Irreversible Progression Research Articles

Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs in genomic and transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), and CRISPR-based screens, have revolutionized the field, offering new avenues for early diagnosis and personalized prognosis. Genomic approaches have elucidated disease-specific genetic risk factors and molecular pathways, while transcriptomic studies have identified stage-specific biomarkers that correlate with disease progression and severity. Furthermore, genome-wide association studies (GWAS), polygenic risk scores (PRS), and spatial transcriptomics are enabling the stratification of patients based on their risk profiles and prognostic trajectories. Advances in functional genomics have uncovered actionable targets, such as ATXN2 in ALS and TREM2 in AD, paving the way for tailored therapeutic strategies. Despite these achievements, challenges remain in translating genomic discoveries into clinical practice due to disease heterogeneity and the complexity of neurodegenerative pathophysiology. Future integration of genetic technologies holds promise for transforming diagnostic and prognostic paradigms, offering hope for improved patient outcomes and precision medicine approaches.

Alzheimer's disease recognition based on waveform and spectral speech signal processing.

Alzheimer's disease (AD) is a neurodegenerative disorder with an irreversible progression. Currently, it is diagnosed using invasive and costly methods, such as cerebrospinal fluid analysis, neuroimaging, and neuropsychological assessments. Recent studies indicate that certain changes in language ability can predict early cognitive decline, highlighting the potential of speech analysis in AD recognition. Based on this premise, this study proposes an AD recognition multi-channel network framework, which is referred to as the ADNet. It integrates both time-domain and frequency-domain features of speech signals, using waveform images and log-Mel spectrograms derived from raw speech as data sources. The framework employs inverted residual blocks to enhance the learning of low-level time-domain features and uses gated multi-information units to effectively combine local and global frequency-domain features. The study tests it on a dataset from the Shanghai cognitive screening (SCS) digital neuropsychological assessment. The results show that the method we proposed outperforms existing speech-based methods, achieving an accuracy of 88.57%, a precision of 88.67%, and a recall of 88.64%. This study demonstrates that the proposed framework can effectively distinguish between the AD and normal controls, and it may be useful for developing early recognition tools for AD.

Adipose-derived Stem Cells and Wound Healing Are Progressively Impaired Long-term After Radiotherapy in Mice.

The pathogenesis of deterministic radiation damage is not clearly understood, but it has been reported that fibroinflammatory pathways are up-regulated. We hypothesized that the number of adipose-derived stem/stromal cells (ASCs) decline after radiotherapies, preventing normalization of fibrosis and angiogenesis, resulting in chronic radiation damages that progress over time. Dorsal skin of 8-week-old male BALB/cfC3H mice was irradiated with 10 Gy weekly for 4 weeks. At 1, 3, 6, 9, and 12 months after radiotherapy (n = 5, 5, 5, 5, and 4), tissue hemoglobin oxygen saturation, and time until epithelialization were evaluated. Skin biopsies were measured for thickness and CD34+/isolectin- stem/stromal cell count. Nonirradiated (NRT) controls were evaluated at each time point as well (n = 5 each). Compared with NRT controls, time until epithelialization was significantly longer at 1 month (28 ± 3, P < 0.01); not statistically different at 3 months (16 ± 2, P = 0.32); and lengthened over time at 6 months (20 ± 2, P = 0.21), 9 months (28 ± 2, P < 0.01), and 12 months (26 ± 3, P < 0.01), as did tissue oxygen saturation. The number of CD34+/isolectin- ASCs decreased over time, at 1 month (5.3 ± 1.3, P = 0.01), 3 months (6.0 ± 1.4, P = 0.03), 6 months (4.0 ± 0.8, P < 0.01), 9 months (1.7 ± 0.5, P < 0.01), and 12 months (0.3 ± 0.5, P < 0.01). The subcutaneous fatty layer was significantly thinner at 3 months (116 ± 33, P < 0.01), 6 months (147 ± 22, P = 0.02), 9 months (52 ± 12, P = 0.04), and 12 months (89 ± 19, P = 0.04), but not at 1 month (141 ± 18, P = 0.43). After 6 months postirradiation, the number of ASCs continued to decline over time, accompanied by irreversible progression of fibrosis, atrophy, and ischemia, which resulted in impaired wound healing.

