Stages Of Progression Research Articles

PROMOTING PARTICIPATION IN COMMUNITY RUNNING FESTIVALS FOR INDIVIDUALS WITH PARKINSON’S DISEASE - A MODEL FOR MEANINGFUL PARTICIPATION

INTRODUCTION AND AIMS Community-based walking and running groups have become popular social phenomena in recent years. Integrating individuals with Parkinson’s disease into community-based walking and running events confers multiple socio-biological benefits, but may be problematic for individuals with Parkinson’s disease in the later stages of the disease progression. METHODS This research evaluates the participation of a group of individuals with Parkinson’s disease in a long-standing community running festival, the Gold Coast Marathon Festival. Evaluation of participation comprised: 1) description of the activities undertaken by the Exercise Physiologists to ensure the safe and effective participation of the interested parties; and 2) a qualitative evaluation of the participant’s experiences with the event. RESULTS Ten adults with Parkinson’s disease (70% male), mean age 69.6 ± 7.8 years (range = 57-79) participated. Time post-diagnosis ranged 1 to 15 years (mean = 6.7 ± 4.4 years). Participants registered to complete one of two distances: 5.7 km (n = 9) or 700 m (n = 1). Activities undertaken by the Exercise Physiologist prior to participating were divided into three themes: participation, safety, and administrative requirements. Participant experiential data was divided into six themes: preparation prior to participating; pre participation planning and organisation; reasons/meaning for choosing to participate; barriers for participating; event recovery; and event suitability. The data collated was triangulated to provide recommendations to facilitate participation in similar events. CONCLUSION The results of this study demonstrate that with effective planning and coordination, participation in community-based walking and running events confer physical and mental health benefits for individuals with Parkinson’s disease. However, significant barriers need to be addressed prior to participation to ensure meaningful participation. This paper provides recommendations for practicing Exercise Physiologists who wish to promote participation of their own clients with Parkinson’s disease in similar initiatives.

Bruceine A alleviates alcoholic liver disease by inhibiting AIM2 inflammasome activation via activating FXR

BackgroundAlcoholic liver disease (ALD), a public health challenge worldwide caused by long-term persistent drinking, is life-threatening with minimal approved therapies. Hepatic steatosis accompanied by inflammation is an initial and inevitable stage in the complex progression of simple alcoholic liver injury to more severe liver diseases such as hepatitis, liver fibrosis, cirrhosis and liver cancer. PurposeWe aimed to identify the therapeutic role of Bruceine A (BA) in ALD whilst attempting to explore whether its protective effects depend specifically on the farnesoid X receptor (FXR). MethodsAutodock was applied to detect the affinity between BA and FXR. Lieber-DeCarli liquid diet with 5% ethanol (v/v) was adopted to establish the mouse ALD model. The lentivirus mediating FXR (LV-FXR) was injected into mice via the tail vein to establish FXR-overexpressed mice. FXR silencing or overexpression plasmids were transfected into AML-12 cells prior to ethanol stimulation. Quantitative real-time PCR, Western blotting and immunofluorescence assays were employed to determine the expression of related genes. We subjected liver sections to H&E and Oil Red O staining to evaluate the liver histological injury and the deposition of lipid droplets. ResultsBA significantly reduced body weight and liver-to-body weight ratios as well as biochemical indexes in mice. Ethanol-induced liver damage and lipid accumulation could be alleviated by BA treatment. BA bound to FXR by two hydrogen bonds. There was a positive correlation between BA administration and FXR expression. BA inhibited the expression of lipid synthesis genes and enhanced the expression of lipid metabolism genes by activating FXR, thus alleviating steatosis in ALD. Moreover, BA exerted an ameliorative effect against inflammation by inhibiting the activation of absent in melanoma 2 (AIM2) inflammasome by activating FXR. FXR overexpression possessed the ability to counter the accumulation of lipid and the activation of AIM2 inflammasome caused by ethanol. FXR deficiency exacerbated ethanol-induced liver steatosis and inflammation. The hepatoprotective effect of BA could be disrupted by FXR antagonist guggulsterone (GS) in vivo and FXR siRNA in vitro. ConclusionBA alleviated alcoholic liver disease by inhibiting AIM2 inflammasome activation through an FXR-dependent mechanism. This study may potentially represent a new therapeutic approach for ALD.

