, and significantly reduced the retrogradation tendency. Compared with native starch, the hardness of freeze-thawed starch without and with added ScAFP after 10 FTs decreased by 17.85% and 9.22%, respectively, indicating ScAFP improved the gel texture properties of freeze-thawed starch. This study provides new strategies for improving the quality of frozen starch-based foods.

3.
J Biomed Res ; 37(6): 460-469, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38018421

RESUMO

ELABELA (ELA), an endogenous ligand of the apelin receptor (also known as apelin peptide jejunum [APJ]), has been shown to decrease in the plasma of patients with diabetic kidney disease (DKD). In the current study, we explored the potential function as well as the underlying mechanisms of ELA in DKD. We first found that the ELA levels were decreased in the kidneys of DKD mice. Then, we found that ELA administration mitigated renal damage and downregulated the expression of fibronectin, collagen Ⅳ, and transforming growth factor-ß1 in the db/db mice and the high glucose cultured HK-2 cells. Furthermore, the autophagy markers, Beclin-1 and LC3-Ⅱ/LC3-Ⅰ ratio, were significantly impaired in DKD, but the ELA treatment reversed these alterations. Mechanistically, the inhibitory effects of ELA on the secretion of fibrosis-associated proteins in high glucose conditions were blocked by pretreatment with 3-methyladenine (an autophagy inhibitor). In summary, these in vivo and in vitro results demonstrate that ELA effectively protects against DKD by activating high glucose-inhibited renal tubular autophagy, potentially serving as a novel therapeutic candidate for DKD.

4.
iScience ; 26(10): 107823, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37744032

RESUMO

Double homeobox (DUX) genes are unique to eutherian mammals, expressed transiently during zygotic genome activation (ZGA) and involved in facioscapulohumeral muscular dystrophy (FSHD) and cancer when misexpressed. We evaluate the 3 human DUX genes and the ancestral single homeobox gene sDUX from the non-eutherian mammal, platypus, and find that DUX4 cytotoxicity is not shared with DUXA or DUXB, but surprisingly is shared with platypus sDUX, which binds DNA as a homodimer and activates numerous ZGA genes and long terminal repeat (LTR) elements. DUXA, although transcriptionally inactive, has DNA binding overlap with DUX4, and DUXA-VP64 activates DUX4 targets and is cytotoxic. DUXA competition antagonizes the activity of DUX4 on its target genes, including in FSHD patient cells. Since DUXA is a DUX4 target gene, this competition potentiates feedback inhibition, constraining the window of DUX4 activity. The DUX gene family therefore comprises antagonistic members of opposing function, with implications for their roles in ZGA, FSHD, and cancer.

5.
Nat Struct Mol Biol ; 30(8): 1153-1159, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37460895

RESUMO

The interbacterial deaminase toxin DddA catalyzes cytosine-to-uracil conversion in double-stranded (ds) DNA and enables CRISPR-free mitochondrial base editing, but the molecular mechanisms underlying its unique substrate selectivity have remained elusive. Here, we report crystal structures of DddA bound to a dsDNA substrate containing the 5'-TC target motif. These structures show that DddA binds to the minor groove of a sharply bent dsDNA and engages the target cytosine extruded from the double helix. DddA Phe1375 intercalates in dsDNA and displaces the 5' (-1) thymine, which in turn replaces the target (0) cytosine and forms a noncanonical T-G base pair with the juxtaposed guanine. This tandem displacement mechanism allows DddA to locate a target cytosine without flipping it into the active site. Biochemical experiments demonstrate that DNA base mismatches enhance the DddA deaminase activity and relax its sequence selectivity. On the basis of the structural information, we further identified DddA mutants that exhibit attenuated activity or altered substrate preference. Our studies may help design new tools useful in genome editing or other applications.


Assuntos
Citosina , DNA , Citosina/metabolismo , Desaminação , Sequência de Bases , DNA/química , Uracila/metabolismo , Citidina Desaminase/genética
7.
PLoS One ; 18(3): e0283323, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36947495

RESUMO

The surface effects on running biomechanics have been greatly investigated. However, the effects on rearfoot strike runners remain unknown. The purpose of this study was to investigate the effects of surfaces on the running kinematics, kinetics, and lower-limb stiffness of habitual rearfoot strikers. Thirty healthy male runners were recruited to run at 3.3 ± 0.2 m/s on a customized runway covered with three different surfaces (artificial grass, synthetic rubber, or concrete), and their running kinematics, kinetics, and lower-limb stiffness were compared. Differences among the three surfaces were examined using statistical parametric mapping and one-way repeated-measure analysis of variance. There were no statistical differences in the lower-limb joint motion, vertical ground reaction force (GRF), loading rates, and lower-limb stiffness when running on the three surfaces. The braking force (17%-36% of the stance phase) and mediolateral GRF were decreased when running on concrete surface compared with running on the other two surfaces. The moments of ankle joint in all three plane movement and frontal plane hip and knee joints were increased when running on concrete surface. Therefore, habitual rearfoot strikers may expose to a higher risk of running-related overuse injuries when running on a harder surface.