Identification of pathological pathways centered on circRNA dysregulation in association with irreversible progression of Alzheimer’s disease

BackgroundCircular RNAs (circRNAs) are highly stable regulators, often accumulated in mammalian brains and thought to serve as “memory molecules” that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the brains of Alzheimer’s disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored.MethodsWe combined Poly(A)-tailing/RNase R digestion experimental approach with CARP, our published computational framework using pseudo-reference alignment for more sensitive and accurate circRNA detection to identify genome-wide circRNA dysregulation and their downstream pathways in the 5xFAD mouse cerebral cortex between 5 and 7 months of age, a critical window marks the transition from reversible to irreversible pathogenic progression. Dysregulated circRNAs and pathways associated with disease progression in 5xFAD cortex were systematically compared with circRNAs affected in postmortem subcortical areas of a large human AD cohort. A top-ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to examine AD-relevant molecular and cellular changes.ResultsWe discovered genome-wide circRNA alterations specifically in 5xFAD cortex associated with AD progression, many of which are commonly dysregulated in the subcortical areas of AD patients. Among these circRNAs, circGigyf2 is highly conserved and showed the highest net reduction specifically in the 7-month 5xFAD cortex. CircGIGYF2 level in AD patients’ cortices negatively correlated with dementia severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs), including the cleavage and polyadenylation factor 6 (CPSF6). Moreover, circGigyf2 downregulation in AD promoted silencing activities of its sponged miRNAs and enhanced polyadenylation site processing efficiency of CPSF6 targets. Furthermore, circGigyf2 depletion in a mouse neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated apoptotic responses upon insults, which strongly support the causative roles of circGigyf2 deficiency in AD neurodegeneration.ConclusionsTogether, our results unveiled brain circRNAs associated with irreversible disease progression in an AD mouse model that is also affected in AD patients and identified novel molecular mechanisms underlying the dysregulation of conserved circRNA pathways contributing to AD pathogenesis.

Cell Membrane Hybrid Liposome-Targeted Delivery of the Heat Shock Protein 90 C-Terminal Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) represents a grave challenge as it is characterized by high fatality rates and irreversible progression without effective clinical interventions available at present. Previous studies have demonstrated that inhibition of heat shock protein 90 (HSP90) by an N-terminal inhibitor disrupts its interaction with TGFβRII, leading to the instability of TGFβRII, thus blocking the role of transforming growth factor-β1 (TGF-β1), which could potentially ameliorate IPF symptoms. However, given that the broad spectrum of HSP90 N-terminal inhibitors may lead to unanticipated side effects, we hypothesize that C-terminal inhibitors of HSP90 can interfere with TGFβRII while minimizing adverse reactions. In this study, silybin, a C-terminal inhibitor of HSP90, was separated into monomers, and silybin A was screened for its superior efficacy against TGFβRII. To facilitate targeted therapy for treating IPF, a cell membrane hybrid liposome loaded with silybin A (Cm-A-Lip) was developed to deliver silybin A to lung fibroblasts through pulmonary drug delivery. A bleomycin-induced IPF mouse model was used to evaluate the efficacy of Cm-A-Lip. By examination of lung hydroxyproline content, wet weight, histology, and inflammatory factor expression, the results showed that pulmonary delivery of Cm-A-Lip could increase the drug retention time in lung tissue compared with intravenous injection. Furthermore, Cm-A-Lip exhibited superior antifibrotic activity relative to conventional liposmomes loaded with silybin A (A-Lip) while concurrently mitigating systemic inflammatory responses associated with silybin A administration, thus enhancing the overall safety profile.

Protective Activity of Melatonin Combinations and Melatonin-Based Hybrid Molecules in Neurodegenerative Diseases.

