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1.
Bioact Mater ; 40: 148-167, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38962659

RESUMO

Implant-associated Staphylococcus aureus (S. aureus) osteomyelitis is a severe challenge in orthopedics. While antibiotic-loaded bone cement is a standardized therapeutic approach for S. aureus osteomyelitis, it falls short in eradicating Staphylococcus abscess communities (SACs) and bacteria within osteocyte-lacuna canalicular network (OLCN) and repairing bone defects. To address limitations, we developed a borosilicate bioactive glass (BSG) combined with ferroferric oxide (Fe3O4) magnetic scaffold to enhance antibacterial efficacy and bone repair capabilities. We conducted comprehensive assessments of the osteoinductive, immunomodulatory, antibacterial properties, and thermal response of this scaffold, with or without an alternating magnetic field (AMF). Utilizing a well-established implant-related S. aureus tibial infection rabbit model, we evaluated its antibacterial performance in vivo. RNA transcriptome sequencing demonstrated that BSG + 5%Fe3O4 enhanced the immune response to bacteria and promoted osteogenic differentiation and mineralization of MSCs. Notably, BSG + 5%Fe3O4 upregulated gene expression of NOD-like receptor and TNF pathway in MSCs, alongside increased the expression of osteogenic factors (RUNX2, ALP and OCN) in vitro. Flow cytometry on macrophage exhibited a polarization effect towards M2, accompanied by upregulation of anti-inflammatory genes (TGF-ß1 and IL-1Ra) and downregulation of pro-inflammatory genes (IL-6 and IL-1ß) among macrophages. In vivo CT imaging revealed the absence of osteolysis and periosteal response in rabbits treated with BSG + 5%Fe3O4 + AMF at 42 days. Histological analysis indicated complete controls of SACs and bacteria within OLCN by day 42, along with new bone formation, signifying effective control of S. aureus osteomyelitis. Further investigations will focus on the in vivo biosafety and biological mechanism of this scaffold within infectious microenvironment.

2.
Nat Hum Behav ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956227

RESUMO

Suicide is a global public health challenge, yet considerable uncertainty remains regarding the associations of both behaviour-related and physiological factors with suicide attempts (SA). Here we first estimated polygenic risk scores (PRS) for SA in 334,706 UK Biobank participants and conducted phenome-wide association analyses considering 2,291 factors. We identified 246 (63.07%) behaviour-related and 200 (10.41%, encompassing neuroimaging, blood and metabolic biomarkers, and proteins) physiological factors significantly associated with SA-PRS, with robust associations observed in lifestyle factors and mental health. Further case-control analyses involving 3,558 SA cases and 149,976 controls mirrored behaviour-related associations observed with SA-PRS. Moreover, Mendelian randomization analyses supported a potential causal effect of liability to 58 factors on SA, such as age at first intercourse, neuroticism, smoking, overall health rating and depression. Notably, machine-learning classification models based on behaviour-related factors exhibited high discriminative accuracy in distinguishing those with and without SA (area under the receiver operating characteristic curve 0.909 ± 0.006). This study provides comprehensive insights into diverse risk factors for SA, shedding light on potential avenues for targeted prevention and intervention strategies.

3.
Transl Psychiatry ; 14(1): 270, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956035

RESUMO

Brain function is vulnerable to the consequences of inadequate sleep, an adverse trend that is increasingly prevalent. The REM sleep phase has been implicated in coordinating various brain structures and is hypothesized to have potential links to brain variability. However, traditional imaging research have encountered challenges in attributing specific brain region activity to REM sleep, remained understudied at the whole-brain connectivity level. Through the spilt-night paradigm, distinct patterns of REM sleep phases were observed among the full-night sleep group (n = 36), the early-night deprivation group (n = 41), and the late-night deprivation group (n = 36). We employed connectome-based predictive modeling (CPM) to delineate the effects of REM sleep deprivation on the functional connectivity of the brain (REM connectome) during its resting state. The REM sleep-brain connectome was characterized by stronger connectivity within the default mode network (DMN) and between the DMN and visual networks, while fewer predictive edges were observed. Notably, connections such as those between the cingulo-opercular network (CON) and the auditory network, as well as between the subcortex and visual networks, also made significant contributions. These findings elucidate the neural signatures of REM sleep loss and reveal common connectivity patterns across individuals, validated at the group level.


