A comprehensive patient-specific prediction model for temporomandibular joint osteoarthritis progression.

Temporomandibular joint osteoarthritis (TMJ OA) is a prevalent degenerative disease characterized by chronic pain and impaired jaw function. The complexity of TMJ OA has hindered the development of prognostic tools, posing a significant challenge in timely, patient-specific management. Addressing this gap, our research employs a comprehensive, multidimensional approach to advance TMJ OA prognostication. We conducted a prospective study with 106 subjects, 74 of whom were followed up after 2 to 3 y of conservative treatment. Central to our methodology is the development of an innovative, open-source predictive modeling framework, the Ensemble via Hierarchical Predictions through Nested cross-validation tool (EHPN). This framework synergistically integrates 18 feature selection, statistical, and machine learning methods to yield an accuracy of 0.87, with an area under the ROC curve of 0.72 and an F1 score of 0.82. Our study, beyond technical advancements, emphasizes the global impact of TMJ OA, recognizing its unique demographic occurrence. We highlight key factors influencing TMJ OA progression. Using SHAP analysis, we identified personalized prognostic predictors: lower values of headache, lower back pain, restless sleep, condyle high gray level-GL-run emphasis, articular fossa GL nonuniformity, and long-run low GL emphasis; and higher values of superior joint space, mouth opening, saliva Vascular-endothelium-growth-factor, Matrix-metalloproteinase-7, serum Epithelial-neutrophil-activating-peptide, and age indicate recovery likelihood. Our multidimensional and multimodal EHPN tool enhances clinicians' decision-making, offering a transformative translational infrastructure. The EHPN model stands as a significant contribution to precision medicine, offering a paradigm shift in the management of temporomandibular disorders and potentially influencing broader applications in personalized healthcare.

Therapeutic CRISPR epigenome editing of inflammatory receptors in the intervertebral disc.

Low back pain (LBP) ranks among the leading causes of disability worldwide and generates a tremendous socioeconomic cost. Disc degeneration, a leading contributor to LBP, can be characterized by the breakdown of the extracellular matrix of the intervertebral disc (IVD), disc height loss, and inflammation. The inflammatory cytokine tumor necrosis factor α (TNF-α) has multiple signaling pathways, including proinflammatory signaling through tumor necrosis factor receptor 1 superfamily, member 1a (TNFR1 or TNFRSF1A), and has been implicated as a primary mediator of disc degeneration. We tested our ability to regulate the TNFR1 signaling pathway in vivo, utilizing CRISPR epigenome editing to slow the progression of disc degeneration in rats. Sprague-Dawley rats were treated with TNF-α and CRISPR interference (CRISPRi)-based epigenome-editing therapeutics targeting TNFR1, showing decreased behavioral pain in a disc degeneration model. Surprisingly, while treatment with the vectors alone was therapeutic, the TNF-α injection became therapeutic after TNFR1 modulation. These results suggest direct inflammatory receptor modulation as a potent strategy for treating disc degeneration.

Dedifferentiation-like reprogramming of degenerative nucleus pulposus cells into notochordal-like cells by defined factors.

The extensive degeneration of functional somatic cells and the depletion of endogenous stem/progenitor populations present significant challenges to tissue regeneration in degenerative diseases. Currently, a cellular reprogramming approach enabling directly generating corresponding progenitor populations from degenerative somatic cells remains elusive. The present study focused on intervertebral disc degeneration (IVDD) and identified a three-factor combination (OCT4, FOXA2, TBXT [OFT]) that could induce the dedifferentiation-like reprogramming of degenerative nucleus pulposus cells (dNPCs) toward induced notochordal-like cells (iNCs). Single-cell transcriptomics dissected the transitions of cell identity during reprogramming. Further, OCT4 was found to directly interact with bromodomain PHD-finger transcription factor to remodel the chromatin during the early phases, which was crucial for initiating this dedifferentiation-like reprogramming. In rat models, intradiscal injection of adeno-associated virus carrying OFT generated iNCs from in situ dNPCs and reversed IVDD. These results collectively present a proof-of-concept for dedifferentiation-like reprogramming of degenerated somatic cells into corresponding progenitors through the development of a factor-based strategy, providing a promising approach for regeneration in degenerative disc diseases.

