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1.
IEEE Internet Things J ; 11(8): 14657-14670, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38605934

RESUMO

The use of medical data for machine learning, including unsupervised methods such as clustering, is often restricted by privacy regulations such as the Health Insurance Portability and Accountability Act (HIPAA). Medical data is sensitive and highly regulated and anonymization is often insufficient to protect a patient's identity. Traditional clustering algorithms are also unsuitable for longitudinal behavioral health trials, which often have missing data and observe individual behaviors over varying time periods. In this work, we develop a new decentralized federated multiple imputation-based fuzzy clustering algorithm for complex longitudinal behavioral trial data collected from multisite randomized controlled trials over different time periods. Federated learning (FL) preserves privacy by aggregating model parameters instead of data. Unlike previous FL methods, this proposed algorithm requires only two rounds of communication and handles clients with varying numbers of time points for incomplete longitudinal data. The model is evaluated on both empirical longitudinal dietary health data and simulated clusters with different numbers of clients, effect sizes, correlations, and sample sizes. The proposed algorithm converges rapidly and achieves desirable performance on multiple clustering metrics. This new method allows for targeted treatments for various patient groups while preserving their data privacy and enables the potential for broader applications in the Internet of Medical Things.

2.
Nano Lett ; 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38619556

RESUMO

Revealing low-dimensional material growth dynamics is critical for crystal growth engineering. However, in a practical high-temperature growth system, the crystal growth process is a black box because of the lack of heat-resistant imaging tools. Here, we develop a heat-resistant optical microscope and embed it in a chemical vapor deposition (CVD) system to investigate two-dimensional (2D) crystal growth dynamics. This in situ optical imaging CVD system can tolerate temperatures of ≤900 °C with a spatial resolution of ∼1 µm. The growth of monolayer MoS2 crystals was studied as a model for 2D crystal growth. The nucleation and growth process have been imaged. Model analysis and simulation have revealed the growth rate, diffusion coefficient, and spatial distribution of the precursor. More importantly, a new vertex-kink-ledge model has been suggested for monolayer crystal growth. This work provides a new technique for in situ microscopic imaging at high temperatures and fundamental insight into 2D crystal growth.

3.
BMC Plant Biol ; 24(1): 297, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38632517

RESUMO

BACKGROUND: Developing and enriching genetic resources plays important role in the crop improvement. The flag leaf affects plant architecture and contributes to the grain yield of wheat (Triticum aestivum L.). The genetic improvement of flag leaf traits faces problems such as a limited genetic basis. Among the various genetic resources of wheat, Thinopyrum intermedium has been utilized as a valuable resource in genetic improvement due to its disease resistance, large spikes, large leaves, and multiple flowers. In this study, a recombinant inbred line (RIL) population was derived from common wheat Yannong15 and wheat-Th. intermedium introgression line SN304 was used to identify the quantitative trait loci (QTL) for flag leaf-related traits. RESULTS: QTL mapping was performed for flag leaf length (FLL), flag leaf width (FLW) and flag leaf area (FLA). A total of 77 QTLs were detected, and among these, 51 QTLs with positive alleles were contributed by SN304. Fourteen major QTLs for flag leaf traits were detected on chromosomes 2B, 3B, 4B, and 2D. Additionally, 28 QTLs and 8 QTLs for flag leaf-related traits were detected in low-phosphorus and drought environments, respectively. Based on major QTLs of positive alleles from SN304, we identified a pair of double-ended anchor primers mapped on chromosome 2B and amplified a specific band of Th. intermedium in SN304. Moreover, there was a major colocated QTL on chromosome 2B, called QFll/Flw/Fla-2B, which was delimited to a physical interval of approximately 2.9 Mb and contained 20 candidate genes. Through gene sequence and expression analysis, four candidate genes associated with flag leaf formation and growth in the QTL interval were identified. CONCLUSION: These results promote the fine mapping of QFll/Flw/Fla-2B, which have pleiotropic effects, and will facilitate the identification of candidate genes for flag leaf-related traits. Additionally, this work provides a theoretical basis for the application of Th. intermedium in wheat breeding.


