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Mitochondria–lysosome interactions are essential for maintaining intracellular homeostasis. Although various fluorescent probes have been developed to visualize such interactions, they remain unable to label mitochondria and lysosomes simultaneously and dynamically track their interaction. Here, we introduce a cell-permeable, biocompatible, viscosity-responsive, small organic molecular probe, Coupa, to monitor the interaction of mitochondria and lysosomes in living cells. Through a functional fluorescence conversion, Coupa can simultaneously label mitochondria with blue fluorescence and lysosomes with red fluorescence, and the correlation between the red–blue fluorescence intensity indicates the progress of mitochondria–lysosome interplay during mitophagy. Moreover, because its fluorescence is sensitive to viscosity, Coupa allowed us to precisely localize sites of mitochondria–lysosome contact and reveal increases in local viscosity on mitochondria associated with mitochondria–lysosome contact. Thus, our probe represents an attractive tool for the localization and dynamic tracking of functional mitochondria–lysosome interactions in living cells. Dynamic labeling and tracking of organelle–organelle contacts is essential to understand the formation and function of these interactions. Here the authors present a small molecule probe, Coupa, that labels mitochondria and lysosomes with blue and red fluorescence, respectively.

Zn 2+ plays important roles in metabolism and signaling regulation. Subcellular Zn 2+ compartmentalization is essential for organelle functions and cell biology, but there is currently no method to determine Zn 2+ signaling relationships among more than two different organelles with one probe. Here, we report simultaneous Zn 2+ tracking in multiple organelles (Zn-STIMO), a method that uses structured illumination microscopy (SIM) and a single Zn 2+ fluorescent probe, allowing super-resolution morphology-correlated organelle identification in living cells. To guarantee SIM imaging quality for organelle identification, we develop a new turn-on Zn 2+ fluorescent probe, NapBu-BPEA, by regulating the lipophilicity of naphthalimide-derived Zn 2+ probes to make it accumulate in multiple organelles except the nucleus. Zn-STIMO with this probe shows that CCCP-induced mitophagy in HeLa cells is associated with labile Zn 2+ enhancement. Therefore, direct organelle identification supported by SIM imaging makes Zn-STIMO a reliable method to determine labile Zn 2+ dynamics in various organelles with one probe. Finally, SIM imaging of pluripotent stem cell-derived organoids with NapBu-BPEA demonstrates the potential of super-resolution morphology-correlated organelle identification to track biospecies and events in specific organelles within organoids. Subcellular Zn 2+ compartmentalisation is essential for cell biology. Here the authors make a turn-on fluorescent Zn 2+ probe that localises to multiple organelles, and correlate its location using organelle morphology derived from structured illumination microscopy.

Prostate cancer (PCa) is the leading cause of cancer-related death among men worldwide. Knowledge of the prognostic factors of PCa and the bone metastasis pattern of patients would be helpful for patients and doctors. The data of 177,255 patients with prostate cancer diagnosed between 2010 and 2013 with at least five years of follow-up were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate Cox regression analysis was used to determine the predictive value of patients’ characteristics for survival after adjusting for other variates. Multivariate logistic regression analysis was used to evaluate the odds ratio of bone metastasis in PCa patients. The predictive value of age, race, marital status, and tumor characteristics were compared. The survival of patients with different socioeconomic statuses and bone metastasis statuses was compared by Kaplan–Meier analysis. A total of 1,335 patients with prostate cancer diagnosed between 2009 and 2015 were enrolled from the Second Affiliated Hospital of Zhejiang University School of Medicine. The survival of patients with different prostate-specific antigen (PSA) levels, Gleason scores, marital statuses and bone metastasis statuses was compared by Kaplan-Meier analysis. In SEER database, 96.74% of patients were 50 years of age or older. Multivariate Cox analysis revealed that for PCa patients, age at presentation, older age, single marital status, lower socioeconomic status, higher PSA level, T1 and N0 stage, and bone metastasis were independent risk factors for increased mortality. Multivariate logistic regression analysis revealed that patients who were married, were living in urban areas, had lower PSA levels, underwent surgery, and radiation had lower OR factors for bone metastasis. Asian or Pacific Islander, better socioeconomic status, lived in urban areas, married marital status, lower PSA levels and lower Gleason scores were better prognostic factors in PCa. Additionally, patients with single or divorced marital status, who were living in rural places had higher PSA levels, and T1 and N0 stages have a high OR for bone metastasis.