Targeting lysosomal quality control as a therapeutic strategy against aging and diseases.

Previously, lysosomes were primarily referred to as the digestive organelles and recycling centers within cells. Recent discoveries have expanded the lysosomal functional scope and revealed their critical roles in nutrient sensing, epigenetic regulation, plasma membrane repair, lipid transport, ion homeostasis, and cellular stress response. Lysosomal dysfunction is also found to be associated with aging and several diseases. Therefore, function of macroautophagy, a lysosome-dependent intracellular degradation system, has been identified as one of the updated twelve hallmarks of aging. In this review, we begin by introducing the concept of lysosomal quality control (LQC), which is a cellular machinery that maintains the number, morphology, and function of lysosomes through different processes such as lysosomal biogenesis, reformation, fission, fusion, turnover, lysophagy, exocytosis, and membrane permeabilization and repair. Next, we summarize the results from studies reporting the association between LQC dysregulation and aging/various disorders. Subsequently, we explore the emerging therapeutic strategies that target distinct aspects of LQC for treating diseases and combatting aging. Lastly, we underscore the existing knowledge gap and propose potential avenues for future research.

Identification of molecular targets and small drug candidates for Huntington's disease via bioinformatics and a network-based screening approach.

Huntington's disease (HD) is a gradually severe neurodegenerative ailment characterised by an increase of a specific trinucleotide repeat sequence (cytosine-adenine-guanine, CAG). It is passed down as a dominant characteristic that worsens over time, creating a significant risk. Despite being monogenetic, the underlying mechanisms as well as biomarkers remain poorly understood. Furthermore, early detection of HD is challenging, and the available diagnostic procedures have low precision and accuracy. The research was conducted to provide knowledge of the biomarkers, pathways and therapeutic targets involved in the molecular processes of HD using informatic based analysis and applying network-based systems biology approaches. The gene expression profile datasets GSE97100 and GSE74201 relevant to HD were studied. As a consequence, 46 differentially expressed genes (DEGs) were identified. 10 hub genes (TPM1, EIF2S3, CCN2, ACTN1, ACTG2, CCN1, CSRP1, EIF1AX, BEX2 and TCEAL5) were further differentiated in the protein-protein interaction (PPI) network. These hub genes were typically down-regulated. Additionally, DEGs-transcription factors (TFs) connections (e.g. GATA2, YY1 and FOXC1), DEG-microRNA (miRNA) interactions (e.g. hsa-miR-124-3p and has-miR-26b-5p) were also comprehensively forecast. Additionally, related gene ontology concepts (e.g. sequence-specific DNA binding and TF activity) connected to DEGs in HD were identified using gene set enrichment analysis (GSEA). Finally, in silico drug design was employed to find candidate drugs for the treatment HD, and while the possible modest therapeutic compounds (e.g. cortistatin A, 13,16-Epoxy-25-hydroxy-17-cheilanthen-19,25-olide, Hecogenin) against HD were expected. Consequently, the results from this study may give researchers useful resources for the experimental validation of Huntington's diagnosis and therapeutic approaches.

Intrinsic structural vulnerability in the hydrophobic core induces species-specific aggregation of canine SOD1 with degenerative myelopathy-linked E40K mutation.