Assuntos
Locos de Características Quantitativas , Triticum , Triticum/genética , Mapeamento Cromossômico , Melhoramento Vegetal , Fenótipo , Folhas de Planta/genética
4.
bioRxiv ; 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38659789

RESUMO

Developmental and Epileptic Encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures and exacerbated by disruptions to excitatory/inhibitory balance in the brain, are commonly caused by mutations in ion channels. Disruption of, or variants in, FGF13 were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded because FGF13 is expressed in both excitatory and inhibitory neurons, FGF13 undergoes extensive alternative splicing producing multiple isoforms with distinct functions, and the overall roles of FGF13 in neurons are incompletely cataloged. To overcome these challenges, we generated a set of novel cell type-specific conditional knockout mice. Interneuron-targeted deletion of Fgf13 led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion of Fgf13 caused no detectable seizures and no survival deficits. While best studied as a voltage-gated sodium channel (Na v ) regulator, we observed no effect of Fgf13 ablation in interneurons on Na v s but rather a marked reduction in K + channel currents. Re-expressing different Fgf13 splice isoforms could partially rescue deficits in interneuron excitability and restore K + channel current amplitude. These results enhance our understanding of the molecular mechanisms that drive the pathogenesis of Fgf13- related seizures and expand our understanding of FGF13 functions in different neuron subsets.

5.
Front Cell Infect Microbiol ; 14: 1370999, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38660489

RESUMO

Diabetes mellitus (DM) refers to a group of chronic diseases with global prevalence, characterized by persistent hyperglycemia resulting from various etiologies. DM can harm various organ systems and lead to acute or chronic complications, which severely endanger human well-being. Traditional treatment mainly involves controlling blood sugar levels through replacement therapy with drugs and insulin; however, some patients still find a satisfactory curative effect difficult to achieve. Extensive research has demonstrated a close correlation between enteric dysbacteriosis and the pathogenesis of various types of DM, paving the way for novel therapeutic approaches targeting the gut microbiota to manage DM. Fecal microbiota transplantation (FMT), a method for re-establishing the intestinal microbiome balance, offers new possibilities for treating diabetes. This article provides a comprehensive review of the correlation between DM and the gut microbiota, as well as the current advancements in FMT treatment for DM, using FMT as an illustrative example. This study aims to offer novel perspectives and establish a theoretical foundation for the clinical diagnosis and management of DM.


Assuntos
Diabetes Mellitus , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Transplante de Microbiota Fecal/métodos , Humanos , Diabetes Mellitus/terapia , Diabetes Mellitus/microbiologia , Disbiose/terapia , Animais , Fezes/microbiologia
7.
Commun Biol ; 7(1): 334, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491121

RESUMO

VPS37A, an ESCRT-I complex component, is required for recruiting a subset of ESCRT proteins to the phagophore for autophagosome closure. However, the mechanism by which VPS37A is targeted to the phagophore remains obscure. Here, we demonstrate that the VPS37A N-terminal domain exhibits selective interactions with highly curved membranes, mediated by two membrane-interacting motifs within the disordered regions surrounding its Ubiquitin E2 variant-like (UEVL) domain. Site-directed mutations of residues in these motifs disrupt ESCRT-I localization to the phagophore and result in defective phagophore closure and compromised autophagic flux in vivo, highlighting their essential role during autophagy. In conjunction with the UEVL domain, we postulate that these motifs guide a functional assembly of the ESCRT machinery at the highly curved tip of the phagophore for autophagosome closure. These results advance the notion that the distinctive membrane architecture of the cup-shaped phagophore spatially regulates autophagosome biogenesis.