Assuntos
Encéfalo , Conectoma , Imageamento por Ressonância Magnética , Privação do Sono , Sono REM , Humanos , Masculino , Privação do Sono/fisiopatologia , Privação do Sono/diagnóstico por imagem , Sono REM/fisiologia , Feminino , Adulto , Encéfalo/fisiopatologia , Encéfalo/diagnóstico por imagem , Adulto Jovem , Rede Nervosa/fisiopatologia , Rede Nervosa/diagnóstico por imagem , Rede de Modo Padrão/diagnóstico por imagem , Rede de Modo Padrão/fisiopatologia
4.
Nat Med ; 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992123

RESUMO

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .

5.
Rev Sci Instrum ; 95(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38980133

RESUMO

In this paper, a long-stroke parallel compliant tip-tilt-piston micropositioning stage driven by voice coil motors (VCMs) is proposed. The stage is equipped with three sets of driving arms, which include a spherical hinge, VCM, and parallelogram guide mechanism, evenly spaced at 120° intervals. The spherical hinge is composed of orthogonal leaf-spring beams, and the VCM is embedded into the parallelogram mechanism to form a compact design. The compliance matrix method and the geometric method facilitated the determination of compliance in all six degree-of-freedom directions of the spherical hinge and the derivation of kinematic equations for decoupling the motion of the stage. In addition, finite element analysis was utilized to determine the maximum stroke and stress of the stage. To validate the proposed design, a stage prototype was constructed and subjected to experimental testing. Furthermore, a feedback controller was designed, integrating proportional integral controller, notch filter, and sliding mode controller feedforward. The experimental results indicate that the stage can achieve a long stroke of ±50.75 mrad × ±44.2 mrad × ±4.425 mm, with the natural frequencies in the three-axis direction of 22.3 × 25.5 × 25.5 Hz3. In addition, the maximum relative tracking error was maintained below 5.25%, highlighting the effectiveness of the control technique in achieving a high tracking performance.

6.
J Sports Sci Med ; 23(2): 465-474, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38841634

RESUMO

This study aimed to identify the optimal surface for sprint interval training to maximize transfer effects on physical performance measures on the grass pitch. Using a randomized controlled trial design, 40 collegiate female soccer players were equally assigned to three experimental groups performing short sprint interval training (SSIT: 4 sets of 10 repetitions with 5 seconds all-out running, with a 50-second recovery period between each effort and a 3-minute rest interval between sets) on SAND, GRASS, LAND, and a control group. Before and after a 7-week training period, participants underwent a series of field-based tests to evaluate countermovement jump (CMJ), 20-m linear sprint, Illinois change of direction (CoD) speed, Yo-Yo IR1, 2.4 km time trial, and maximal kicking distance (MKD) performance. A two-way analysis of variance with repeated measures was conducted on the data, along with Bonferroni post hoc testing. After the intervention, the control group did not show any changes, while the SAND, GRASS and LAND training groups demonstrated improvements (p = 0.001) in their performance as follows: CMJ (effect size [ES] = 1.21, 0.97, 0.64), 20-m linear sprint (ES = -0.81, -0.55, -0.41), Illinois CoD (ES = -0.72, -0.79, -0.41), Yo-Yo IR1 (ES = 1.86, 1.19, 1.12), 2.4 km time trail (ES = -0.82, -0.62, -0.49), and MKD (ES = 0.60, 0.90, 0.72), respectively. Comparative analysis of SAND, GRASS, and LAND revealed that performing SSIT on SAND results in a significantly greater gain in CMJ than LAND (p = 0.041). Analyzing individual responses to training interventions indicated that the training surface had a favorable influence on CMJ (SAND vs. LAND, p = 0.009), but on other variables no statistically significant (p > 0.05) differences were observed. Considering these findings, it is advised that strength and conditioning coaches use the SAND surface as the initial choice for SSIT sessions regarding greater gains (i.e., ES) in performance. This recommendation aims to facilitate more favorable transfer in physical fitness adaptation on a soccer grass pitch. In case of unavailability of SAND surface, GRASS surface would be a suitable alternative to enhance the physical fitness of collegiate female soccer players.