The identification of protective agents for the treatment of neurodegenerative diseases is the mainstay therapeutic goal to modify the disease course and arrest the irreversible disability progression. Pharmacological therapies synergistically targeting multiple pathogenic pathways, including oxidative stress, mitochondrial dysfunction, and inflammation, are prime candidates for neuroprotection. Combination or synergistic therapy with melatonin, whose decline correlates with altered sleep/wake cycle and impaired glymphatic "waste clearance" system in neurodegenerative diseases, has a great therapeutic potential to treat inflammatory neurodegenerative states. Despite the protective outcomes observed in preclinical studies, mild or poor outcomes were observed in clinical settings, suggesting that melatonin combinations promoting synergistic actions at appropriate doses might be more suitable to treat multifactorial neurodegenerative disorders. In this review, we first summarize the key melatonin actions and pathways contributing to cell protection and its therapeutic implication in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We remark the major controversies in the field, mostly generated by the lack of a common consensus for the optimal dosing, molecular targets, and toxicity. Then, we review the literature investigating the efficacy of melatonin combinations with approved or investigational neuroprotective agents and of melatonin-containing hybrid molecules, both in vitro and in animal models of AD, PD, and MS, as well as the efficacy of add-on melatonin in clinical settings. We highlight the rationale for such melatonin combinations with a focus on the comparison with single-agent treatment and on the assays in which an additive or a synergistic effect has been achieved. We conclude that a better characterization of the mechanisms underlying such melatonin synergistic actions under neuroinflammation at appropriate doses needs to be tackled to advance successful clinical translation of neuroprotective melatonin combination therapies or melatonin-based hybrid molecules.

Long‐Term Monitoring of ApoE4 within Aqueous Humor Using Intraocular Lenses Containing Target‐Responsive Inverse Opal Hydrogel

Neurodegenerative diseases, including Alzheimer's disease (AD), pose significant challenges to global healthcare because of their irreversible postsymptomatic progression. Conventional radiographic techniques have limitations in early detection, owing to the time lapse between symptom recognition by individuals and precise inspection using medical instruments. Current research explores ophthalmic approaches to address this gap, investigating the physiological link between ocular health and brain diseases. Intraocular lenses (IOLs), widely used in cataract and refractive surgeries, provide a safe and minimally invasive platform for the continuous monitoring of neurodegenerative disease biomarkers, including those associated with AD. By integrating biomolecule‐responsive sensors with IOLs, it becomes feasible to achieve early diagnosis and long‐term, noninvasive monitoring postimplantation. Herein, a fluorescently labeled inverse opal hydrogel (FIOH) is merged with IOLs for ApoE4 detection, a key risk factor for AD. The permeability and inherent photonic properties of FIOH facilitate the cumulative enhancement of the fluorescence signal. In a simulation of the aqueous humor circulation, the detection limit for ApoE4 is determined to be 0.1 nM. Therefore, FIOH‐integrated IOLs hold promise not only for early detection but also for providing a reliable platform for the continuous, noninvasive monitoring of neurodegenerative diseases after the initial, minimally invasive implantation.

ECG as a screening tool for detection of significant functional mitral regurgitation in patients with left bundle branch block

Abstract Background Functional mitral regurgitation (FMR) may occur in the left bundle branch block (LBBB) due to mechanical left ventricular (LV) dyssynchrony, by the imbalance between the tethering and the closing forces exerted on the mitral apparatus1-3. Progressive FMR and LV remodeling result in a reciprocal worsening downward spiral and worse clinical outcomes1-3. Therefore, timely screening and follow-up of these patients to prevent the irreversible progression of FMR is required. To date, only LBBB morphology and QRS duration have been proven predictors of FMR4. Purpose This study aimed to assess the relationship between ECG parameters of LV dyssynchrony and the severity of FMR in patients with LBBB. Methods We retrospectively included 154 consecutive patients with LBBB, in sinus rhythm, who had an echocardiogram, with no more than mild organic valvular heart disease. We measured the following intraventricular dyssynchrony markers: LV activation times (LVAT), intrinsicoid deflection (ID) in lateral and aVF leads and a newly defined marker – the difference (Diff) between aVL and aVF ID’s (Diff_IDaVL_aVF). These two leads record the electrical activation of the two opposing myocardial segments adjacent to the posteromedial and anterolateral papillary muscles, respectively5 (Figure 1). Based on the severity of FMR, the patients were divided into two groups: no/mild FMR (grade II or less) (61%), and significant FMR (grade III and IV) (39%). Results In patients with significant FMR, the LVAT measured in lateral leads, the IDaVL and Diff_IDaVL_aVF were significantly longer, but IDaVF was significantly shorter compared to patients with no/mild FMR (p&amp;lt;0.001). Of all studied ECG parameters, the Diff_IDaVL_ aVF was the parameter that had the strongest correlation with significant FMR (r correlation coefficient 0.82, p &amp;lt; 0.001). In multivariable analysis the Diff_IDaVL_aVF (p = 0.010) was the only parameter independently correlated with significant FMR. On ROC analysis the best cut-off for significant FMR prediction was 55 ms (AUC of 0.99, sensitivity 90% and specificity 97%) (Figure 2). Conclusions In LBBB, a simple intraventricular dyssynchrony ECG parameter can provide insights into FMR severity. A 55 msec Diff_IDaVL_aVF identifies significant FMR that may benefit from early medical or CRT treatment to avoid progression and worse prognosis.