Mechanism of action and clinical trial results of Lecanemab (Leqembi® 200 ‍mg, 500 ‍mg for Intravenous Infusion), a novel treatment for Alzheimer's disease

Lecanemab is a humanized monoclonal antibody directed against human soluble amyloid-β aggregates. It was developed for the treatment of early Alzheimer's disease (mild cognitive impairment or mild dementia stage of Alzheimer's disease). Among the amyloid-β (Aβ) involved in Alzheimer's disease, Lecanemab selectively binds to the highly neurotoxic Aβ protofibrils, and is thought to reduce Aβ protofibrils and amyloid plaques (Aβ plaques) in the brain. The efficacy and safety of Lecanemab in early Alzheimer's disease were investigated in an international Phase II placebo-controlled study (Study 201) and an international Phase III placebo-controlled study (Study 301). Both studies included Japanese subjects. Lecanemab was given accelerated approval in the United States in January 2023, followed by traditional approval in July 2023. In Japan, it was approved for "control of the progression of mild cognitive impairment or mild dementia stage of Alzheimer's disease" in September 2023, and was added to the NHI drug price list in December 2023.

The comprehensive roles of lncRNA FAM99A/FAM99B in hepatocellular carcinoma: Expressions, regulatory mechanisms and functional pathway analysis

AimsThe incidence and mortality of liver hepatocellular carcinoma (LIHC) were increasing year by year. The aim of this study was to investigate the comprehensive roles of lncRNA FAM99A and FAM99B in LIHC. Main methodsAccording to the data of TCGA and GTEx, the expression levels of FAM99A and FAM99B in LIHC were evaluated, and the overall survival (OS), disease-free survival (DFS), immune cell infiltration and tumor stage were analyzed. The subcellular localization of FAM99A and FAM99B in various cancer cell lines was predicted by lncATLAS database. In addition, we also used ENCORI, KEGG, LinkedOmics, Metascape and other databases. It was verified by in vivo and in vitro experiments. Key findingsCompared with adjacent normal tissues, FAM99A and FAM99B were down-regulated in LIHC tissues, and significantly correlated with immune cell infiltration. With the progression of tumor stage and grade, the expression of FAM99A and FAM99B showed a decreasing trend, and the prognosis of patients were also poor. In addition, the biological functions, signaling pathways and protein interactions of FAM99A and FAM99B in LIHC were enriched to study the potential molecular mechanisms. The overlapping RNA binding proteins (RBP) of FAM99A and FAM99B mainly included CSTF2T, BCCIP, RBFOX2 and SF3B4. Finally, experiments showed that overexpression of FAM99A attenuated the proliferation, invasion, colony formation and tumor growth of LIHC cells. SignificanceTaken together, the above studies demonstrated that FAM99A and FAM99B had an inhibitory effect on the progression of LIHC, which might be promising diagnostic biomarkers and therapeutic targets for LIHC patients.

Branching topology of the human embryo transcriptome revealed by entropy sort feature weighting.