Assuntos
Autofagossomos , Autofagia , Autofagossomos/metabolismo , Autofagia/fisiologia , Membranas Intracelulares/metabolismo , Endossomos/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo
8.
Arch Microbiol ; 206(4): 167, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38485861

RESUMO

Various forms of malignancies have been linked to Helicobacter pylori. Despite advancements in chemotherapeutic and surgical approaches, the management of cancer, particularly at advanced stages, increasingly relies on the integration of immunotherapy. As a novel, safe therapeutic modality, immunotherapy harnesses the immune system of the patient to treat cancer, thereby broadening treatment options. However, there is evidence that H. pylori infection may influence the effectiveness of immunotherapy in various types of cancer. This association is related to H. pylori virulence factors and the tumor microenvironment. This review discusses the influence of H. pylori infection on immunotherapy in non-gastrointestinal and gastrointestinal tumors, the mechanisms underlying this relationship, and directions for the development of improved immunotherapy strategies.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias , Humanos , Fatores de Virulência/genética , Helicobacter pylori/genética , Neoplasias/terapia , Imunoterapia , Infecções por Helicobacter/terapia , Microambiente Tumoral
9.
Small ; : e2310519, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38415911

RESUMO

Rechargeable aqueous ammonium ion (NH4 + ) batteries have attracted much attention due to the unique properties of NH4 + . Polyaniline (PA) with outstanding conductivity is a potential cathode material, but it can be oxidized to pernigraniline (PG) rapidly, resulting in its poor stability. In this study, polyaniline@poly(o-fluoroaniline)@carbon layer (PA@POFA@C) is prepared for excellent and durable NH4 + storage. PA@POFA@C exhibits a high capacity of 208 mAh g-1 at 0.2 A g-1 and maintains 126 mAh g-1 at 10 A g-1 . More importantly, an excellent capacity retention rate of 88.24% is achieved after 2000 cycles with ≈100% coulombic efficiency. Spectroscopy studies suggest analogous confinement effect can effectively limit the escape of hydrogen in imine group, and form the hydrogen-restricted region between the PA and POFA layer which can provide H+ for the complete reduction of PG. Meanwhile, the hydrophobic effect of POFA effectively restrains the hydrolysis of PG. Interestingly, the introduction of C layer improves the hydrophilicity of electrode and shortens the activation process, serving as the outermost protective layer of the electrode. Finally, PA@POFA@C achieves desirable electrochemical performances with analogous confinement effect. This research provides ideas for the preparation of advanced polymer electrodes for aqueous NH4 + batteries.

10.
Eur J Med Chem ; 268: 116254, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38377826

RESUMO

Pyroptosis is one kind of programmed cell death in which the cell membrane ruptures and subsequently releases cell contents and pro-inflammatory cytokines including IL-1ß and IL-18. Pyroptosis is caused by many types of pathological stimuli, such as hyperglycemia (HG), oxidative stress, and inflammation, and is mediated by gasdermin (GSDM) protein family. Increasing evidence indicates that pyroptosis plays an important role in multiple diseases, such as cancer, kidney diseases, inflammatory diseases, and cardiovascular diseases. Therefore, the regulation of pyroptosis is crucial for the occurrence, development, and treatment of many diseases. Hydrogen sulfide (H2S) is a biologically active gasotransmitter following carbon monoxide (CO) and nitrogen oxide (NO) in mammalian tissues. So far, three enzymes, including 3-mercaptopyruvate sulphurtransferase (3-MST), cystathionine γ- Lyase (CSE), and Cystine ß-synthesis enzyme (CBS), have been found to catalyze the production of endogenous H2S in mammals. H2S has been reported to have multiple biological functions including anti-inflammation, anti-oxidative stress, anti-apoptosis and so on. Hence, H2S is involved in various physiological and pathological processes. In recent years, many studies have demonstrated that H2S plays a critical role by regulating pyroptosis in various pathological processes, such as ischemia-reperfusion injury, alcoholic liver disease, and diabetes cardiomyopathy. However, the relevant mechanism has not been completely understood. Therefore, elucidating the mechanism by which H2S regulates pyroptosis in diseases will help understand the pathogenesis of multiple diseases and provide important new avenues for the treatment of many diseases. Here, we reviewed the progress of H2S regulation of pyroptosis in different pathological processes, and analyzed the molecular mechanism in detail to provide a theoretical reference for future related research.