Assuntos
Desempenho Atlético , Aptidão Física , Poaceae , Corrida , Futebol , Humanos , Futebol/fisiologia , Feminino , Desempenho Atlético/fisiologia , Aptidão Física/fisiologia , Adulto Jovem , Corrida/fisiologia , Areia , Treinamento Intervalado de Alta Intensidade/métodos , Teste de Esforço
7.
BMC Musculoskelet Disord ; 25(1): 479, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890706

RESUMO

BACKGROUND: This work aimed to investigate the change in fingerprint depth and the recovery rule of fingerprint biological recognition function after repairing finger abdominal defects and rebuilding fingerprint with a free flap. METHOD: From April 2018 to March 2023, we collected a total of 43 cases of repairing finger pulp defects using the free flap of the fibular side of the great toe with the digital nerve. After surgery, irregular follow-up visits were conducted to observe fingerprint clarity, perform the ninhydrin test or detect visible sweating with the naked eye. We recorded fingerprint clarity, nail shape, two-point discrimination, cold perception, warm perception and fingerprint recognition using smartphones. The reconstruction process of the repaired finger was recorded to understand the changes in various observation indicators and their relationship with the depth of the fingerprint. The correlation between fingerprint depth and neural repair was determined, and the process of fingerprint biological recognition function repair was elucidated. RESULT: All flaps survived, and we observed various manifestations in different stages of nerve recovery. The reconstructed fingerprint had a clear fuzzy process, and the depth changes of the fingerprint were consistent with the changes in the biological recognition function curve. CONCLUSION: The free flap with the digital nerve is used to repair finger pulp defects. The reconstructed fingerprint has a biological recognition function, and the depth of the fingerprint is correlated with the process of nerve repair. The fingerprint morphology has a dynamic recovery process, and it can reach a stable state after 6-8 months.


Assuntos
Traumatismos dos Dedos , Retalhos de Tecido Biológico , Lesões dos Tecidos Moles , Humanos , Masculino , Feminino , Adulto , Retalhos de Tecido Biológico/transplante , Retalhos de Tecido Biológico/inervação , Pessoa de Meia-Idade , Traumatismos dos Dedos/cirurgia , Lesões dos Tecidos Moles/cirurgia , Adulto Jovem , Recuperação de Função Fisiológica , Procedimentos de Cirurgia Plástica/métodos , Dedos do Pé/cirurgia , Dedos do Pé/inervação , Dedos/inervação , Dedos/cirurgia , Resultado do Tratamento , Fíbula/transplante , Fíbula/cirurgia , Adolescente , Idoso
8.
PLoS One ; 19(6): e0296140, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38900759