Assuntos
, Extremidade Inferior , Masculino , Humanos , Fenômenos Biomecânicos , Articulação do Tornozelo , Articulação do Joelho
8.
Front Bioeng Biotechnol ; 11: 1105248, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36761294

RESUMO

Although tissue engineering offered new approaches to repair bone defects, it remains a great challenge to create a bone-friendly microenvironment and rebuild bone tissue rapidly by a scaffold with a bionic structure. In this study, a multifunctional structurally optimized hydrogel scaffold was designed by integrating polyvinyl alcohol (PVA), gelatin (Gel), and sodium alginate (SA) with aspirin (ASA) and nano-hydroxyapatite (nHAP). The fabrication procedure is through a dual-crosslinking process. The chemical constitution, crystal structure, microstructure, porosity, mechanical strength, swelling and degradation property, and drug-release behavior of the hydrogel scaffold were analyzed. Multi-hydrogen bonds, electrostatic interactions, and strong "egg-shell" structure contributed to the multi-network microstructure, bone tissue-matched properties, and desirable drug-release function of the hydrogel scaffold. The excellent performance in improving cell viability, promoting cell osteogenic differentiation, and regulating the inflammatory microenvironment of the prepared hydrogel scaffold was verified using mouse pre-osteoblasts (MC3T3-E1) cells. And the synergistic osteogenic and anti-inflammatory functions of aspirin and nano-hydroxyapatite were also verified. This study provided valuable insights into the design, fabrication, and biological potential of multifunctional bone tissue engineering materials with the premise of constructing a bone-friendly microenvironment.

9.
bioRxiv ; 2023 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-36711898

RESUMO

Double homeobox (DUX) genes are unique to eutherian mammals and normally expressed transiently during zygotic genome activation. The canonical member, DUX4, is involved in facioscapulohumeral muscular dystrophy (FSHD) and cancer, when misexpressed in other contexts. We evaluate the 3 human DUX genes and the ancestral single homeobox gene sDUX from the non-eutherian mammal, platypus, and find that DUX4 activities are not shared with DUXA or DUXB, which lack transcriptional activation potential, but surprisingly are shared with platypus sDUX. In human myoblasts, platypus sDUX drives cytotoxicity, inhibits myogenesis, and induces DUX4 target genes, particularly those associated with zygotic genome activation (ZGA), by binding DNA as a homodimer in a way that overlaps the DUX4 homeodomain crystal structure. DUXA lacks transcriptional activity but has DNA-binding and chromatin accessibility overlap with DUX4 and sDUX, including on ZGA genes and LTR elements, and can actually be converted into a DUX4-like cytotoxic factor by fusion to a synthetic transactivation domain. DUXA competition antagonizes the activity of DUX4 on its target genes, including in FSHD patient cells. Since DUXA is an early DUX4 target gene, this activity potentiates feedback inhibition, constraining the window of DUX4 activity. The DUX gene family therefore comprises cross-regulating members of opposing function, with implications for their roles in ZGA, FSHD, and cancer. HIGHLIGHTS: Platypus sDUX is toxic and inhibits myogenic differentiation.DUXA targets overlap substantially with those of DUX4.DUXA fused to a synthetic transactivation domain acquires DUX4-like toxicity.DUXA behaves as a competitive inhibitor of DUX4.