The involvement of HDAC3 in the pathogenesis of lung injury and pulmonary fibrosis.

Acute lung injury (ALI) and its severe counterpart, acute respiratory distress syndrome (ARDS), are critical respiratory conditions with high mortality rates due primarily to acute and intense pulmonary inflammation. Despite significant research advances, effective pharmacological treatments for ALI and ARDS remain unavailable, highlighting an urgent need for therapeutic innovation. Notably, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the irreversible progression of fibrosis, which is initiated by repeated damage to the alveolar epithelium and leads to excessive extracellular matrix deposition. This condition is further complicated by dysregulated tissue repair and fibroblast dysfunction, exacerbating tissue remodeling processes and promoting progression to terminal pulmonary fibrosis. Similar to that noted for ALI and ARDS, treatment options for IPF are currently limited, with no specific drug therapy providing a cure. Histone deacetylase 3 (HDAC3), a notable member of the HDAC family with four splice variants (HD3α, -β, -γ, and -δ), plays multiple roles. HDAC3 regulates gene transcription through histone acetylation and adjusts nonhistone proteins posttranslationally, affecting certain mitochondrial and cytoplasmic proteins. Given its unique structure, HDAC3 impacts various physiological processes, such as inflammation, apoptosis, mitochondrial homeostasis, and macrophage polarization. This article explores the intricate role of HDAC3 in ALI/ARDS and IPF and evaluates its therapeutic potential the treatment of these severe pulmonary conditions.

MEOX1 triggers myofibroblast apoptosis resistance, contributing to pulmonary fibrosis in mice.

The apoptosis resistance of myofibroblasts is a hallmark in the irreversible progression of pulmonary fibrosis (PF). While the underlying molecular mechanism remains elusive. In this study, we unveiled a previously unrecognized mechanism underlying myofibroblast apoptosis resistance during PF. Our investigation revealed heightened expression of mesenchyme homeobox 1 (MEOX1) in the lungs of idiopathic pulmonary fibrosis (IPF) patients and bleomycin-induced PF mice. Silencing MEOX1 significantly attenuated PF progression in mice. In vitro, we found a notable increase in MEOX1 expression in transforming growth factor-β1 (TGF-β1)-induced myofibroblasts. Silencing MEOX1 enhanced apoptosis of myofibroblasts. Mechanistically, we identified G-protein signaling pathway regulatory factor 4 (RGS4) as a critical downstream target of MEOX1, as predicted by bioinformatics analysis. MEOX1 enhanced apoptosis resistance by upregulating RGS4 expression in myofibroblasts. In conclusion, our study highlights MEOX1 as a promising therapeutic target for protecting against PF by modulating myofibroblast apoptosis resistance.