Canine degenerative myelopathy (DM), a fatal neurodegenerative disease in dogs, shares clinical and genetic features with amyotrophic lateral sclerosis, a human motor neuron disease. Mutations in the SOD1 gene encoding Cu/Zn superoxide dismutase (SOD1) cause canine DM and a subset of inherited human amyotrophic lateral sclerosis. The most frequent DM causative mutation is homozygous E40K mutation, which induces the aggregation of canine SOD1 but not of human SOD1. However, the mechanism through which canine E40K mutation induces species-specific aggregation of SOD1 remains unknown. By screening human/canine chimeric SOD1s, we identified that the humanized mutation of the 117th residue (M117L), encoded by exon 4, significantly reduced aggregation propensity of canine SOD1E40K. Conversely, introducing a mutation of leucine 117 to methionine, a residue homologous to canine, promoted E40K-dependent aggregation in human SOD1. M117L mutation improved protein stability and reduced cytotoxicity of canine SOD1E40K. Furthermore, crystal structural analysis of canine SOD1 proteins revealed that M117L increased the packing within the hydrophobic core of the ß-barrel structure, contributing to the increased protein stability. Our findings indicate that the structural vulnerability derived intrinsically from Met 117 in the hydrophobic core of the ß-barrel structure induces E40K-dependent species-specific aggregation in canine SOD1.

Neuromotor decline is associated with gut dysbiosis following surgical decompression for Degenerative Cervical Myelopathy.

Degenerative cervical myelopathy (DCM) describes a spectrum of disorders that cause progressive and chronic cervical spinal cord compression. The clinical presentation can be complex and can include locomotor impairment, hand and upper extremity dysfunction, pain, loss of bladder and bowel function, as well as gastrointestinal dysfunction. Once diagnosed, surgical decompression is the recommended treatment for DCM patients with moderate to severe impairment. Our body is composed of a large community of microorganisms, known as the microbiota. Traumatic and non-traumatic spinal cord injuries (SCIs) can induce changes in the gut microbiota and gut microbiota derived metabolites. These changes have been reported as important disease-modifying factors after injury. However, whether gut dysbiosis is associated with functional neurological recovery after surgical decompression has not been examined to date. Here, DCM was induced in C57BL/6 mice by implanting an aromatic polyether material underneath the C5-6 laminae. The extent of gut dysbiosis was assessed by gas chromatography and 16S rRNA sequencing from fecal samples before and after decompression. Neuromotor activity was assessed using the Catwalk test. Our results show that DCM pre- and post- surgical decompression is associated with gut dysbiosis, without altering short chain fatty acids (SCFAs) levels. Significant differences in Clostridia, Verrumicrobiae, Lachnospiracea, Firmicutes, Bacteroidales, and Clostridiaceae were observed between the DCM group (before decompression) and after surgical decompression (2 and 5 weeks). The changes in gut microbiota composition correlated with locomotor features of the Catwalk. For example, a longer duration of ground contact and dysfunctional swing in the forelimbs, were positively correlated with gut dysbiosis. These results show for the first time an association between gut dysbiosis and locomotor deterioration after delayed surgical decompression. Thus, providing a better understanding of the extent of changes in microbiota composition in the setting of DCM pre- and post- surgical decompression.

The role of hydrogen sulfide regulation of ferroptosis in different diseases.

Ferroptosis is a programmed cell death that relies on iron and lipid peroxidation. It differs from other forms of programmed cell death such as necrosis, apoptosis and autophagy. More and more evidence indicates that ferroptosis participates in many types of diseases, such as neurodegenerative diseases, ischemia-reperfusion injury, cardiovascular diseases and so on. Hence, clarifying the role and mechanism of ferroptosis in diseases is of great significance for further understanding the pathogenesis and treatment of some diseases. Hydrogen sulfide (H2S) is a colorless and flammable gas with the smell of rotten eggs. Many years ago, H2S was considered as a toxic gas. however, in recent years, increasing evidence indicates that it is the third important gas signaling molecule after nitric oxide and carbon monoxide. H2S has various physiological and pathological functions such as antioxidant stress, anti-inflammatory, anti-apoptotic and anti-tumor, and can participate in various diseases. It has been reported that H2S regulation of ferroptosis plays an important role in many types of diseases, however, the related mechanisms are not fully clear. In this review, we reviewed the recent literature about the role of H2S regulation of ferroptosis in diseases, and analyzed the relevant mechanisms, hoping to provide references for future in-depth researches.