10.
Biomed Pharmacother ; 157: 114087, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36481400

RESUMO

BACKGROUND AND OBJECTIVE: Doxorubicin (DOX) is one of the most commonly used antineoplastic agents; however, its considerable nephrotoxicity restricts its clinical use. Kaempferol (KPF), a naturally-occurring flavonoid, possesses various biological benefits, including anti-tumor activity that has garnered increasing attention. This study aimed to evaluate the possible reno-protective role of KPF in DOX nephrotoxicity. METHODS: Male BALB/c mice were injected with DOX via the tail vein to imitate renal damage. Their body and kidney were weighed after 2 weeks of KPF therapy, and urine, serum, and tissue samples were obtained to establish proteinuria, serum creatinine, and pathological alterations. The variations in SOD, GSH, CTA, MDA, and SOD2 expression in renal tissues were measured, and p-ASK1, p-p38, and P-JNK were evaluated by western blot. Cell viability was detected using MTT tests. Apoptosis was assessed by TUNEL, Hoechst 33342, PI staining, and western blot. Fluorescent ROS probes were used to assess oxidative cell damage. RESULTS: KPF ameliorated DOX-induced renal injury, improved proteinuria and renal function, restored GSH content, SOD activity and CTA activity in kidneys, inhibited the overproduction of MDA, and suppressed DOX-induced activation of the MAPK signaling pathway. In NRK-52E cells, KPF significantly inhibited DOX-induced ROS overproduction, restrained the activation of MAPK signaling pathway, and alleviated DOX-induced cell morphological damage and loss of cell viability, While it did not affect the toxicity of DOX to 4T1 cells. CONCLUSION: KPF provides a protective effect against DOX-induced nephrotoxicity while maintaining the cytotoxicity of DOX in breast cancer cells, thereby it may provide a viable solution to lessen renal toxicity in cancer patients receiving DOX.


Assuntos
Doxorrubicina , Quempferóis , Animais , Camundongos , Masculino , Doxorrubicina/farmacologia , Quempferóis/farmacologia , Rim , Transdução de Sinais , Estresse Oxidativo , Apoptose
11.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35165203

RESUMO

High-fidelity replication of the large RNA genome of coronaviruses (CoVs) is mediated by a 3'-to-5' exoribonuclease (ExoN) in nonstructural protein 14 (nsp14), which excises nucleotides including antiviral drugs misincorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and has also been implicated in viral RNA recombination and resistance to innate immunity. Here, we determined a 1.6-Å resolution crystal structure of severe acute respiratory syndrome CoV 2 (SARS-CoV-2) ExoN in complex with its essential cofactor, nsp10. The structure shows a highly basic and concave surface flanking the active site, comprising several Lys residues of nsp14 and the N-terminal amino group of nsp10. Modeling suggests that this basic patch binds to the template strand of double-stranded RNA substrates to position the 3' end of the nascent strand in the ExoN active site, which is corroborated by mutational and computational analyses. We also show that the ExoN activity can rescue a stalled RNA primer poisoned with sofosbuvir and allow RdRp to continue its extension in the presence of the chain-terminating drug, biochemically recapitulating proofreading in SARS-CoV-2 replication. Molecular dynamics simulations further show remarkable flexibility of multidomain nsp14 and suggest that nsp10 stabilizes ExoN for substrate RNA binding to support its exonuclease activity. Our high-resolution structure of the SARS-CoV-2 ExoN-nsp10 complex serves as a platform for future development of anticoronaviral drugs or strategies to attenuate the viral virulence.


Assuntos
Exorribonucleases/química , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Domínios Proteicos , RNA Viral/química , SARS-CoV-2/enzimologia , Proteínas não Estruturais Virais/química , Sítios de Ligação/genética , COVID-19/virologia , Domínio Catalítico , Cristalografia por Raios X , Exorribonucleases/genética , Exorribonucleases/metabolismo , Humanos , Lisina/química , Lisina/genética , Lisina/metabolismo , Mutação de Sentido Incorreto , Ligação Proteica , RNA Viral/genética , RNA Viral/metabolismo , SARS-CoV-2/fisiologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
12.
Nat Commun ; 12(1): 7325, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34916516

RESUMO

Single-domain Variable New Antigen Receptors (VNARs) from the immune system of sharks are the smallest naturally occurring binding domains found in nature. Possessing flexible paratopes that can recognize protein motifs inaccessible to classical antibodies, VNARs have yet to be exploited for the development of SARS-CoV-2 therapeutics. Here, we detail the identification of a series of VNARs from a VNAR phage display library screened against the SARS-CoV-2 receptor binding domain (RBD). The ability of the VNARs to neutralize pseudotype and authentic live SARS-CoV-2 virus rivalled or exceeded that of full-length immunoglobulins and other single-domain antibodies. Crystallographic analysis of two VNARs found that they recognized separate epitopes on the RBD and had distinctly different mechanisms of virus neutralization unique to VNARs. Structural and biochemical data suggest that VNARs would be effective therapeutic agents against emerging SARS-CoV-2 mutants, including the Delta variant, and coronaviruses across multiple phylogenetic lineages. This study highlights the utility of VNARs as effective therapeutics against coronaviruses and may serve as a critical milestone for nearing a paradigm shift of the greater biologic landscape.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Cristalografia por Raios X , Receptores de Antígenos/química , Receptores de Antígenos/imunologia , Tubarões/imunologia , Enzima de Conversão de Angiotensina 2 , Animais , COVID-19 , Epitopos , Mutação , Filogenia , Ligação Proteica , SARS-CoV-2 , Alinhamento de Sequência , Anticorpos de Domínio Único , Glicoproteína da Espícula de Coronavírus/imunologia
13.
Acta Bioeng Biomech ; 23(2): 73-80, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34846369