RESUMO

Implant-associated osteomyelitis remains a major orthopaedic problem. As neutrophil swarming to the surgical site is a critical host response to prevent infection, visualization and quantification of this dynamic behavior at the native microenvironment of infection will elucidate previously unrecognized mechanisms central to understanding the host response. We recently developed longitudinal intravital imaging of the bone marrow (LIMB) to visualize host cells and fluorescent S. aureus on a contaminated transfemoral implant in live mice, which allows for direct visualization of bacteria colonization of the implant and host cellular responses using two-photon laser scanning microscopy. To the end of rigorous and reproducible quantitative outcomes of neutrophil swarming kinetics in this model, we developed a protocol for robust segmentation, tracking, and quantifications of neutrophil dynamics adapted from Trainable Weka Segmentation and TrackMate, two readily available Fiji/ImageJ plugins. In this work, Catchup mice with tdTomato expressing neutrophils received a transfemoral pin with or without ECFP/EGFP-expressing USA300 methicillin-resistant Staphylococcus aureus (MRSA) to obtain 30-minute LIMB videos at 2-, 4-, and 6-hours post-implantation. The developed semi-automated neutrophil tracking protocol was executed independently by two users to quantify the distance, displacement, speed, velocity, and directionality of the target cells. The results revealed high inter-user reliability for all outcomes (ICC > 0.96; p > 0.05). Consistent with the established paradigm on increased neutrophil swarming during active infection, the results also demonstrated increased neutrophil speed and velocity at all measured time points, and increased displacement at later time points (6 hours) in infected versus uninfected mice (p < 0.05). Neutrophils and bacteria also exhibit directionality during migration in the infected mice. The semi-automated cell tracking protocol provides a streamlined approach to robustly identify and track individual cells across diverse experimental settings and eliminates inter-observer variability.


Assuntos
Rastreamento de Células , Fêmur , Neutrófilos , Animais , Neutrófilos/imunologia , Camundongos , Fêmur/microbiologia , Rastreamento de Células/métodos , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/imunologia , Modelos Animais de Doenças , Osteomielite/microbiologia , Staphylococcus aureus Resistente à Meticilina/fisiologia , Infecções Relacionadas à Prótese/microbiologia , Próteses e Implantes/microbiologia , Staphylococcus aureus/fisiologia , Feminino
9.
Eur J Pharmacol ; 975: 176668, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38788791

RESUMO

Tartaric acid (TA) has been shown beneficial effects on blood pressure and lipid levels. However, its effect on non-alcoholic fatty liver disease (NAFLD) remains unknown. This study aimed to investigate the role of TA in experimental NAFLD. Mice were fed a Western diet for 8 weeks, followed by administration of TA or a vehicle for an additional 12 weeks while continuing on the Western diet. Blood biochemistry including transaminases and glucose tolerance test and liver tissue RNA sequencing (RNA-seq), lipid content, and histology were investigated. The HepG2 cell line was used to explore the mechanism by which TA regulates lipid metabolism. We found that TA significantly improved weight gain, insulin resistance, hepatic steatosis, inflammation and fibrosis in Western diet-fed mice. By comparing gene expression differences, we found that TA affects pathways related to lipid metabolism, inflammatory response, and fibrosis. Furthermore, TA effectively reduced oleic acid-induced lipid accumulation in HepG2 cells and downregulated the genes associated with fatty acid synthesis, which were enriched in the AMP-activated protein kinase (AMPK) signaling pathway. TA also enhanced the phosphorylation of AMPK which could be reverted by the AMPK inhibitor Compound C in HepG2 cells. Our study suggests that TA improves experimental NAFLD by activating the AMPK signaling pathway. These findings indicate that TA may serve as a potential therapy for the human NAFLD.


Assuntos
Proteínas Quinases Ativadas por AMP , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Transdução de Sinais , Tartaratos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Humanos , Células Hep G2 , Proteínas Quinases Ativadas por AMP/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Camundongos , Tartaratos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Modelos Animais de Doenças
10.
Microbiol Spectr ; 12(6): e0009624, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38695572