Photoreceptor-Mimetic Microflowers for Restoring Light Responses in Degenerative Retina through a 2D Nanopetal/Cell Biointerface.

Retinitis pigmentosa is the main cause of inherited human blindness and is associated with dysfunctional photoreceptors (PRs). Compared with traditional methods, optoelectronic stimulation can better preserve the structural integrity and genetic content of the retina. However, enhancing the spatiotemporal accuracy of stimulation is challenging. Quantum dot-doped ZnIn2S4 microflowers (MF) are utilized to construct a biomimetic photoelectric interface with a 0D/3D heterostructure, aiming to restore the light response in PR-degenerative mice. The MF bio interface has dimensions similar to those of natural PRs and can be distributed within the curved spatial region of the retina, mimicking cellular dispersion. The soft 2D nano petals of the MF provide a large specific surface area for photoelectric activation and simulate the flexibility interfacing between cells. This bio interface can selectively restore the light responses of seven types of retina ganglion cells that encode brightness. The distribution of responsive cells forms a pattern similar to that of normal mice, which may reflect the generation of the initial "neural code" in the degenerative retina. Patch-clamp recordings indicate that the bio interface can induce spiking and postsynaptic currents at the single-neuron level. The results will shed light on the development of a potential bionic subretinal prosthetic toolkit for visual function restoration.

Extracellular Vesicle-Contained Thrombospondin 1 Retards Age-Related Degenerative Tendinopathy by Rejuvenating Tendon Stem/Progenitor Cell Senescence.

Advanced age is a major risk factor for age-related degenerative tendinopathy. During aging, tendon stem/progenitor cell (TSPC) function declines owing to the transition from a normal quiescent state to a senescent state. Extracellular vesicles (EVs) from young stem cells are reported to possess anti-aging functions. However, it remains unclear whether EVs from young TSPCs (TSPC-EVs) can rejuvenate senescent TSPCs to delay age-related degeneration. Here, this study finds that TSPC-EVs can mitigate the aging phenotypes of senescent TSPCs and maintain their tenogenic capacity. In vitro studies reveal that TSPC-EVs can reinstall autophagy in senescent TSPCs to alleviate cellular senescence, and that the re-establishment of autophagy is mediated by the PI3K/AKT pathway. Mechanistically, this study finds that thrombospondin 1, a negative regulator of the PI3K/AKT pathway, is enriched in TSPC-EVs and can be transported to senescent TSPCs. Moreover, in vivo studies show that the local delivery of TSPC-EVs can rejuvenate senescent TSPCs and promote their tenogenic differentiation, thereby rescuing tendon regeneration in aged rats. Taken together, TSPC-EVs as a novel cell-free approach have promising therapeutic potential for aging-related degenerative tendinopathy.

Magnetic resonance imaging characteristics in patients with psoriatic arthritis and axial manifestations from the MAXIMISE cohort.

OBJECTIVE: The current analysis of the MAXIMISE trial was conducted to investigate the presence of post-inflammatory and degenerative spinal changes and inflammatory changes in spinal processes identified in baseline MRIs and their potential for predicting differential treatment effects in a cohort of PsA patients with axial manifestations. METHODS: Baseline spinal MRIs from the MAXIMISE trial were re-read to identify additional inflammatory (spinal process), post-inflammatory, and degenerative changes, and investigate the differential treatment effect of these imaging features using logistic regression modelling. RESULTS: In addition to bone marrow oedema assessed at primary analysis, spinal process inflammation and post-inflammatory changes evaluated by FAt Spondyloarthritis Spine Score were documented in 11.1% and 20.2% patients, respectively. At least one type of degenerative change was noted in 64% patients, with Pfirrmann grade ≥3 (51.1%) being the most common. Combining primary and re-read MRI findings, 67.1% of patients presented with inflammatory or post-inflammatory changes while 21.2% had degenerative changes alone. Although not statistically significant, post-inflammatory changes were associated with a trend for better efficacy outcomes in terms of ASAS20, ASAS40 and BASDAI50 responses; a trend for worse outcomes was observed in the presence of degenerative changes. CONCLUSION: The current analysis revealed the occurrence of additional inflammatory and post-inflammatory changes suggestive of axial PsA (axPsA) and a trend for better clinical outcomes for patients treated with secukinumab. These results elucidate the imaging characteristics and improve our current understanding of axPsA thereby supporting the interpretation of future trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02721966.