Analysis of single cell transcriptomics (scRNA-seq) data is typically performed after sub-setting to highly variable genes (HVGs). Here we show that Entropy Sorting provides an alternative mathematical framework for feature selection. On synthetic datasets, continuous entropy sort feature weighting (cESFW) outperforms HVG selection in distinguishing cell state specific genes. We apply cESFW to six merged scRNA-seq datasets spanning human early embryo development. Without smoothing or augmenting the raw counts matrices, cESFW generates a high-resolution embedding displaying coherent developmental progression from 8-cell to post-implantation stages and delineating 15 distinct cell states. The embedding highlights sequential lineage decisions during blastocyst development while unsupervised clustering identifies branch point populations obscured in previous analyses. The first branching region, where morula cells become specified for inner cell mass or trophectoderm, includes cells previously asserted to lack a developmental trajectory. We quantify the relatedness of different pluripotent stem cell cultures to distinct embryo cell types and identify marker genes of naïve and primed pluripotency. Finally, by revealing genes with dynamic lineage-specific expression we provide markers for staging progression from morula to blastocyst.

Application of Glucocorticoids in Therapy of Multiple Sclerosis

Multiple sclerosis is an autoimmune disease affecting the central nervous system that causes significant disability and healthcare burden. Pulse-dosaged glucocorticoids therapy remains the mainstay of treatment of exacerbations of multiple sclerosis. A total of 98 patients were examined, including 28 patients with relapsing-remitting multiple sclerosis (24 women and 4 men) and 70 patients with secondary progressive multiple sclerosis (57 women and 13 men). The number of glucocorticoids therapy courses in 98 patients at all disease stages totalled 536: 98 in relapsing-remitting multiple sclerosis (9 at debuts and 89 at relapsing-remitting stage) and 438 in secondary progredient multiple sclerosis (11 at debuts, 178 at relapsing-remitting stage, and 249 at secondary progression stage). The efficacy of repeated courses of glucocorticoids therapy in patients with RR and secondary progredient multiple sclerosis was evaluated at different stages of the disease progression: debut in relapsing-remitting and secondary progredient multiple sclerosis, relapsing-remitting stage in relapsing-remitting and secondary progredient multiple sclerosis, and secondary progression stage in secondary progredient multiple sclerosis, including retrospective analysis. Important conclusions have been made about complex systemic reorganisation at different stages of relapsing-remitting and secondary-progredient types of multiple sclerosis, efficiency of glucocorticoids therapy in different types of multiple sclerosis and stages of pathological process and about influence of glucocorticoids therapy on the prognosis of the disease.

FMRI 데이터를 이용한 알츠하이머 진행상태 분류

The development of functional magnetic resonance imaging (fMRI) has significantly contributed to mapping brain functions and understanding brain networks during rest. This paper proposes a CNN-LSTM-based classification model to classify the progression stages of Alzheimer's disease. Firstly, four preprocessing steps are performed to remove noise from the fMRI data before feature extraction. Secondly, the U-Net architecture is utilized to extract spatial features once preprocessing is completed. Thirdly, the extracted spatial features undergo LSTM processing to extract temporal features, ultimately leading to classification. Experiments were conducted by adjusting the temporal dimension of the data. Using 5-fold cross-validation, an average accuracy of 96.4% was achieved, indicating that the proposed method has high potential for identifying the progression of Alzheimer's disease by analyzing fMRI data.

Unstimulated Luteinizing Hormone for Assessment of Suppression During Treatment of Central Precocious Puberty with 6-Month Subcutaneous Leuprolide Acetate: Correlations with Clinical Response.

Phase 3 trial of 6-month subcutaneous leuprolide acetate (SC-LA) in children with central precocious puberty (CPP) demonstrated efficacy and safety. Aims of this secondary analysis: evaluate unstimulated luteinizing hormone (LH) as efficacy measure; assess clinical suppression metrics; and present biochemical and clinical data for subgroups not achieving hormone suppression. 62 children with treatment-naïve CPP received 2 doses of 45 mg SC-LA at 24-week intervals. Unstimulated and GnRH-stimulated LH, E2, and T concentrations were measured. Clinical measures included bone age (BA) and predicted adult height (PAH). 84% and 86% of children achieved unstimulated LH<1IU/L at weeks 24 and 48, respectively. Of 8 children not achieving unstimulated LH<1IU/L at week 24 that completed the study, all showed lack of pubertal stage progression and stable/decreased BA to chronological age ratio (BA/CA). Received operating characteristic (ROC) analyses suggested unstimulated LH is a good diagnostic predictor of GnRH-stimulated LH<4IU/L at week 24 and 48 (AUC=0.88). Across all children, mean BA/CA improved from 1.4 (screening) to 1.3 (week 48) and mean PAH increased by 3cm. Of 7 girls not achieving stimulated LH<4IU/L at week 24, all achieved E2<10pg/mL, showed lack of pubertal stage progression, and had stable or decreased BA/CA by week 48. Additionally, 6/7 had increased PAH by week 48 and 4 had unstimulated LH<1IU/L. Unstimulated LH has value as an efficacy measure and concentrations <1IU/L may be an adequate surrogate of treatment response in children with CPP. All children who completed the study had evidence of pubertal suppression.