Erectile dysfunction(ED), a prevalent condition within the male genitourinary system, significantly impairs the quality of life for affected men. Although certain inflammatory indicators, such as the neutrophil-to-lymphocyte ratio(NLR), systemic inflammatory response index (SIRI), and systemic immune-inflammation index(SII), have been linked to ED, the correlation with other markers and their impact on survival outcomes in ED patients remain largely unexplored. This research aims to investigate the correlation between inflammatory biomarkers derived from a complete blood cell count(CBC) and the occurrence of ED. Data regarding ED were extracted from the 2001–2004 National Health and Nutrition Examination Survey(NHANES), and mortality events were ascertained through the National Death Index up to December 2019. The CBC-derived inflammatory indicators assessed in this study included the NLR, derived neutrophil-to-lymphocyte ratio(dNLR), monocyte-to-lymphocyte ratio(MLR), neutrophil-monocyte to lymphocyte ratio (NMLR), SIRI, and SII. The prognostic significance of these CBC-derived inflammatory indicators was evaluated using random survival forests(RSF) analysis. Our study encompassed a cohort of 3,639 individuals, among whom 1,031 were diagnosed with ED. Among individuals with ED, 610 experienced all-cause mortality. Following adjustment for all confounding variables, it was observed that elevated levels of NLR(OR = 1.09, 95%CI 1.00–1.19, p  = 0.021), MLR (OR = 2.97, 95% CI 1.18–7.50, p  = 0.01), NMLR(OR = 1.10, 95% CI 1.01–1.11, p  = 0.006), and SIRI(OR = 1.11, 95% CI 1.01–1.22, p  = 0.017) were associated with an increased prevalence of ED. Among participants with ED, those in the highest quartile of NLR(HR = 1.06, 95% CI 1.00–1.11, p  = 0.032), MLR(HR = 2.00, 95% CI 1.33–3.01, p  < 0.001), NMLR (HR = 1.06, 95% CI 1.01–1.11, p  = 0.024), and SII(HR = 1.00, 95% CI 1.00–1.00, p  = 0.015) exhibited an elevated risk of all-cause mortality compared to those in the lower levels of inflammation-derived indicators. Our research suggests that, compared with other inflammatory markers derived from complete blood cell count, MLR has the highest predictive power for the prevalence of ED and all-cause mortality in these populations.

Lipid droplets (LDs) feature a unique monolayer lipid membrane that has not been extensively studied due to the lack of suitable molecular probes that are able to distinguish this membrane from the LD lipid core. In this work, we present a three-pronged molecular probe design strategy that combines lipophilicity-based organelle targeting with microenvironment-dependent activation and design an LD membrane labeling pro-probe called LDM . Upon activation by the HClO/ClO − microenvironment that surrounds LDs, LDM pro-probe releases LDM-OH probe that binds to LD membrane proteins thus enabling visualization of the ring-like LD membrane. By utilizing LDM , we identify the dynamic mechanism of LD membrane contacts and their protein accumulation parameters. Taken together, LDM represents the first molecular probe for imaging LD membranes in live cells to the best of our knowledge, and represents an attractive tool for further investigations into the specific regulatory mechanisms with LD-related metabolism diseases and drug screening. Lipid droplets (LDs) and their membrane proteins play essential roles in many biological processes, but the monolayer lipid membrane of LDs has not been extensively studied due to the lack of suitable molecular probes. Here, the authors report an LD membrane labelling pro-probe called LDM, which, upon activation by the HClO/ClO− microenvironment that surrounds LDs, undergoes a color change and releases LDM-OH probe that binds to LD membrane proteins.