Outcomes of Mitral Valve Repair for Posterior Leaflet Prolapse, Anterior Leaflet Prolapse, and Bileaflet Prolapse.

Background: Mitral valve repair (MVr) is an effective treatment for degenerative mitral regurgitation (DMR).And the outcomes and repair rates for posterior leaflet prolapse (PLP), anterior leaflet prolapse (ALP), and bileaflet prolapse (BLP) vary. This study aimed to compare the outcomes of mitral valve repair for patients with PLP, ALP, and BLP. Methods: From 2010 to 2019, 1192 patients with degenerative mitral valve regurgitation underwent surgery at our hospital. And 1069 patients were identified. The average age of all patients was (54.74 ± 12.17) years old for all patients. 273 patients (25.5%) had ALP, 148 patients (13.8%) had BLP, and 648 patients (60.6%) had PLP. All patients were followed up for an average duration of 5.1 years. We compared the outcomes of patients with ALP, PLP, and BLP. Results: Patients with ALP were the youngest of the 3 groups and had the highest prevalence of atrial fibrillation. Patients with PLP had the highest prevalence of hypertension, whereas patients with BLP and ALP had larger left ventricular end-diastolic and left ventricular end-systolic diameters. ALP and BLP repairs had a longer cardiopulmonary bypass and aortic cross-clamp time.10 patients dead in-hospital, 5 patients had PLP, 3 had ALP, and 2 had BLP. The 10-year survival cumulative incidences of reoperation among ALP, BLP, and PLP repairs were not significantly different. ALP repair still had higher cumulative incidences of recurrent mitral regurgitation (MR) compared to PLP. Conclusions: The rates of long-term survival and freedom from reoperation were not significantly different among patients with ALP, BLP, and PLP. ALP repair has higher cumulative incidences of recurrent MR compared to PLP.

Characterization of Age-Related and Sex-Related Differences of Relaxation Parameters in the Intervertebral Disc Using MR-Fingerprinting.

BACKGROUND: Multiparameter characterization using MR fingerprinting (MRF) can quantify multiple relaxation parameters of intervertebral disc (IVD) simultaneously. These parameters may vary by age and sex. PURPOSE: To investigate age- and sex-related differences in the relaxation parameters of the IVD of the lumbar spine using a multiparameter MRF technique. STUDY TYPE: Prospective. SUBJECTS: 17 healthy subjects (8 male; mean age = 34 ± 10 years, range 20-60 years). FIELD STRENGTH/SEQUENCE: 3D-MRF sequence for simultaneous acquisition of proton density, T1 , T2 , and T1ρ maps at 3.0T. ASSESSMENT: Global mean T1 , T2 , and T1ρ of all lumbar IVDs and mean T1 , T2 , and T1ρ of each individual IVD (L1-L5) were measured. Gray level co-occurrence matrix was used to quantify textural features (median, contrast, correlation, energy, and homogeneity) from T1 , T2 , and T1ρ maps. STATISTICAL TESTS: Spearman rank correlations (R) evaluated the association between age and T1 , T2 , and T1ρ of IVD. Mann-Whitney U-tests evaluated differences between males and females in T1 , T2 , and T1ρ of IVD. Statistical significance was defined as P-value <0.05. RESULTS: There was a significant negative correlation between age and global mean values of all IVDs for T1 (R = -0.637), T2 (R = -0.509), and T1ρ (R = -0.726). For individual IVDs, there was a significant negative correlation between age and mean T1 at all IVD segments (R range = -0.530 to -0.708), between age and mean T2 at L2-L3, L3-L4, and L4-L5 (R range = -0.493 to 0.640), and between age and mean T1ρ at all segments except L1-L2 (R range = -0.632 to -0.763). There were no significant differences between sexes in global mean T1 , T2, and T1ρ (P-value = 0.23-0.76) The texture features with the highest significant correlations with age for all IVDs were global T1ρ mean (R = -0.726), T1 energy (R = -0.681), and T1 contrast (R = 0.709). CONCLUSION: This study showed that the 3D-MRF technique has potential to characterize age-related differences in T1 , T2, or T1ρ of IVD in healthy subjects. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Comparing CT-Like Images Based on Ultra-Short Echo Time and Gradient Echo T1-Weighted MRI Sequences for the Assessment of Vertebral Disorders Using Histology and True CT as the Reference Standard.