Identifying the Unmet Needs of People Living With Amyotrophic Lateral Sclerosis: A National Survey to Inform Interdisciplinary Palliative Care.

Introduction/Aims: This national survey builds on previous qualitative research examining potential palliative care needs among people living with ALS (pALS) by quantifying and investigating relationships among pALS' stage of illness progression; physical, emotional, social, spiritual, and intimacy-related concerns; advance care planning behaviors; perceptions of feeling heard and understood by healthcare providers; and overall quality of life. Methods: Researchers partnered with national organizations to recruit pALS to participate in a one-time survey comprising items from validated instruments (eg, the ALS Specific Quality of Life Instrument-Revised) and researcher-generated measures. Data were analyzed using logistic and linear regression. Results: Among pALS (n = 112), many respondents indicated they had discussed their wishes for end-of-life care with family or friends, shared their wishes with providers, and documented their wishes in writing (79.5%, 49.1%, and 63.4%, respectively). Mean (M) quality of life scores were moderate (M ≈ 6 of 10). Illness stage was associated with documentation of end-of-life care wishes but not with having discussed these wishes with others or with overall quality of life. Reported emotional intimacy received was comparable to that desired (difference = .01 of 10); however, a greater desire for physical intimacy relative to that received was indicated (difference = 1.75 of 10). Discussion: Interdisciplinary palliative care teams may enhance ALS care by promoting advance care planning behaviors (particularly discussing one's wishes with healthcare providers), providing interventions to improve quality of life, and supporting pALS in navigating challenges related to physical intimacy.

Block-wise imputation EM algorithm in multi-source scenario: ADNI case

Alzheimer’s disease is the most common form of dementia and the early detection is essential to prevent its proliferation. Real data available has been of paramount importance in order to achieve progress in the automatic detection despite presenting two major challenges: Multi-source observations containing Magnetic resonance (MRI), Positron emission tomography (PET) and Cerebrospinal fluid data (CSF); and also missing values within all these sources. Most machine learning techniques perform this predictive task by using a single data modality. Nevertheless, the integration of all these sources of evidence could possibly bring a higher performance at different stages of disease progression. The Expectation Maximization (EM) algorithm has been successfully employed to handle missing values, but it is not designed for typical Machine Learning scenarios where an imputation model is created over training data and subsequently applied on a testing set. In this work, we propose EMreg-KNN, a novel supervised and multi-source imputation algorithm. Based on the EM algorithm, EMreg-KNN builds a regression ensemble model for the imputation of future data thus allowing the further utilization of any vector-based Machine Learning method to automatically assess the Alzheimer’s disease diagnosis. Using the ADNI database, the proposed method achieves significant improvements on F1, AUC and Accuracy measures over classical imputation methods for this database using four classification algorithms. Considering these classifiers in four different classification scenarios, our algorithm is experimentally superior in terms of the F measure, in nearly 82% of the cases under evaluation.