RESUMO

Pseudomonas can lead to peritoneal dialysis-associated peritonitis, which is characterized by a poor prognosis, such as a substantial failure rate and a high death rate. This study aimed to provide an overview of Pseudomonas peritonitis's clinical features, the regimens of antibiotic, antibiotic resistance, and outcomes in peritoneal dialysis (PD) patients. This study observed patients with Pseudomonas peritonitis in two large PD centers in South China from January 2008 to December 2022. The demographics, symptomatology, antibiotics regimens, resistance to common antibiotics, and clinical outcomes of all included patients were reviewed. A total of 3,459 PD patients were included, among them 57 cases of peritonitis caused by Pseudomonas, including 48 cases (84.2%) of Pseudomonas aeruginosa. The incidence rate of Pseudomonas peritonitis was 0.0041 episode per patient-year. Of them, 28.1% (16 cases) of the patients were accompanied by exit site infection (ESI), and all had abdominal pain and turbid ascites at the time of onset. The most commonly used antibiotic combination was ceftazidime combined with amikacin. Approximately 89% of Pseudomonas species were sensitive to ceftazidime, and 88% were sensitive to amikacin. The overall primary response rate was 28.1% (16 patients), and the complete cure rate was 40.4% (23 patients). There was no significant difference in the complete cure rate of peritonitis using three and other antibiotic treatment regimens (44.8% vs 46.4%; P = 0.9). The successful treatment group had higher baseline albumin level (35.9 ± 6.2; P = 0.008) and residual urine volume (650.7 ± 375.5; P = 0.04). Although the incidence of peritonitis caused by Pseudomonas was low, the symptoms were serious, and prognosis was very poor. Pseudomonas was still highly susceptible to first-line antibiotics currently in use against Gram-negative bacteria. Patients with successful treatment had higher albumin levels and higher urine output. IMPORTANCE: Although the incidence of peritoneal dialysis-associated peritonitis caused by Pseudomonas is very low, it seriously affects the technique survival of peritoneal dialysis patients. However, there are few studies and reports on Pseudomonas peritonitis in the Chinese mainland area. Therefore, the purpose of this study is to describe the clinical characteristics, the regimens of antibiotic, drug resistance, and outcome of peritoneal dialysis patients in southern China in the past 15 years and summarize the clinical experience in the treatment of Pseudomonas peritonitis.


Assuntos
Antibacterianos , Diálise Peritoneal , Peritonite , Infecções por Pseudomonas , Pseudomonas , Humanos , Peritonite/tratamento farmacológico , Peritonite/microbiologia , Peritonite/epidemiologia , Antibacterianos/uso terapêutico , China/epidemiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/epidemiologia , Diálise Peritoneal/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Pseudomonas/efeitos dos fármacos , Pseudomonas/isolamento & purificação , Adulto , Pseudomonas aeruginosa/efeitos dos fármacos , Estudos Retrospectivos , Ceftazidima/uso terapêutico , Testes de Sensibilidade Microbiana , Amicacina/uso terapêutico
11.
Int J Biol Macromol ; 270(Pt 2): 132029, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38704064

RESUMO

Cuproptosis affects osteosarcoma locally, and the exploitation of cuproptosis-related biomaterials for osteosarcoma treatment is still in its infancy. We designed and synthesized a novel injectable gel of Cu ion-coordinated Tremella fuciformis polysaccharide (TFP-Cu) for antiosteosarcoma therapy. This material has antitumor effects, the ability to stimulate immunity and promote bone formation, and a controlled Cu2+ release profile in smart response to tumor microenvironment stimulation. TFP-Cu can selectively inhibit the proliferation of K7M2 tumor cells by arresting the cell cycle and promoting cell apoptosis and cuproptosis. TFP-Cu also promoted the M1 polarization of RAW264.7 cells and regulated the immune microenvironment. These effects increased osteogenic gene and protein expression in MC3T3-E1 cells. TFP-Cu could significantly limit tumor growth in tumor-bearing mice by inducing tumor cell apoptosis and improving the activation of anti-CD8 T cell-mediated immune responses. Therefore, TFP-Cu could be a potential candidate for treating osteosarcoma and bioactive drug carrier for further cancer-related applications.