Assuntos
Sulfeto de Hidrogênio , Animais , Humanos , Sulfeto de Hidrogênio/metabolismo , Piroptose , Inflamação , Óxido Nítrico/metabolismo , Citocinas , Mamíferos/metabolismo
11.
World J Gastroenterol ; 30(4): 421-423, 2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38313233

RESUMO

According to the latest global cancer statistics, colorectal cancer (CRC) has emerged as the third most prevalent malignant tumor across the globe. In recent decades, the medical field has implemented several levels of CRC screening tests, encompassing fecal tests, endoscopic examinations, radiological examinations and blood tests. Previous studies have shown that leukocyte immunoglobulin-like receptor B2 (LILRB2) is involved in inhibiting immune cell function, immune evasion, and promoting tumor progression in acute myeloid leukemia and non-small cell lung cancer. However, its interaction with CRC has not been reported yet. Recently, a study published in the World Journal of Gastroenterology revealed that LILRB2 and its ligand, angiopoietin-like protein 2, are markedly overexpressed in CRC. This overexpression is closely linked to tumor progression and is indicative of a poor prognosis. The study highlights the potential of utilizing the concentration of LILRB2 in serum as a promising biomarker for tumors. However, there is still room for discussion regarding the data processing and analysis in this research.


Assuntos
Neoplasias Colorretais , Glicoproteínas de Membrana , Receptores Imunológicos , Humanos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Glicoproteínas de Membrana/genética , Transdução de Sinais , Biomarcadores Tumorais/metabolismo , Receptores Imunológicos/genética
12.
Am Surg ; : 31348241227191, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38214220

RESUMO

Colorectal cancer (CRC) is a common malignant tumor that primarily affects the elderly population. Surgery is one of the main treatment modalities for CRC. Frailty is a prevalent characteristic among the elderly and a leading cause of mortality. The frailty index (FI) is a comprehensive tool for assessing patients' frailty status, quantifying indicators such as weight loss, fatigue, and nutritional status, to reflect the degree of frailty. In recent years, the FI has undergone modifications to more accurately evaluate the risk of surgical complications and prognosis in CRC patients. This review summarizes the methods for frailty assessment, the development and modifications of the FI, and compiles the research findings and applications of the FI in predicting surgical complications, postoperative recovery, and survival rates in CRC patients. Furthermore, limitations in the current modified frailty index (mFI) and future research directions are discussed. This review provides essential references for further understanding the role of frailty in CRC patients and the clinical application of the mFI.

13.
Bioact Mater ; 34: 381-400, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38269309

RESUMO

Preventing local tumor recurrence while promoting bone tissue regeneration is an urgent need for osteosarcoma treatment. However, the therapeutic efficacy of traditional photosensitizers is limited, and they lack the ability to regenerate bone. Here, a piezo-photo nanoheterostructure is developed based on ultrasmall bismuth/strontium titanate nanocubes (denoted as Bi/SrTiO3), which achieve piezoelectric field-driven fast charge separation coupling with surface plasmon resonance to efficiently generate reactive oxygen species. These hybrid nanotherapeutics are integrated into injectable biopolymer hydrogels, which exhibit outstanding anticancer effects under the combined irradiation of NIR and ultrasound. In vivo studies using patient-derived xenograft models and tibial osteosarcoma models demonstrate that the hydrogels achieve tumor suppression with efficacy rates of 98.6 % and 67.6 % in the respective models. Furthermore, the hydrogel had good filling and retention capabilities in the bone defect region, which exerted bone repair therapeutic efficacy by polarizing and conveying electrical stimuli to the cells under mild ultrasound radiation. This study provides a comprehensive and clinically feasible strategy for the overall treatment and tissue regeneration of osteosarcoma.