Formational stages of natural fractures revealed by U-Pb dating and C-O-Sr-Nd isotopes of dolomites in the Ediacaran Dengying Formation, Sichuan Basin, southwest China

Deep core (>4.9 km) from Ediacaran Deng IV Member algal dolomites in the Gaoshiti-Moxi block in the Sichuan Basin, southwest China, reveals multiple generations of dolomite-lined and dolomite-filled opening-mode fractures. Three progressive stages of fracture formation are marked by crosscutting relations visible in the core, by acoustic emission experiments revealing evidence of past stress directions, and by fluid inclusions, U-Pb ages, C-O-Sr-Nd isotope patterns, and rare earth element data for dolomite cements in fractures, which document ages and differing thermal conditions and fluid compositions during fracture. In calcite-filled fractures, U-Pb ages and carbon and oxygen isotope signatures vary greatly, indicating that fractures developed with intensified tectonic activity marked by regional structures and with enhanced diagenetic alteration. In stage I, WNW-striking opening-mode fractures formed that contain dolomite deposits precipitated from basinal fluids between ca. 549 Ma and ca. 532 Ma. At this time, the Sichuan Basin experienced Xingkai taphrogenesis (rifting) from the late Neoproterozoic to early Cambrian. The central Sichuan paleo-uplift was undergoing ENE extension, and preexisting ESE- and nearly E-W−striking faults were oblique to the ENE principal stress orientation. This led to a local stress field favoring dextral shear near fault zones accommodated by the fractures. In stage II, ENE-striking fractures that are younger based on crosscutting relations contain dolomite deposits from basinal fluids with ages from ca. 423 Ma to ca. 411 Ma. Contemporaneous with Xuefeng thrusting, the central Sichuan paleo-uplift was in a NNE-striking transpressional stress field, which likely further generated ENE-striking fractures. In stage III, nearly N-S−striking fractures formed in the Gaoshiti-Moxi block. High-temperature fluids related to the Permian Emeishan large igneous province invaded these fractures from ca. 260 Ma to ca. 256 Ma. At this time, the Sichuan Basin was uplifted under the influence of the Emei taphrogenesis in the late Permian, and the central Sichuan paleo-uplift was subjected to E-W−striking extension. In fractures in these carbonate rocks, micro-computed tomography imaging reveals that macropores (>10 μm, 12.1%−21.8%) and small pores (2−10 μm, 76.6%−86.1%) dominate the dolomite mineral deposits, and that there are few (1.6%−1.8%) micropores or nanopores (<2 μm). Medium-sized throats (1−3 μm) are the main connecting channels. We infer that fractures served as conduits for fluid migration, leading to the dissolution of matrix pores adjacent to the fractures. This secondary porosity not only enhances reservoir storage capacity but also augments reservoir connectivity. Our study shows that in situ U-Pb dating and full-diameter rock acoustic emission data can effectively constrain the timing of fractures. By integrating this information with regional tectonic sequences and fracture diagenetic sequences from combined relative timing, geochemistry, and rock mechanics evidence, we clarify the factors controlling fracture formation.

MMP13-responsive hydrogel microspheres for osteoarthritis treatment by precise delivery of celecoxib

Osteoarthritis (OA) is characterized by cartilage degradation, inflammatory responses, and osteophyte formation. Matrix metalloproteinase 13 (MMP13) is a hallmark of OA development, and increased MMP13 expression is closely associated with extracellular matrix degradation. MMP13 expression varies significantly at different stages of OA progression. While cyclooxygenase 2 (COX-2) inhibitors are commonly used to treat OA, their long-term systemic administration increases the risks of adverse effects. Therefore, with the aim of achieving localized and responsive delivery of the COX-2 inhibitor celecoxib, the current study investigated an innovative MMP13-responsive micro-nano hydrogel microsphere system. Celecoxib-loaded cationic liposomes are non-covalently attached within the microsphere, enabling controlled drug release for OA treatment. In an OA environment with elevated MMP13 expression, the system is degraded via the action of MMP13 substrate peptide (MMP13sp), facilitating accelerated release of drug-loaded liposomes to improve the inflammatory microenvironment and treat OA rapidly. Compared to a phosphate-buffered saline solution with hyaluronidase (HAase), the prepared hyaluronic acid methacrylate microspheres HAMA/MMP13sp/Lipo@celecoxib exhibited rapid degradation in a solution containing a physiological concentration of MMP13/HAase, demonstrating specific enzyme responsiveness for precise anti-inflammatory drug release. The MMP13-responsive hydrogel microsphere system achieves intelligent and controllable drug release in OA, effectively decelerating disease progression and promoting articular cartilage repair.