Mitral valve prolapse is often benign, but progression to mitral regurgitation may require invasive intervention and there is no specific medical therapy. An association of mitral valve prolapse with Marfan syndrome resulting from pathogenic FBN1 variants supports the use of hypomorphic fibrillin-1 mgR mice to investigate mechanisms and therapy for mitral valve disease. mgR mice developed severe myxomatous mitral valve degeneration with mitral regurgitation by 12 weeks of age. Persistent activation of TGF-β and mTOR signaling along with macrophage recruitment preceded histological changes at 4 weeks of age. Short-term mTOR inhibition with rapamycin from 4 to 5 weeks of age prevented TGF-β overactivity and leukocytic infiltrates, while long-term inhibition of mTOR or TGF-β signaling from 4 to 12 weeks of age rescued mitral valve leaflet degeneration. Transcriptomic analysis identified integrins as key receptors in signaling interactions, and serologic neutralization of integrin signaling or a chimeric integrin receptor altering signaling prevented mTOR activation. We confirmed increased mTOR signaling and a conserved transcriptome signature in human specimens of sporadic mitral valve prolapse. Thus, mTOR activation from abnormal integrin-dependent cell-matrix interactions drives TGF-β overactivity and myxomatous mitral valve degeneration, and mTOR inhibition may prevent disease progression of mitral valve prolapse.

Background This study was to evaluate and compare the biomechanical features of multilevel lateral lumbar interbody fusion (LLIF) with or without supplemental instrumentations. Methods Six human lumbar specimens were tested under multidirectional nondestructive moments (7.5 N·m), with a 6 degree-of-freedom spine simulator. The overall and intervertebral range of motion (ROM) were measured optoelectronically. Each specimen was tested under the following conditions at L2–5 levels: intact; stand-alone; cage supplemented with lateral plate (LP); cage supplemented with unilateral or bilateral pedicle screw/rod (UPS or BPS). Results Compared with intact condition, the overall and intersegmental ROM were significantly reduced after multilevel stand-alone LLIF. The ROM was further reduced after using LP instrumentation. In flexion-extension (FE) and axial rotation (AR), pedicle screw/rod demonstrated greater overall ROM reduction compared to LP ( P  < 0.01), and bilateral greater than unilateral ( P  < 0.01). In lateral bending (LB), BPS demonstrated greater overall ROM reduction compared to UPS and LP ( P  < 0.01), however, UPS and LP showed similar reduction ( P  = 0.245). Intervertebral ROM reductions showed similar trend as the overall ones after using different types of instrumentation. However, at L2/3 ( P  = 0.57) and L3/4 ( P  = 0.097) levels, the intervertebral ROM reductions in AR were similar between UPS and LP. Conclusions The overall and intervertebral stability increased significantly after multilevel LLIF with or without supplemental instrumentation. BPS provided the greatest stability, followed by UPS and LP. However, in clinical practice, less invasive adjunctive fixation methods including UPS and LP may provide sufficient biomechanical stability for multilevel LLIF.