ALZHEIMER (AD) - A MULTIFACTORIAL NEURODEGENERATIVE DISEASE - A COHORT STUDY

Situated within the broad spectrum of neurodegenerative disorders, Alzheimer's disease (AD) is known for its complexity, heterogeneity, multiple genetic mutations, epigenetic and biochemical modifications, and irreversible progression from early stages characterized by deficits in the ability to encode and store new information to subsequent progressive cognitive, functional, behavioral decline. Objective: The conducted study aimed to compile conclusive statistics, identify genetic factors, and correlate them with environmental ones, thus highlighting the importance of developing evaluation programs and early introduction of medication in order to decelerate the progression of neurodegenerative processes. Materials and methods: The analytical, observational, retrospective study was conducted on an extended cohort of 2277 patients admitted with chronic neurological diseases to the Neurology Department of "Dr. Iacob Czihac" Clinical Military Emergency Hospital Iași from January 1, 2022 to December 31, 2023. Among these, 219 patients were diagnosed with AD at various stages. Forty-three cases exhibiting genetic predisposition (19.63%) were selected and thoroughly analyzed based on medical records. Results: The study emphasizes the significant position of AD among chronic neurological diseases. Although the majority do not present hereditary antecedents (80.36%), predisposing conditions, environmental factors, stress, and the region of residence play fundamental roles in the disease's determinism. It is observed that individuals in the 60-70 age category (71.23%) from urban areas (63.01%), especially females (63.47%), have a higher probability of developing AD. Maternally transmitted Alzheimer's prevalence was 58.13%, while paternally inherited AD accounted for 32.55%, with only 4 cases having antecedents on both lines (9.30%). Conclusion: Unequivocally characterized by a vast etiology, AD is a multifactorial disorder resulting from the bilateral interaction and continuous corroboration of genetic and environmental factors.

Urolithin A Ameliorates the TGF Beta-Dependent Impairment of Podocytes Exposed to High Glucose.

Increased activity of transforming growth factor-beta (TGF-β) is a key factor mediating kidney impairment in diabetes. Glomerular podocytes, the crucial component of the renal filter, are a direct target of TGF-β action, resulting in irreversible cell loss and progression of chronic kidney disease (CKD). Urolithin A (UA) is a member of the family of polyphenol metabolites produced by gut microbiota from ellagitannins and ellagic acid-rich foods. The broad spectrum of biological activities of UA makes it a promising candidate for the treatment of podocyte disorders. In this in vitro study, we investigated whether UA influences the changes exerted in podocytes by TGF-β and high glucose. Following a 7-day incubation in normal (NG, 5.5 mM) or high (HG, 25 mM) glucose, the cells were treated with UA and/or TGF-β1 for 24 h. HG and TGF-β1, each independent and in concert reduced expression of nephrin, increased podocyte motility, and up-regulated expression of b3 integrin and fibronectin. These typical-for-epithelial-to-mesenchymal transition (EMT) effects were inhibited by UA in both HG and NG conditions. UA also reduced the typically elevated HG expression of TGF-β receptors and activation of the TGF-β signal transducer Smad2. Our results indicate that in podocytes cultured in conditions mimicking the diabetic milieu, UA inhibits and reverses changes underlying podocytopenia in diabetic kidneys. Hence, UA should be considered as a potential therapeutic agent in podocytopathies.

Evidence from recent clinical trials in fibrotic interstitial lung diseases.

Idiopathic pulmonary fibrosis (IPF) is the prototype of fibrosing interstitial lung diseases. It is mirrored by progressive pulmonary fibrosis (PPF), an umbrella term which characterizes disease behavior of various fibrotic interstitial lung diseases with irreversible progression, accounting for loss of lung function, exercise intolerance and respiratory failure leading to early mortality. Pirfenidone and nintedanib halve the decline in lung function but do not halt disease progression. Since the publication in 2014 of pivotal pirfenidone and nintedanib studies, a number of clinical trials were conducted, many of them did not reach their primary endpoints. In IPF, promising phase 2 trials were followed by large phase 3 trials that did not confirm a favorable efficacy to tolerability favorable profile, including those with ziritaxestat, an autotaxin-1 inhibitor, zinpentraxin-alpha (human recombinant pentraxin-2), and the monoclonal antibody pamrevlumab targeting connective tissue growth factor. Nevertheless, newer compounds that hold promise are currently being evaluated in phase 3 or phase 2b randomized controlled trials, including: nerandomilast, a preferential phosphodiesterase 4B inhibitor; admilparant, a lysophosphatidic acid receptor antagonist; inhaled treprostinil, a prostacyclin agonist; and bexotegrast, a dual-selective inhibitor of αvβ6 and αvβ1 integrins. Nerandomilast, admilparant, inhaled treprostinil, and inhaled AP01 (pirfenidone), are currently studied in patients with PPF. Despite recent frustrating negative results, there is a growing portfolio of candidate drugs developed in both IPF and PPF.