BACKGROUND: Several magnetic resonance (MR) techniques have been suggested for radiation-free imaging of osseous structures. PURPOSE: To compare the diagnostic value of ultra-short echo time and gradient echo T1-weighted MRI for the assessment of vertebral pathologies using histology and computed tomography (CT) as the reference standard. STUDY TYPE: Prospective. SUBJECTS: Fifty-nine lumbar vertebral bodies harvested from 20 human cadavers (donor age 73 ± 13 years; 9 male). FIELD STRENGTH/SEQUENCE: Ultra-short echo time sequence optimized for both bone (UTEb) and cartilage (UTEc) imaging and 3D T1-weighted gradient-echo sequence (T1GRE) at 3 T; susceptibility-weighted imaging (SWI) gradient echo sequence at 1.5 T. CT was performed on a dual-layer dual-energy CT scanner using a routine clinical protocol. ASSESSMENT: Histopathology and conventional CT were acquired as standard of reference. Semi-quantitative and quantitative morphological features of degenerative changes of the spines were evaluated by four radiologists independently on CT and MR images independently and blinded to all other information. Features assessed were osteophytes, endplate sclerosis, visualization of cartilaginous endplate, facet joint degeneration, presence of Schmorl's nodes, and vertebral dimensions. Vertebral disorders were assessed by a pathologist on histology. STATISTICAL TESTS: Agreement between T1GRE, SWI, UTEc, and UTEb sequences and CT imaging and histology as standard of reference were assessed using Fleiss' κ and intra-class correlation coefficients, respectively. RESULTS: For the morphological assessment of osteophytes and endplate sclerosis, the overall agreement between SWI, T1GRE, UTEb, and UTEc with the reference standard (histology combined with CT) was moderate to almost perfect for all readers (osteophytes: SWI, κ range: 0.68-0.76; T1GRE: 0.92-1.00; UTEb: 0.92-1.00; UTEc: 0.77-0.85; sclerosis: SWI, κ range: 0.60-0.70; T1GRE: 0.77-0.82; UTEb: 0.81-0.92; UTEc: 0.61-0.71). For the visualization of the cartilaginous endplate, UTEc showed the overall best agreement with the reference standard (histology) for all readers (κ range: 0.85-0.93). DATA CONCLUSIONS: Morphological assessment of vertebral pathologies was feasible and accurate using the MR-based bone imaging sequences compared to CT and histopathology. T1GRE showed the overall best performance for osseous changes and UTEc for the visualization of the cartilaginous endplate. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Contribution of extracellular vesicles for the pathogenesis of retinal diseases: shedding light on blood-retinal barrier dysfunction.