RESUMO

PURPOSE: Sports surface is one of the known external factors affecting running performance and injury. To date, we have found no study that examined the lower extremity stiffness in habitual forefoot strikers running on different overground surfaces. Therefore, the objective of this study was to investigate lower extremity stiffness and relevant kinematic adjustments in habitual forefoot strikers while running on different surfaces. METHODS: Thirty-one male habitual forefoot strikers were recruited in this study. Runners were instructed to run at a speed of 3.3 m/s (±5%) on three surfaces, named synthetic rubber, concrete, and artificial grass. RESULTS: No significant differences were found in leg stiffness, vertical stiffness, and joint stiffness in the sagittal plane during running on the three surfaces ( p > 0.05). Running on artificial grass exerted a greater displacement in knee joint angle than running on synthetic rubber ( p = 0.002, 95% CI = 1.52-7.35 degrees) and concrete ( p = 0.006, 95% CI = 1.04-7.25 degrees). In the sagittal plane, peak knee moment was lower on concrete than on artificial grass ( p = 0.003, 95% CI = 0.11-0.58 Nm/kg), whereas peak ankle moment was lower on synthetic rubber than on concrete ( p < 0.001, 95% CI = 0.03-0.07 Nm/kg) and on artificial grass ( p < 0.001, 95% CI = 0.02-0.06 Nm/kg). Among the three surfaces, the maximal ground reaction forces on concrete were the lowest ( p < 0.05). CONCLUSIONS: This study indicated that running surfaces cannot influence lower extremity stiffness in habitual forefoot strikers at current running speed. Kinematic adjustments of knee and ankle, as well as ground reaction forces, may contribute to maintaining similar lower extremity stiffness.


Assuntos
Tornozelo , , Articulação do Tornozelo , Fenômenos Biomecânicos , Humanos , Articulação do Joelho , Extremidade Inferior , Masculino
14.
Technol Cancer Res Treat ; 20: 15330338211033059, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34318731

RESUMO

Intratumor heterogeneity is partly responsible for the poor prognosis of glioblastoma (GBM) patients. In this study, we aimed to assess the effect of different heterogeneous subregions of GBM on overall survival (OS) stratification. A total of 105 GBM patients were retrospectively enrolled and divided into long-term and short-term OS groups. Four MRI sequences, including contrast-enhanced T1-weighted imaging (T1C), T1, T2, and FLAIR, were collected for each patient. Then, 4 heterogeneous subregions, i.e. the region of entire abnormality (rEA), the regions of contrast-enhanced tumor (rCET), necrosis (rNec) and edema/non-contrast-enhanced tumor (rE/nCET), were manually drawn from the 4 MRI sequences. For each subregion, 50 radiomics features were extracted. The stratification performance of 4 heterogeneous subregions, as well as the performances of 4 MRI sequences, was evaluated both alone and in combination. Our results showed that rEA was superior in stratifying long-and short-term OS. For the 4 MRI sequences used in this study, the FLAIR sequence demonstrated the best performance of survival stratification based on the manual delineation of heterogeneous subregions. Our results suggest that heterogeneous subregions of GBMs contain different prognostic information, which should be considered when investigating survival stratification in patients with GBM.