Identification of immune-associated biomarkers of diabetes nephropathy tubulointerstitial injury based on machine learning: a bioinformatics multi-chip integrated analysis

BackgroundDiabetic nephropathy (DN) is a major microvascular complication of diabetes and has become the leading cause of end-stage renal disease worldwide. A considerable number of DN patients have experienced irreversible end-stage renal disease progression due to the inability to diagnose the disease early. Therefore, reliable biomarkers that are helpful for early diagnosis and treatment are identified. The migration of immune cells to the kidney is considered to be a key step in the progression of DN-related vascular injury. Therefore, finding markers in this process may be more helpful for the early diagnosis and progression prediction of DN.MethodsThe gene chip data were retrieved from the GEO database using the search term ' diabetic nephropathy ‘. The ' limma ' software package was used to identify differentially expressed genes (DEGs) between DN and control samples. Gene set enrichment analysis (GSEA) was performed on genes obtained from the molecular characteristic database (MSigDB. The R package ‘WGCNA’ was used to identify gene modules associated with tubulointerstitial injury in DN, and it was crossed with immune-related DEGs to identify target genes. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on differentially expressed genes using the ‘ClusterProfiler’ software package in R. Three methods, least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE) and random forest (RF), were used to select immune-related biomarkers for diagnosis. We retrieved the tubulointerstitial dataset from the Nephroseq database to construct an external validation dataset. Unsupervised clustering analysis of the expression levels of immune-related biomarkers was performed using the ‘ConsensusClusterPlus ‘R software package. The urine of patients who visited Dongzhimen Hospital of Beijing University of Chinese Medicine from September 2021 to March 2023 was collected, and Elisa was used to detect the mRNA expression level of immune-related biomarkers in urine. Pearson correlation analysis was used to detect the effect of immune-related biomarker expression on renal function in DN patients.ResultsFour microarray datasets from the GEO database are included in the analysis : GSE30122, GSE47185, GSE99340 and GSE104954. These datasets included 63 DN patients and 55 healthy controls. A total of 9415 genes were detected in the data set. We found 153 differentially expressed immune-related genes, of which 112 genes were up-regulated, 41 genes were down-regulated, and 119 overlapping genes were identified. GO analysis showed that they were involved in various biological processes including leukocyte-mediated immunity. KEGG analysis showed that these target genes were mainly involved in the formation of phagosomes in Staphylococcus aureus infection. Among these 119 overlapping genes, machine learning results identified AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1 and FSTL1 as potential tubulointerstitial immune-related biomarkers. External validation suggested that the above markers showed diagnostic efficacy in distinguishing DN patients from healthy controls. Clinical studies have shown that the expression of AGR2, CX3CR1 and FSTL1 in urine samples of DN patients is negatively correlated with GFR, the expression of CX3CR1 and FSTL1 in urine samples of DN is positively correlated with serum creatinine, while the expression of DEFB1 in urine samples of DN is negatively correlated with serum creatinine. In addition, the expression of CX3CR1 in DN urine samples was positively correlated with proteinuria, while the expression of DEFB1 in DN urine samples was negatively correlated with proteinuria. Finally, according to the level of proteinuria, DN patients were divided into nephrotic proteinuria group (n = 24) and subrenal proteinuria group. There were significant differences in urinary AGR2, CCR2 and DEFB1 between the two groups by unpaired t test (P < 0.05).ConclusionsOur study provides new insights into the role of immune-related biomarkers in DN tubulointerstitial injury and provides potential targets for early diagnosis and treatment of DN patients. Seven different genes ( AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1, FSTL1 ), as promising sensitive biomarkers, may affect the progression of DN by regulating immune inflammatory response. However, further comprehensive studies are needed to fully understand their exact molecular mechanisms and functional pathways in DN.

C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment. Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD. A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded. Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO). The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS). The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.

Surgical treatment of secondary hyperparathyroidism in children with chronic kidney disease. Experience in 19 patients.