Characterization of Alternative Splicing in High-Risk Wilms' Tumors.

The significant heterogeneity of Wilms' tumors between different patients is thought to arise from genetic and epigenetic distortions that occur during various stages of fetal kidney development in a way that is poorly understood. To address this, we characterized the heterogeneity of alternative mRNA splicing in Wilms' tumors using a publicly available RNAseq dataset of high-risk Wilms' tumors and normal kidney samples. Through Pareto task inference and cell deconvolution, we found that the tumors and normal kidney samples are organized according to progressive stages of kidney development within a triangle-shaped region in latent space, whose vertices, or "archetypes", resemble the cap mesenchyme, the nephrogenic stroma, and epithelial tubular structures of the fetal kidney. We identified a set of genes that are alternatively spliced between tumors located in different regions of latent space and found that many of these genes are associated with the epithelial-to-mesenchymal transition (EMT) and muscle development. Using motif enrichment analysis, we identified putative splicing regulators, some of which are associated with kidney development. Our findings provide new insights into the etiology of Wilms' tumors and suggest that specific splicing mechanisms in early stages of development may contribute to tumor development in different patients.

Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis.

While our understanding of the single-cell gene expression patterns underlying the transformation of vascular cell types during the progression of atherosclerosis is rapidly improving, the clinical and pathophysiological relevance of these changes remains poorly understood. Single-cell RNA sequencing data generated with SmartSeq2 (≈8000 genes/cell) in nearly 19 000 single cells isolated during atherosclerosis progression in Ldlr-/-Apob100/100 mice with human-like plasma lipoproteins and from humans with asymptomatic and symptomatic carotid plaques was clustered into multiple subtypes. For clinical and pathophysiological context, the advanced-stage and symptomatic subtype clusters were integrated with 135 tissue-specific (atherosclerotic aortic wall, mammary artery, liver, skeletal muscle, and visceral and subcutaneous, fat) gene-regulatory networks (GRNs) inferred from 600 coronary artery disease patients in the STARNET (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task) study. Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated (macrophage) phenotypes. Integrative analysis of these 6 clusters with STARNET revealed significant enrichments of 3 arterial wall GRNs: GRN33 (macrophage), GRN39 (SMC), and GRN122 (macrophage) with major contributions to coronary artery disease heritability and strong associations with clinical scores of coronary atherosclerosis severity (SYNTAX/Duke scores). The presence and pathophysiological relevance of GRN39 were verified in 5 independent RNAseq data sets obtained from the human coronary and aortic artery, and primary SMCs and by targeting its top-key drivers, FRZB and ALCAM, in cultured human vascular SMCs. By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced-stage, symptomatic atherosclerosis.

Effect of siponimod on lymphocyte subsets in active secondary progressive multiple sclerosis and clinical implications.