Assuntos
Glioblastoma/diagnóstico , Glioblastoma/mortalidade , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Bases de Dados Factuais , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Adulto Jovem
15.
bioRxiv ; 2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33821277

RESUMO

High-fidelity replication of the large RNA genome of coronaviruses (CoVs) is mediated by a 3'-to-5' exoribonuclease (ExoN) in non-structural protein 14 (nsp14), which excises nucleotides including antiviral drugs mis-incorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and has also been implicated in viral RNA recombination and resistance to innate immunity. Here we determined a 1.6-Å resolution crystal structure of SARS-CoV-2 ExoN in complex with its essential co-factor, nsp10. The structure shows a highly basic and concave surface flanking the active site, comprising several Lys residues of nsp14 and the N-terminal amino group of nsp10. Modeling suggests that this basic patch binds to the template strand of double-stranded RNA substrates to position the 3' end of the nascent strand in the ExoN active site, which is corroborated by mutational and computational analyses. Molecular dynamics simulations further show remarkable flexibility of multi-domain nsp14 and suggest that nsp10 stabilizes ExoN for substrate RNA-binding to support its exoribonuclease activity. Our high-resolution structure of the SARS-CoV-2 ExoN-nsp10 complex serves as a platform for future development of anti-coronaviral drugs or strategies to attenuate the viral virulence.

16.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33658373

RESUMO

Spontaneous deamination of DNA cytosine and adenine into uracil and hypoxanthine, respectively, causes C to T and A to G transition mutations if left unrepaired. Endonuclease Q (EndoQ) initiates the repair of these premutagenic DNA lesions in prokaryotes by cleaving the phosphodiester backbone 5' of either uracil or hypoxanthine bases or an apurinic/apyrimidinic (AP) lesion generated by the excision of these damaged bases. To understand how EndoQ achieves selectivity toward these structurally diverse substrates without cleaving undamaged DNA, we determined the crystal structures of Pyrococcus furiosus EndoQ bound to DNA substrates containing uracil, hypoxanthine, or an AP lesion. The structures show that substrate engagement by EndoQ depends both on a highly distorted conformation of the DNA backbone, in which the target nucleotide is extruded out of the helix, and direct hydrogen bonds with the deaminated bases. A concerted swing motion of the zinc-binding and C-terminal helical domains of EndoQ toward its catalytic domain allows the enzyme to clamp down on a sharply bent DNA substrate, shaping a deep active-site pocket that accommodates the extruded deaminated base. Within this pocket, uracil and hypoxanthine bases interact with distinct sets of amino acid residues, with positioning mediated by an essential magnesium ion. The EndoQ-DNA complex structures reveal a unique mode of damaged DNA recognition and provide mechanistic insights into the initial step of DNA damage repair by the alternative excision repair pathway. Furthermore, we demonstrate that the unique activity of EndoQ is useful for studying DNA deamination and repair in mammalian systems.


Assuntos
Proteínas Arqueais/química , DNA Arqueal/química , Endonucleases/química , Pyrococcus furiosus/enzimologia , Proteínas Arqueais/genética , Domínio Catalítico , DNA Arqueal/genética , Desaminação , Endonucleases/genética , Pyrococcus furiosus/genética
17.
Nat Commun ; 12(1): 1626, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712616

RESUMO

Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.


Assuntos
Alelos , Cardiomiopatias/genética , Proteínas de Manutenção de Minicromossomo/genética , Proteínas de Manutenção de Minicromossomo/imunologia , Encurtamento do Telômero , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Replicação do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endonucleases/genética , Endonucleases/metabolismo , Humanos , Células Matadoras Naturais
18.
Front Physiol ; 12: 786584, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34975539

RESUMO

Background: The purpose of the study was to determine the effect of kinesiology tape (KT) on lower limb muscle activation during computerized dynamic posturography (CDP) tasks and ankle kinesthesia in individuals with chronic ankle instability (CAI). Methods: Thirty-five men with CAI participated in this study. The experimental procedure followed a repeated measures design. Muscle activation of lower extremity and ankle kinesthesia of participants were measured using four taping treatments, namely, KT, athletic tape (AT), sham tape (ST), and no tape (NT) in a randomized order. Muscle activation was assessed using surface electromyography (sEMG) synchronized with CDP tests from seven lower extremity muscles of the unstable limb. Ankle kinesthesia was measured by using a threshold to detect the passive motion direction of the unstable ankle. Parameters were analyzed by using a one-way repeated measures ANOVA and followed by pairwise comparisons with a Bonferroni correction. Results: No significant difference was observed among different taping treatments for the majority of parameters during CDP. Except for condition 4 with open eyes, sway-referenced surface, and fixed surround in the sensory organization test (SOT), gastrocnemius medialis root mean square (RMS) was 28.19% lower in AT compared with NT (p = 0.021, 95% CI = 0.002-0.039), while gastrocnemius lateralis RMS was 20.25% lower in AT compared with KT (p = 0.038, 95% CI = 0.000-0.021). In forward-small sudden translation from motor control test (MCT), for peroneal longus (PL), RMS was 24.04% lower in KT compared with ST (p = 0.036, 95% CI = 0.000-0.018). In toes-down sudden rotation from adaption test (ADT), for PL, RMS was 23.41% lower in AT compared with ST (p = 0.015, 95% CI = 0.002-0.027). In addition, no significant difference was observed for a threshold to the detection of passive motion direction among different taping treatments. Conclusion: This study indicated that KT had minimal effect on the muscle activation of the unstable lower limb during static stance, self-initiated, and externally triggered perturbation tasks from CDP and ankle kinesthesia among individuals with CAI, suggesting that the benefit of KT was too small to be clinically worthwhile during application for CAI.