Early diagnosis of patients with acute myocardial infarction (AMI) who are at a high risk of heart failure (HF) progression remains controversial. This study aimed at identifying new predictive biomarkers of post-AMI HF and at revealing the pathogenesis of HF involving these marker genes. A transcriptomic dataset of whole blood cells from AMI patients with HF progression (post-AMI HF, n = 16) and without progression (post-AMI non-HF, n = 16) was analyzed using the weighted gene co-expression network analysis (WGCNA). The results indicated that one module consisting of 720 hub genes was significantly correlated with post-AMI HF. The hub genes were validated in another transcriptomic dataset of peripheral blood mononuclear cells (post-AMI HF, n = 9; post-AMI non-HF, n = 8). PRKAR1A, SDCBP, SPRED2, and VAMP3 were upregulated in the two datasets. Based on a single-cell RNA sequencing dataset of leukocytes from heart tissues of normal and infarcted mice, PRKAR1A was further verified to be upregulated in monocytes/macrophages on day 2, while SDCBP was highly expressed in neutrophils on day 2 and in monocytes/macrophages on day 3 after AMI. Cell-cell communication analysis the \"CellChat\" package showed that, based on the interaction of ligand-receptor (L-R) pairs, there were increased autocrine/paracrine cross-talk networks of monocytes/macrophages and neutrophils in the acute stage of MI. Functional enrichment analysis of the abovementioned L-R genes together with PRKAR1A and SDCBP performed through the Metascape platform suggested that PRKAR1A and SDCBP were mainly involved in inflammation, apoptosis, and angiogenesis. The receiver operating characteristic (ROC) curve analysis demonstrated that PRKAR1A and SDCBP, as well as their combination, had a promising prognostic value in the identification of AMI patients who were at a high risk of HF progression. This study identified that PRKAR1A and SDCBP may serve as novel biomarkers for the early diagnosis of post-AMI HF and also revealed their potentially regulatory mechanism during HF progression.

Due to the disconnection of surviving neural elements after spinal cord injury (SCI), such patients had to suffer irreversible loss of motor or sensory function, and thereafter enormous economic and emotional burdens were brought to society and family. Despite many strategies being dealing with SCI, there is still no effective regenerative therapy. To date, significant progress has been made in studies of SCI repair strategies, including gene regulation of neural regeneration, cell or cell-derived exosomes and growth factors transplantation, repair of biomaterials, and neural signal stimulation. The pathophysiology of SCI is complex and multifaceted, and its mechanisms and processes are incompletely understood. Thus, combinatorial therapies have been demonstrated to be more effective, and lead to better neural circuits reconstruction and functional recovery. Combinations of biomaterials, stem cells, growth factors, drugs, and exosomes have been widely developed. However, simply achieving axon regeneration will not spontaneously lead to meaningful functional recovery. Therefore, the formation and remodeling of functional neural circuits also depend on rehabilitation exercises, such as exercise training, electrical stimulation (ES) and Brain–Computer Interfaces (BCIs). In this review, we summarize the recent progress in biological and engineering strategies for reconstructing neural circuits and promoting functional recovery after SCI, and emphasize current challenges and future directions.

Despite being considered the standard surgical procedure for symptomatic cervical disc disease, anterior cervical decompression and fusion invariably accelerates adjacent segment degeneration. Cervical total disc replacement is a motion-preserving procedure developed as a substitute to fusion. Whether cervical total disc replacement is superior to fusion remains unclear. We comprehensively searched PubMed, EMBASE, Medline, and the Cochrane Library in accordance with the inclusion criteria to identify possible studies. The retrieved results were last updated on December 12, 2014. We classified the studies as short-term and midterm follow-up. Nineteen randomized controlled trials involving 4516 cases were identified. Compared with anterior cervical decompression and fusion, cervical total disc replacement had better functional outcomes (neck disability index [NDI], NDI success, neurological success, neck pain scores reported on a numerical rating scale [NRS], visual analog scales scores and overall success), greater segmental motion at the index level, fewer adverse events and fewer secondary surgical procedures at the index and adjacent levels in short-term follow-up (P < 0.05). With midterm follow-up, the cervical total disc replacement group indicated superiority in the NDI, neurological success, pain assessment (NRS), and secondary surgical procedures at the index level (P < 0.05). The Short Form 36 (SF-36) and segmental motion at the adjacent level in the short-term follow-up showed no significant difference between the two procedures, as did the secondary surgical procedure rates at the adjacent level with midterm follow-up (P > 0.05). Cervical total disc replacement presented favorable functional outcomes, fewer adverse events, and fewer secondary surgical procedures. The efficacy and safety of cervical total disc replacement are superior to those of fusion. Longer-term, multicenter studies are required for a better evaluation of the long-term efficacy and safety of the two procedures.