Circulating immune cells play a pathogenic role in multiple sclerosis (MS). However, the role of specific lymphocyte subpopulations is not unveiled yet, especially in progressive stages. We aimed to investigate lymphocyte changes during siponimod treatment in active secondary progressive MS (aSPMS) and their associations with clinical outcomes. We enrolled 46 aSPMS patients starting on siponimod treatment with at least 6months of follow-up and two visits within the scheduled timeframes and 14 sex- and age-matched healthy controls (HCs). Clinical and laboratory data were collected retrospectively at baseline, 3rd, 6th, 12th, and 24th month for MS patients, and at baseline for HCs. At baseline SPMS patients presented with increased naïve regulatory T lymphocytes (p = 0.02) vs. HCs. Over time, SPMS patients showed decreased T CD4+ (coeff. range = -24/-17, 95% CI range = -31.60 to -10.40), B lymphocyte (coeff. range = -3.77/-2.54, 95% CI range = -6.02 to -0.35), memory regulatory B cells (coeff. range = -0.78/-0.57, 95% CI range = -1.24 to -0.17) and CD4/CD8 ratio (coeff. range = -4.44/-0.67, 95% CI range = -1.61 to -0.17) from month 3 thereafter vs. baseline, and reduced CD3+CD20+ lymphocytes from month 12 thereafter (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03). Patients not experiencing disability progression while on siponimod treatment showed B lymphocyte reduction from month 3 (coeff. range = -4.23/-2.32, 95% CI range = -7.53 to -0.15) and CD3+CD20+ lymphocyte reduction from month 12 (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03) vs. patients experiencing progression. Patients treated with siponimod showed a T and B lymphocyte reduction, especially CD4+, CD3+CD20+ and naïve regulatory T cells and memory regulatory B cells. Disability progression while on siponimod treatment was associated with a less pronounced effect on B and CD3+CD20+ lymphocytes.

Understanding the Role of Connexins in Hepatocellular Carcinoma: Molecular and Prognostic Implications.

Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent mechanisms, their loss of expression may be associated with tumorigenic activity, while it is hypothesized that connexins favor the clonal expansion of tumor cells and promote cell migration, invasion, and proliferation, affecting metastasis and chemoresistance in some cases. Hepatocellular carcinoma (HCC), characterized by unfavorable prognosis and limited responsiveness to current therapeutic strategies, has been linked to gap junction proteins as tumorigenic factors with prognostic value. Notably, several members of connexins have emerged as promising markers for assessing the progression and aggressiveness of HCC, as well as the chemosensitivity and radiosensitivity of hepatocellular tumor cells. Our review sheds light on the multifaceted role of connexins in HCC pathogenesis, offering valuable insights on recent advances in determining their prognostic and therapeutic potential.

Daily process and key characteristics of phytoplankton bloom during a low-water level period in a large subtropical reservoir bay.

Reservoirs, heavily influenced by artificial management, often harbor phytoplankton assemblages dominated by cyanobacteria or dinoflagellates, triggering significant changes in aquatic ecosystems. However, due to limited sampling frequency and insufficient attention to species composition, the bloom processes and key characteristics of phytoplankton community structure have not been systematically elucidated. During the low-water level period when blooms are most likely to occur (June to September) in a tributary bay of the Three Gorges Reservoir, daily sampling was conducted to investigate phytoplankton community composition, identify significant environmental factors, and evaluate important structure characteristics of phytoplankton community. The results showed that Microcystis aeruginosa maintained a clear dominance for almost a month in stage 1, with low Shannon and evenness but a high dominance index. Phytoplankton total density and biomass decreased drastically in stage 2, but Microcystis aeruginosa still accounted for some proportion. The highest Shannon and evenness but the lowest dominance index occurred in stage 3. Peridiniopsis niei occurred massively in stage 4, but its dominant advantages lasted only one to two days. NH4-N was responsible for the dominance of Microcystis aeruginosa, while TP and PO4-P was responsible for the dominance of Peridiniopsis niei; however, precipitation contributed to their drastic decrease or disappearance to some extent. The TN : TP ratio could be considered as an important indicator to determine whether Microcystis aeruginosa or Peridiniopsis niei dominated the phytoplankton community. Throughout the study period, physiochemical factors explained more variation in phytoplankton data than meteorological and hydrological factors. Pairwise comparisons revealed an increase in average β diversity with stage progression, with higher β diversities based on abundance data than those based on presence/absence data. Repl had a greater effect on β diversity differences based on presence/absence data, whereas RichDiff had a greater effect on β diversity differences based on species abundance data. Co-occurrence networks for stage 1 showed the most complex structure, followed by stage 4, while the network for stage 3 was relatively sparse, although the overall community division remained compact. This study provides a useful attempt to explore the status and changes in phytoplankton community structure during the bloom process through high-resolution investigation.