Retinal degenerative diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), loom as threats to vision, causing detrimental effects on the structure and function of the retina. Central to understanding these diseases, is the compromised state of the blood-retinal barrier (BRB), an effective barrier that regulates the influx of immune and inflammatory components. Whether BRB breakdown initiates retinal distress, or is a consequence of disease progression, remains enigmatic. Nevertheless, it is an indication of retinal dysfunction and potential vision loss.The intricate intercellular dialogues among retinal cell populations remain unintelligible in the complex retinal milieu, under conditions of inflammation and oxidative stress. The retina, a specialized neural tissue, sustains a ceaseless demand for oxygen and nutrients from two vascular networks. The BRB orchestrates the exchange of molecules and fluids within this specialized region, comprising the inner BRB (iBRB) and the outer BRB (oBRB). Extracellular vesicles (EVs) are small membranous structures, and act as messengers facilitating intercellular communication in this milieu.EVs, both from retinal and peripheral immune cells, increase complexity to BRB dysfunction in DR and AMD. Laden with bioactive cargoes, these EVs can modulate the retinal microenvironment, influencing disease progression. Our review delves into the multifaceted role of EVs in retinal degenerative diseases, elucidating the molecular crosstalk they orchestrate, and their microRNA (miRNA) content. By shedding light on these nanoscale messengers, from their biogenesis, release, to interaction and uptake by target cells, we aim to deepen the comprehension of BRB dysfunction and explore their therapeutic potential, therefore increasing our understanding of DR and AMD pathophysiology.

The role of miR-155-5p in inflammation and mechanical loading during intervertebral disc degeneration.

BACKGROUND: Intervertebral disc (IVD) degeneration is a multifactorial pathological process resulting in the dysregulation of IVD cell activity. The catabolic shift observed in IVD cells during degeneration leads to increased inflammation, extracellular matrix (ECM) degradation, aberrant intracellular signaling and cell loss. Importantly, these pathological processes are known to be interconnected and to collectively contribute to the progression of the disease. MicroRNAs (miRNAs) are known as strong post-transcriptional regulators, targeting multiple genes simultaneously and regulating numerous intracellular pathways. Specifically, miR-155-5p has been of particular interest since it is known as a pro-inflammatory mediator and contributing factor to diseases like cancer and osteoarthritis. This study investigated the role of miR-155-5p in IVD degeneration with a specific focus on inflammation and mechanosensing. METHODS: Gain- and loss-of-function studies were performed through transfection of human Nucleus pulposus (NP) and Annulus fibrosus (AF) cells isolated from degenerated IVDs with miR-155-5p mimics, inhibitors or their corresponding non-targeting control. Transfected cells were then subjected to an inflammatory environment or mechanical loading. Conditioned media and cell lysates were collected for phosphorylation and cytokine secretion arrays as well as gene expression analysis. RESULTS: Increased expression of miR-155-5p in AF cells resulted in significant upregulation of interleukin (IL)-8 cytokine secretion during cyclic stretching and a similar trend in IL-6 secretion during inflammation. Furthermore, miR-155-5p mimics increased the expression of the brain-derived neurotrophic factor (BDNF) in AF cells undergoing cyclic stretching. In NP cells, miR-155-5p gain-of-function resulted in the activation of the mitogen-activated protein kinase (MAPK) signaling pathway through increased phosphorylation of p38 and p53. Lastly, miR-155-5p inhibition caused a significant increase in the anti-inflammatory cytokine IL-10 in AF cells and the tissue inhibitor of metalloproteinases (TIMP)-4 in NP cells respectively. CONCLUSION: Overall, these results show that miR-155-5p contributes to IVD degeneration by enhancing inflammation through pro-inflammatory cytokines and MAPK signaling, as well as by promoting the catabolic shift of AF cells during mechanical loading. The inhibition of miR-155-5p may constitute a potential therapeutic approach for IVD degeneration and low back pain.

Controlled mitral valvuloplasty using steerable catheter- waist- formed balloon system: A clinical case series.

As the general population ages, the incidence of degenerative mitral stenosis (MS) among patients has increased. Percutaneous mitral valvuloplasty (PMV) has emerged as a well-established option for mitral rheumatic stenosis with specific characteristics. However, a blank therapeutic space must be filled with the treatment options for degenerative or rheumatic mitral stenosis in patients with many comorbidities and contraindication for valvuloplasty. We here present a comprehensive overview of the current possibilities, despite their scarce success. That is the reason why we propose a case series to facilitate a better understanding of our innovative technique in this challenging clinical context.