Assuntos
Apoptose , Cobre , Osteossarcoma , Microambiente Tumoral , Animais , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Cobre/química , Cobre/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Basidiomycota/química , Células RAW 264.7 , Géis/química , Polissacarídeos/farmacologia , Polissacarídeos/química , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Polissacarídeos Fúngicos/farmacologia , Polissacarídeos Fúngicos/química
12.
Water Res ; 258: 121817, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38810598

RESUMO

Electrochemical uranium extraction (EUE) from seawater is a very promising strategy, but its practical application is hindered by the high potential for electrochemical system, as well as the low selectivity, efficiency, and poor stability of electrode. Herein, we developed creatively a low potential strategy for persistent uranium recovery by electrochemistry-assisted in-situ regeneration of oxygen vacancies and Ti(III) active sites coupled with indirect reduction of uranium, finally achieving high selectivity, efficient and persistent uranium recovery. As-designed titanium dioxide rich in oxygen vacancies (TiO2-VO) electrode displayed an EUE efficiency of ∼99.9 % within 180 min at a low potential of 0.09 V in simulated seawater with uranium of 5∼20 ppm. Moreover, the TiO2-VO electrode also showed high selectivity (89.9 %) to uranium, long-term cycling stability and antifouling activity in natural seawater. The excellent EUE property was attributed to the fact that electrochemistry-assisted in-situ regeneration of oxygen vacancies and Ti(III) active sites enhanced EUE cycling process and achieved persistent uranium recovery. The continuous regeneration of oxygen vacancies not only reduced the adsorption energy of U(VI)O22+ but also serve as a storage and transportation channel for electrons, accelerating electron transfer from Ti(III) to U(VI) at solid-liquid interface and promoting EUE kinetic rate.


Assuntos
Oxigênio , Água do Mar , Titânio , Urânio , Urânio/química , Titânio/química , Oxigênio/química , Água do Mar/química , Eletrodos , Eletroquímica , Técnicas Eletroquímicas , Poluentes Radioativos da Água/química
13.
EMBO J ; 43(13): 2606-2635, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38806659

RESUMO

Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Cílios , Cinesinas , Neuroglia , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Cinesinas/metabolismo , Cinesinas/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Neuroglia/metabolismo , Cílios/metabolismo , Neurônios/metabolismo , Mutação , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia
14.
Cell ; 187(10): 2521-2535.e21, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38697107

RESUMO

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.


Assuntos
Imunoterapia , Lipídeos , RNA , Microambiente Tumoral , Animais , Cães , Feminino , Humanos , Camundongos , Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Glioblastoma/terapia , Glioblastoma/imunologia , Glioma/terapia , Glioma/imunologia , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Neoplasias/imunologia , RNA/química , RNA/uso terapêutico , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Lipídeos/química
15.
J Headache Pain ; 25(1): 67, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38679721

RESUMO

BACKGROUND: Acupuncture showed better improvement than sham acupuncture in reducing attack frequency of tension-type headache (TTH), but its effectiveness relative to first-line drugs for TTH is unknown, which impedes the recommendation of acupuncture for patients who are intolerant to drugs for TTH. We aimed to estimate the relative effectiveness between acupuncture and tricyclic antidepressants (TCAs) through indirect treatment comparison (ITC) meta-analysis. METHODS: We searched Ovid Medline, Embase, and Cochrane Library from database inception until April 13, 2023. Randomized controlled trials of TCAs or acupuncture in the prevention of TTH in adults were included. The primary outcome was headache frequency. The secondary outcomes were headache intensity, responder rate, and adverse event rate. Bayesian random-effect models were used to perform ITC meta-analysis, and confidence of evidence was evaluated by using the GRADE approach. RESULTS: A total of 34 trials involving 4426 participants were included. Acupuncture had similar effect with TCAs in decreasing TTH frequency (amitriptyline: mean difference [MD] -1.29, 95% CI -5.28 to 3.02; amitriptylinoxide: MD -0.05, 95% CI -6.86 to 7.06) and reducing TTH intensity (amitriptyline: MD 2.35, 95% CI -1.20 to 5.78; clomipramine: MD 1.83, 95% CI -4.23 to 8.20). Amitriptyline had a higher rate of adverse events than acupuncture (OR 4.73, 95% CI 1.42 to 14.23). CONCLUSION: Acupuncture had similar effect as TCAs in reducing headache frequency of TTH, and acupuncture had a lower adverse events rate than amitriptyline, as shown by very low certainty of evidence.