14.
Autophagy ; 20(2): 349-364, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37733908

RESUMO

The VPS37A gene encodes a subunit of the endosomal sorting complex required for transport (ESCRT)-I complex that is frequently lost in a wide variety of human solid cancers. We have previously demonstrated the role of VPS37A in directing the ESCRT membrane scission machinery to seal the phagophore for autophagosome completion. Here, we report that VPS37A-deficient cells exhibit an accumulation of the apoptotic initiator CASP8 (caspase 8) on the phagophore and are primed to undergo rapid apoptosis through the intracellular death-inducing signaling complex (iDISC)-mediated CASP8 activation upon exposure to endoplasmic reticulum (ER) stress. Using CRISPR-Cas9 gene editing and comparative transcriptome analysis, we identified the ATF4-mediated stress response pathway as a crucial mediator to elicit iDISC-mediated apoptosis following the inhibition of autophagosome closure. Notably, ATF4-mediated iDISC activation occurred independently of the death receptor TNFRSF10B/DR5 upregulation but required the pro-apoptotic transcriptional factor DDIT3/CHOP to enhance the mitochondrial amplification pathway for full-activation of CASP8 in VPS37A-deficient cells stimulated with ER stress inducers. Our analysis also revealed the upregulation of NFKB/NF-kB signaling as a potential mechanism responsible for restraining iDISC activation and promoting cell survival upon VPS37A depletion. These findings have important implications for the future development of new strategies to treat human cancers, especially those with VPS37A loss.Abbreviations: ATG: autophagy related; BMS: BMS-345541; CASP: caspase; CHMP: charged multivesicular body protein; DKO: double knockout; Dox: doxycycline; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; gRNA: guide RNA; GSEA: gene set enrichment analysis; GSK157: GSK2656157; iDISC: intracellular death-inducing signaling complex; IKK: inhibitor of NFKB kinase; IPA: ingenuity pathway analysis; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NFKB/NF-kB: nuclear factor kappa B; OZ: 5Z-7-oxozeaenol; RNA-seq: RNA sequencing; UPR: unfolded protein response; TFT: transcription factor target; THG: thapsigargin; TUN: tunicamycin; VPS: vacuolar protein sorting.


Assuntos
NF-kappa B , Neoplasias , Humanos , Caspase 8/genética , NF-kappa B/metabolismo , Autofagia , RNA Guia de Sistemas CRISPR-Cas , Apoptose/genética , Estresse do Retículo Endoplasmático , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo
15.
J Gastroenterol Hepatol ; 39(2): 328-336, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38016701

RESUMO

BACKGROUND AND AIM: Fecal microbiota transplantation (FMT) has been shown to positively affect the treatment of inflammatory bowel disease (IBD). However, the safety and efficacy of FMT may depend on the route of microbiota delivery. This study investigates the acceptance, satisfaction, and selection preference of a new delivery route, transendoscopic enteral tubing (TET), for treating IBD. METHODS: A survey was conducted among patients with IBD from five medical centers across China. The objective was to assess their acceptance, subjective feelings, and major concerns regarding two types of TET: colonic TET and mid-gut TET. In addition, the survey also analyzed the factors affecting the selection of TET and TET types among these patients. RESULTS: The final analysis included 351 questionnaires. Up to 76.6% of patients were willing to accept TET and preferred to choose colonic TET when they first learned about TET. Patients with longer disease duration, history of enema therapy, or enteral nutrition were more open to considering TET among IBD patients. After treatment, 95.6% of patients were satisfied with TET, including colonic TET (95.9%) and mid-gut TET (95.1%). Patients with a history of enema therapy and ulcerative colitis preferred colonic TET. In contrast, those with a history of enteral nutrition and Crohn's disease were willing to choose mid-gut TET. However, some patients hesitated to accept TET due to concerns about efficacy, safety, and cost. CONCLUSIONS: TET was highly accepted and satisfied patients with IBD. Disease type and combination therapy influenced the choice of colonic or mid-gut TET.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Transplante de Microbiota Fecal/efeitos adversos , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/etiologia , Doença de Crohn/terapia , Doença de Crohn/etiologia , Colite Ulcerativa/terapia , Satisfação Pessoal
16.
Am Surg ; 90(3): 411-418, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37698898