Reconsidering Neurogenetic Indication in the Human Brain: Broad Expression of Doublecortin Transcript in the Hippocampal and Cortical Cell Populations.

INTRODUCTION: Neurogenesis in the adult brain may play an important role in memory and cognition; however, knowledge of neurogenic markers in the human brain remains limited. We compared the single-nucleus transcriptome of the hippocampus with that of other cortical regions to identify hippocampus-specific neurogenic markers. METHODS: We analyzed 26,189 nuclei from four human brains collected within 16 h of death. Clustering and annotation were performed to examine differential expression, gene ontology, and intercellular communication. DCX expression was validated by ddPCR. RESULTS: Immature markers such as DCX, CALB2, NES, SOX2, PAX6, DPYSL3, and TUBB3 were expressed in both hippocampus and prefrontal cortex, with higher levels in the prefrontal cortex. ddPCR confirmed higher expression of DCX in the prefrontal cortex. DCX was involved in both neurogenesis and neuroprotection pathways. CONCLUSION: Neurogenic markers are not definitive indicators of adult neurogenesis as their roles are more complex than previously understood.

Evolving role of VIADISC for chronic low back and discogenic pain: a narrative review.

INTRODUCTION: Chronic lower back pain is a leading cause of disability and healthcare spending worldwide. Discogenic pain, pain originating from the intervertebral disk, is a common etiology of chronic lower back pain. Currently, accepted treatments for chronic discogenic pain focus only on the management of symptoms, such as pain. There are no approved treatments that stop or reverse degenerating intervertebral discs. Biologic therapies promoting disc regeneration have been developed to expand treatment options. VIADISC™ NP, is a viable disc allograft supplementation that, in a recent trial, demonstrated a significant reduction in pain and increased function in patients suffering from symptomatic degenerative disc disease. AREAS COVERED: This manuscript summarizes the epidemiology and etiology of low back pain, the pathophysiology of degenerative disc disease, current treatments, and a need for newer therapies. The rationale behind intradiscal biologics for the treatment of symptomatic degenerative disc disease is also discussed. EXPERT OPINION: Characterization of the biology leading to disc degeneration has allowed for the development of intradiscal biologics. They may soon be capable of preventing and reversing disc degeneration. Clinical trials have shown promise, but further research into efficacy and safety is needed before these therapies are widely employed.

Encapsulated cell technology: Delivering cytokines to treat posterior ocular diseases.

Encapsulated cell technology (ECT) is a targeted delivery method that uses the genetically engineered cells in semipermeable polymer capsules to deliver cytokines. Thus far, ECT has been extensively utilized in pharmacologic research, and shows enormous potentials in the treatment of posterior segment diseases. Due to the biological barriers within the eyeball, it is difficult to attain effective therapeutic concentration in the posterior segment through topical administration of drug molecules. Encouragingly, therapeutic cytokines provided by ECT can cross these biological barriers and achieve sustained release at the desired location. The encapsulation system uses permeable materials that allow growth factors and cytokines to diffuse efficiently into retinal tissue. Moreover, the ECT based treatment can be terminated timely when we need to retrieve the implant, which makes the therapy reversible and provides a safer alternative for intraocular gene therapy. Meanwhile, we also place special emphasis on optimizing encapsulation materials and enhancing preservation techniques to achieve the stable release of growth factors and cytokines in the eyeball. This technology holds great promise for the treatment of patients with dry AMD, RP, glaucoma and MacTel. These findings would enrich our understandings of ECT and promote its future applications in treatment of degenerative retinopathy. This review comprises articles evaluating the exactness of artificial intelligence-based formulas published from 2000 to March 2024. The papers were identified by a literature search of various databases (PubMed/MEDLINE, Google Scholar, Cochrane Library and Web of Science).