19.
Appl Bionics Biomech ; 2020: 8866340, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299469

RESUMO

Foot strike patterns influence the running efficiency and may be an injury risk. However, differences in the leg stiffness between runners with habitual forefoot (hFFS) and habitual rearfoot (hRFS) strike patterns remain unclear. This study aimed at determining the differences in the stiffness, associated loading rate, and kinematic performance between runners with hFFS and hRFS during running. Kinematic and kinetic data were collected amongst 39 runners with hFFS and 39 runners with hRFS running at speed of 3.3 m/s, leg stiffness (Kleg), and vertical stiffness (Kvert), and impact loads were calculated. Results found that runners with hFFS had greater Kleg (P = 0.010, Cohen's d = 0.60), greater peak vertical ground reaction force (vGRF) (P = 0.040, Cohen's d = 0.47), shorter contact time(t c ) (P < 0.001, Cohen's d = 0.85), and smaller maximum leg compression (ΔL ) (P = 0.002, Cohen's d = 0.72) compared with their hRFS counterparts. Runners with hFFS had lower impact peak (IP) (P < 0.001, Cohen's d = 1.65), vertical average loading rate (VALR) (P < 0.001, Cohen's d = 1.20), and vertical instantaneous loading rate (VILR) (P < 0.001, Cohen's d = 1.14) compared with runners with hRFS. Runners with hFFS landed with a plantar flexed ankle, whereas runners with hRFS landed with a dorsiflexed ankle (P < 0.001, Cohen's d = 3.35). Runners with hFFS also exhibited more flexed hip (P = 0.020, Cohen's d = 0.61) and knee (P < 0.001, Cohen's d = 1.15) than runners with hRFS at initial contact. These results might indicate that runners with hFFS were associated with better running economy through the transmission of elastic energy.

20.
Front Physiol ; 11: 596159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33281628

RESUMO

OBJECTIVE: Previous studies made controversial claims about the alleged effects of Kinesio taping (KT) on pain relief. To date, the mechanism by which KT relieves pain remains unclear. Moreover, pain evaluation lacks objective and quantitative parameters. This study compared the acute effects of different KT interventions on the local thresholds of pressure pain and current perception in healthy adults to determine the potential mechanisms by which KT relieves pain. METHODS: Thirty healthy female subjects randomly received four KT interventions, namely, no taping (NT), placebo taping (PT), Y strips of KT (KY), and fan strips of KT (KF), on the waist. Current perception threshold (CPT), pressure pain threshold (PPT), soft tissue hardness, and the visual analog scale (VAS) scores of the subjects' perceived pain were immediately measured after taping. Repeated-measures ANOVA was performed to determine significant differences in these parameters among the four interventions. RESULTS: Significant differences in CPT values among the interventions were observed at the frequency of 5 Hz (F = 3.499, p = 0.019, η p 2 = 0.111). Post hoc analysis revealed that CPT was significantly higher for KF than for NT (p = 0.008, 95% CI = 1.390-11.990). Significant differences in PPT values (F = 4.352, p = 0.012, η p 2 = 0.130) and soft tissue hardness (F = 2.957, p = 0.049, η p 2 = 0.093) were observed among the different taping conditions. Post hoc analysis revealed that PPT was significantly higher for KF than for PT (p = 0.011, 95% CI = 0.071-0.749), and soft tissue hardness was significantly higher for KF than for NT (p = 0.010, 95% CI = 0.461-4.586) and KY (p = 0.040, 95% CI = 0.059-3.800). No significant differences in self-perceived pain among the interventions were observed. CONCLUSION: The healthy adult females had higher PPT values, lower soft tissue hardness, and higher CPT values at 5 Hz under KF intervention applied on the waist than those under the other taping interventions. Moreover, the different taping conditions had no significant differences in terms of VAS of perceived pain. These results provide guidance for the application of KT on pain management.

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