RESUMO

PURPOSE: The albumin to alkaline phosphatase ratio (AAPR) is a newly developed blood biomarker that has been reported to have prognostic value in several types of cancers. The aim of this study was to investigate the predictive value of AAPR in overall survival after radical colon cancer surgery in patients with stage I-III colorectal cancer (CRC). METHODS: The clinical data of 221 eligible patients with stage I ∼ III CRC were retrospectively analyzed. A series of survival analyses were performed to assess the prognostic value of AAPR. Univariate and multifactorial Cox analyses were performed to identify independent risk factors. Columnar graph prediction models were further constructed based on independent risk factors such as AAPR, and their predictive properties were validated. RESULTS: The optimal cutoff value of preoperative AAPR for postoperative overall survival (OS) in patients undergoing laparoscopic radical CRC was .495 as shown by univariate and multifactorial Cox regression analysis. The factors of age ≤65 years, Tumor-Node-Metastasis (TNM) stage I-II, tumor grading (high/medium differentiation), CEA ≤5, and AAPR ≥.495 were associated with better OS (P < .05). CONCLUSIONS: Preoperative AAPR level was a good predictor of postoperative survival in patients undergoing laparoscopic radical CRC surgery, and AAPR <.495 was an independent risk factor for decreased postoperative OS.


Assuntos
Albuminas , Fosfatase Alcalina , Neoplasias Colorretais , Idoso , Humanos , Albuminas/análise , Fosfatase Alcalina/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Nomogramas , Prognóstico , Estudos Retrospectivos , Período Pré-Operatório
17.
Mol Neurobiol ; 61(3): 1271-1281, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37697221

RESUMO

Autophagy is a conservative self-degradation system, which includes the two major processes of enveloping abnormal proteins, organelles and other macromolecules, and transferring them into lysosomes for the subsequent degradation. It holds the stability of the intracellular environment under stress. So far, three types of autophagy have been found: microautophagy, chaperone-mediated autophagy and macroautophagy. Many diseases have the pathological process of autophagy dysfunction, such as nervous system diseases. Pyroptosis is one kind of programmed cell death mediated by gasdermin (GSDM). In this process of pyroptosis, the activated caspase-3, caspase-4/5/11, or caspase-1 cleaves GSDM into the N-terminal pore-forming domain (PFD). The oligomer of PFD combines with the cell membrane to form membrane holes, thus leading to pyroptosis. Pyroptosis plays a key role in multiple tissues and organs. Many studies have revealed that autophagy and pyroptosis participate in the nervous system, but the mechanisms need to be fully clarified. Here, we focused on the recent articles on the role and mechanism of pyroptosis and autophagy in the pathological processes of the nervous system.


Assuntos
Inflamassomos , Piroptose , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Autofagia , Sistema Nervoso/metabolismo , Caspases/metabolismo
18.
bioRxiv ; 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-37790404

RESUMO

Aberrant mitochondrial fission/fusion dynamics have been reported in cancer cells. While post translational modifications are known regulators of the mitochondrial fission/fusion machinery, we show that alternative splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. Ovarian cancer specimens express an alternative splice transcript variant of Drp1 lacking exon 16 of the variable domain, and high expression of this splice variant relative to other transcripts is associated with poor patient outcome. Unlike the full-length variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration, and TCA cycle metabolites, and is associated with a more metastatic phenotype in vitro and in vivo. These pro-tumorigenic effects can also be inhibited by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternative splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.