The degeneration of locus coeruleus occurring during Alzheimer's disease clinical progression: a neuroimaging follow-up investigation.

The noradrenergic nucleus Locus Coeruleus (LC) is precociously involved in Alzheimer's Disease (AD) pathology, and its degeneration progresses during the course of the disease. Using Magnetic Resonance Imaging (MRI), researchers showed also in vivo in patients the disruption of LC, which can be observed both in Mild Cognitively Impaired individuals and AD demented patients. In this study, we report the results of a follow-up neuroradiological assessment, in which we evaluated the LC degeneration overtime in a group of cognitively impaired patients, submitted to MRI both at baseline and at the end of a 2.5-year follow-up. We found that a progressive LC disruption can be observed also in vivo, involving the entire nucleus and associated with clinical diagnosis. Our findings parallel neuropathological ones, which showed a continuous increase of neuronal death and volumetric atrophy within the LC with the progression of Braak's stages for neurofibrillary pathology. This supports the reliability of MRI as a tool for exploring the integrity of the central noradrenergic system in neurodegenerative disorders.

Remote Associations Between Tau and Cortical Amyloid-β Are Stage-Dependent.

Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-β (Aβ) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. In this study, we utilized Aβ and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aβ deposition. Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aβ associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. No significant tau-Aβ association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aβ in lateral temporal lobe regions. The strongest tau-Aβ associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aβ (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aβ associations were no longer significant. The results indicate that associations between tau and Aβ are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.

Biomechanical Effects of Hindfoot Alignment in Supination External Rotation Malleolar Fractures: A Human Cadaveric Model.

Pressure distribution in the ankle joint is known to be dependent on various factors, including hindfoot alignment. We seek to evaluate how hindfoot alignment affects contact pressures in the ankle joint in the setting of supination external rotation (SER) type ankle fractures. SER fractures were created in 10 human cadaver lower extremity specimens, simulating progressive stages of injury: without fracture (step 0), SER fracture and intact deltoid ligament (step 1), superficial deltoid ligament disruption (step 2), and deep deltoid ligament disruption (step 3). At each step, varus and valgus alignment was simulated by displacing the calcaneal tuberosity 7 mm medial or lateral. Each limb was axially loaded following each osteotomy at a static load of 350 N. The center of force (COF), contact area (CA), and peak contact pressure (PP) under load were measured, and radiographs of the ankle mortise were taken to analyze the medial clear space (MCS) and talar tilt (TT). The COF (5.3 mm, P = .030) and the CA (-188.4 mm2, P = .015) changed in step 3 in the valgus hindfoot alignment compared to baseline parameters, indicating the importance of deep deltoid ligament integrity in maintaining normal ankle joint contact stress in the valgus hindfoot. These changes were not seen in the setting of varus alignment (COF: 2.3 mm, P = .059; CA -121 mm2, P = .133). PP were found to not change significantly in either varus or valgus (varus: -4.9 N, P = .132; valgus: -4 N, P = .464).The MCS demonstrated widening in step 3 compared to step 2 (0.7 mm, P = .020) in both varus and valgus hindfoot. The TT increased significantly in step 3 in the valgus hindfoot (2.8 degrees, P = .020) compared to step 0. SER-IV fractures with valgus hindfoot alignment showed significant changes in pressure distribution and radiographic parameters when compared to SER-IV fractures with varus hindfoot alignment. Based on this cadaver modeling study, patients with SERIV fracture with varus hindfoot alignment and complete deltoid ligament lesion may not need fracture fixation, whereas those with valgus hindfoot alignment likely need fracture fixation.