Assuntos
Terapia por Acupuntura , Antidepressivos Tricíclicos , Cefaleia do Tipo Tensional , Humanos , Cefaleia do Tipo Tensional/terapia , Cefaleia do Tipo Tensional/prevenção & controle , Cefaleia do Tipo Tensional/tratamento farmacológico , Antidepressivos Tricíclicos/uso terapêutico , Terapia por Acupuntura/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Sci Rep ; 14(1): 9083, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38643294

RESUMO

Simulated moving bed (SMB) technology is considered one of the most successful techniques in chromatographic separation. However, due to the nonlinearity caused by discrete events and sensitivity to numerous separation performance parameters, purity control in SMB systems has been a challenging issue. Fuzzy controllers are increasingly popular in industrial environments due to their simplicity and effectiveness in handling nonlinearity. However, traditional fuzzy controllers used in industry often overlook considerations of error acceleration, resulting in slight deviations from target values under steady-state conditions and oscillatory behavior when system parameters change. This study proposes an advanced fuzzy controller, where in a series of experiments, the purity control targets for component B are set at 94% and 96%, and for component A are set at 96% and 96%, respectively. Experimental results indicate that the advanced fuzzy controller achieves higher precision, with an average deviation of around 0.1%, for both components B and A. Importantly, under variations in adsorbent parameter(from 0.01 to 0.03), feed concentration(from 4.5 to 5.2), and switching time(from 178 to 182), the experimental results demonstrate smoother control with the advanced controller, particularly when oscillations occur with conventional fuzzy controllers due to switching time variations, indicating robust control with the advanced fuzzy controller.

17.
Sci Adv ; 10(10): eadk3854, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38446880

RESUMO

Liquid crystal elastomers (LCEs) have garnered attention for their remarkable reversible strains under various stimuli. Early studies on LCEs mainly focused on basic dimensional changes in macrostructures or quasi-three-dimensional (3D) microstructures. However, fabricating complex 3D microstructures and cross-scale LCE-based structures has remained challenging. In this study, we report a compatible method named melt electrowriting (MEW) to fabricate LCE-based microfiber actuators and various 3D actuators on the micrometer to centimeter scales. By controlling printing parameters, these actuators were fabricated with high resolutions (4.5 to 60 µm), actuation strains (10 to 55%), and a maximum work density of 160 J/kg. In addition, through the integration of a deep learning-based model, we demonstrated the application of LCE materials in temperature field sensing. Large-scale, real-time, LCE grid-based spatial temperature field sensors have been designed, exhibiting a low response time of less than 42 ms and a high precision of 94.79%.

18.
BMC Geriatr ; 24(1): 237, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448801

RESUMO

BACKGROUND: Quantitative computed tomography (QCT)-based lumbar bone mineral density (LBMD) has been used to diagnose osteoporosis. This study explored the value of lower thoracic BMD (TBMD) in diagnosing osteoporosis in older adults during CT lung cancer screening. METHODS: This study included 751 subjects who underwent QCT scans with both LBMD and TBMD. 141 of them was selected for a validation. Osteoporosis was diagnosed based on LBMD using the ACR criteria (gold standard). TBMD thresholds were obtained using receiver operating characteristic curve. TBMD was also translated into LBMD (TTBMD) and osteoporosis was defined based on TTBMD using ACR criteria. The performance of TBMD and TTBMD in identifying osteoporosis was determined by Kappa test. The associations between TBMD- and TTBMD-based osteoporosis and fracture were tested in 227 subjects with followed up status of spine fracture. RESULTS: The performance of TBMD in identifying osteoporosis was low (kappa = 0.66) if using the ACR criteria. Two thresholds of TBMD for identifying osteopenia (128 mg/cm3) and osteoporosis (91 mg/cm3) were obtained with areas under the curve of 0.97 and 0.99, respectively. The performance of the identification of osteoporosis/osteopenia using the two thresholds or TTBMD both had good agreement with the gold standard (kappa = 0.78, 0.86). Similar results were observed in validation population. Osteoporosis identified using the thresholds (adjusted hazard ratio (HR) = 18.72, 95% confidence interval (CI): 5.13-68.36) or TTBMD (adjusted HR = 10.28, 95% CI: 4.22-25.08) were also associated with fractures. CONCLUSION: Calculating the threshold of TBMD or normalizing TBMD to LBMD are both useful in identifying osteoporosis in older adults during CT lung cancer screening.