19.
Nephrology (Carlton) ; 29(1): 5-17, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37667547

RESUMO

AIM: Acute kidney injury is a severe disease that is closely associated with substantial morbidity and mortality. The most common cause of AKI is renal ischemia-reperfusion injury. Mesenchymal stem cells (MSCs) have previously been shown to have renoprotective effects. However, extracellular vesicles secreted by MSCs are thought to be the key for the therapeutic effects of MSCs. This study investigated whether small EVs derived from ACE2-modified human umbilical cord MSCs could alleviate RIRI and explored their underlying molecular mechanisms METHODS: A lentivirus carrying an ACE2 overexpression vector was constructed and used to infect MSCs. The small EVs were isolated from MSC-conditioned medium by ultracentrifugation. HK-2 cells were cocultured with MSC-ACE2-EVs and subjected to hypoxia/reoxygenation injury. MSCs-ACE2-EVs were injected into RIRI mice. Biochemical and morphological characteristics were assessed, and the levels of inflammatory-related factors, oxidative stress products, and apoptosis in HK-2 cells and kidney tissues were assessed RESULTS: In vitro, MSC-ACE2-EVs had stronger anti-inflammatory, antioxidative stress, and antiapoptotic effects in HK-2 cells subjected to H/R than MSC-NC-EVs. In vivo, MSC-ACE2-EVs could target the injured kidney, reduce blood creatinine and urea nitrogen levels, and protect the kidney from I/R, and this effect may have been related to the activation of the Nrf2/HO-1 signalling pathway CONCLUSION: Taken together, our results demonstrated the anti-inflammatory, antioxidative stress, and antiapoptotic effects of MSC-ACE2-EVs, which protected against I/R injury in vitro and vivo. MSC-ACE2-EVs may be therapeutic agents for RIRI.


Assuntos
Vesículas Extracelulares , Células-Tronco Mesenquimais , Traumatismo por Reperfusão , Humanos , Camundongos , Animais , Enzima de Conversão de Angiotensina 2/metabolismo , Rim/metabolismo , Vesículas Extracelulares/fisiologia , Anti-Inflamatórios/metabolismo , Cordão Umbilical , Células-Tronco Mesenquimais/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo
20.
Acta Microbiol Immunol Hung ; 70(4): 288-294, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38063919

RESUMO

Aim of this study was to explore molecular characteristics and resistance mechanisms of carbapenem-resistant Raoultella ornithinolytica (CR-ROR) isolated from patients in a hospital in China. Three CR-ROR strains were collected and bacterial identification was done by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) Vitek-MS and by digital DDH analysis. VITEK 2 compact system and Kirby-Bauer (K-B) disk diffusion were used for antimicrobial susceptibility testing. Whole genome sequencing was carried out using the Illumina platform NovaSeq sequencer. Abricate software was used for the prediction of antibiotic resistance genes of three CR-ROR strains. The phylogenetic tree was constructed through genome SNPs to investigate the genetic relationship of three CR-ROR strains. Three CR-ROR (WF1357, WF2441, and WF3367) strains were collected in this study. Two strains were isolated from neurosurgery (WF1357 and WF2441), and one was isolated from pulmonology department (WF3367). All strains harboured multiple antibiotic resistance genes. Two strains (WF1357, WF2441) carried the blaNDM-1 gene, one of the strains (WF3367) carried the blaKPC-2 gene. Three CR-RORs were resistant to different antimicrobial agents including carbapenems. The three CR-ROR strains collected in this study and 51 CR-ROR strain genomes downloaded from NCBI, were divided into six evolutionary groups (A-F). In this study, three CR-ROR strains were found to have a higher level of resistance to antibacterial agents and carried multiple antibiotic resistance genes. The CR-ROR strains carrying multiple antibacterial resistant genes require the stringent monitoring to avoid the spread of multidrug-resistant bacterial strains.


Assuntos
Carbapenêmicos , beta-Lactamases , Humanos , Carbapenêmicos/farmacologia , Filogenia , beta-Lactamases/genética , Enterobacteriaceae/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana , Klebsiella pneumoniae/genética
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