Assuntos
Doenças Ósseas Metabólicas , Fraturas Ósseas , Neoplasias Pulmonares , Osteoporose , Humanos , Idoso , Detecção Precoce de Câncer , Densidade Óssea , Neoplasias Pulmonares/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia , Vértebras Torácicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X
19.
Small ; : e2401506, 2024 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-38431925

RESUMO

Reaching rapid reaction kinetics of oxygen reduction (ORR) and oxygen evolution reactions (OER) is critical for realizing efficient rechargeable zinc-air batteries (ZABs). Herein, a novel CoNi-CoN3 composite site containing CoNi alloyed nanoparticles and CoN3 moieties is first constructed in N-doped carbon nanosheet matrix (CoNi-CoN3 /C). Benefiting from the high electroactivity of CoNi-CoN3 composite sites and large surface area, CoNi-CoN3 /C shows a superior half-wave potential (0.88 V versus RHE) for ORR and a small overpotential (360 mV) for OER at 10 mA cm-2 . Theoretical calculations have demonstrated that the introduction of CoNi alloys has modulated the electronic distributions near the CoN3 moiety, inducing the d-band center of CoNi-CoN3 composite site to shift down, thus stabilizing the valence state of Co active sites and balancing the adsorption of OER/ORR intermediates. Accordingly, the reaction energy trends exhibit optimized overpotentials for OER/ORR, leading to superior battery performances. For aqueous and flexible quasi-solid-state rechargeable ZABs with CoNi-CoN3 /C as catalyst, a large power density (250 mW cm-2 ) and high specific capacity (804 mAh g-1 ) are achieved. The in-depth understanding of the electroactivity enhancement mechanism of interactive metal nanoparticles and metal coordinated with nitrogen (MNx ) moieties is crucial for designing novel high-performance metal/nitrogen-doped carbon (M─N─C) catalysts.

20.
Toxics ; 12(3)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38535914

RESUMO

Ruthenium is required to separate from high-level liquid waste (HLLW) because Ru is a valuable resource and is negatively influential on the vitrification process of HLLW. However, the separation of Ru is very challenging due to its complicated complexation properties. In this study, the adsorption and desorption characteristics of ruthenium on a synthesized SiPyR-N3 (weak-base anion exchange resin with pyridine functional groups) composite were investigated in nitric acid and nitrite-nitric acid systems, respectively, and the adsorption mechanism was explored. The experimental results showed that SiPyR-N3 has a significantly better adsorption effect on Ru in the nitrite-nitric acid system than in the nitric acid system, with an increase in the adsorption capacity of approximately three times. The maximum adsorption capacity of Ru is 45.6 mg/g in the nitrite-nitric acid system. The SiPyR-N3 possesses good adsorption selectivity (SFRu/other metal ions is around 100) in 0.1 M NO2--0.1 M HNO3 solution. The adsorption processes of Ru in the two different systems are fitted with the pseudo-second-order kinetic model and Langmuir model for uptake kinetics and adsorption isotherms, respectively. The results obtained from the FT-IR, XPS, and UV absorption spectrometry indicate that NO2- was involved in the adsorption process either as a complexing species with the metal ions or as free NO2- from the solution. A 0.1 M HNO3 + 1 M thiourea mixed solution shows effective desorption performance, and the desorption efficiency can reach 92% at 328 K.

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