Secondary hyperparathyroidism (sHPT) is an important contributor to bone disease and cardiovascular calcifications in children with chronic kidney disease (CKD). When conservative measures are ineffective, parathyroidectomy is indicated. The aim of our study was to evaluate the efficacy and safety of subtotal parathyroidectomy (sPTX) in pediatric and adolescent patients, and to provide a rationale for considering this aggressive treatment in CKD patients with uncontrolled sHPT. We retrospectively analyzed the medical records of 19 pediatric CKD patients on dialysis with refractory sHPT who underwent sPTX at our institution between 2010 and 2020. All patients had clinical, radiological, and biochemical signs of renal osteodystrophy. One year after sPTX, parathyroid hormone (PTH) levels (median and interquartile range (IQR)) dropped from 2073 (1339-2484) to 164 (93-252) pg/mL (p=0.0001), alkaline phosphatase (ALP) levels from 1166 (764-2373) to 410 (126-421) IU/L (p=0.002), and the mean (±SDS) calcium-phosphate (Ca*P) product from 51±11 to 41±13mg2/dL2 (p=0.07). Postoperatively, all patients presented with severe hungry bone syndrome (HBS) and required intravenous and oral calcium and calcitriol supplementation. None of them had other postoperative complication. Histological findings had a good correlation with preoperative parathyroid ultrasound imaging (n: 15) in 100 % and with technetium-99m (99mTc) sestamibi scintigraphy (n: 15) in 86.6 %. Clinical and radiological signs of bone disease improved in all patients. Pediatric sPTX is effective and safe to control sHPT and calcium-phosphate metabolism in children with CKD on dialysis and may mitigate irreversible bone deformities and progression of cardiovascular disease.

THE IMPORTANCE OF PUBLIC RELATIONS IN PUBLIC ADMINISTRATION AND ITS SITUATION IN GEORGIA

In the contemporary landscape, the multifaceted development of a nation across economic, social, political, scientific, technological, and cultural spheres hinges significantly upon a robust understanding and utilization of information communication processes within governmental frameworks. Central to the efficacy of public administration is the orchestration of public relations initiatives within governmental bodies, leveraging them as conduits for information dissemination and feedback mechanisms. The absence of a timely and structured information dissemination and feedback system within government apparatuses engenders uncertainty and misapprehension regarding anticipated outcomes and societal trajectories. This lacuna precipitates a disengagement of citizens from governmental institutions and fosters skepticism toward their formulated agendas. Such circumstances precipitate a crisis in public relations, wherein the dearth of information catalyzes public apprehension surrounding purported issues, thereby inflating their significance beyond reality and engendering a climate of sustained discourse, ultimately culminating in adverse public sentiment. This phenomenon represents a dynamic and irreversible progression, fertile ground for the escalation of genuine crises. In such exigencies, governmental entities are compelled to proactively saturate the informational landscape with content pertinent to public interest, undertake diligent analysis of public sentiment, steward reputation management efforts, ensure transparency and accessibility of information, and facilitate bidirectional communication channels. Keywords: public relations, democratic governance, PR effectiveness, public administration.

Is there a Place for Klotho in Alzheimer’s disease?

Alzheimer’s disease, a major healthcare concern, lacks an effective pharmacological therapy to change its irreversible progression. In this work, we present Klotho, a protein associated with aging that is involved in the regulation of numerous physiological processes and is a serious candidate to be a pharmacological target to act on. Klotho’s mRNA has been found in neurons of a variety of brain regions (cortex, hippocampus). The best studied and prominent function of Klotho is as the co-receptor of fibroblast growth factor 23 (FGF23), through which Klotho controls renal phosphate excretion and vitamin D metabolism. Reduced serum levels of Klotho in mice have been associated with a shorter life expectancy and with numerous pathological conditions such as renal disease, vascular calcification, neurodegeneration, and others. Moreover, overexpression of Klotho leads to opposite effects resulting in increased survival rates. In this review we address different signaling pathways in which Klotho is involved in one way or another, focusing on those pathways that could serve as pharmacological targets to modify the evolution of Alzheimer’s disease. We describe how Klotho inhibits signaling cascades involved in cellular senescence, fibrosis, inflammation, and apoptosis all of which are mediated by tumor growth factor β (TGF- β), nuclear factor kappa K (NF- κ B), insulin-like growth factor 1 (IGF-1) or Wnt. We also highlight how Klotho is able to activate anti-inflammatory and antioxidant signaling pathways. Although there are no drugs that act specifically on Klotho, compounds currently on the market such as hormone-based drugs, pravastatin, losartan, fosinopril, and rapamycin have been shown to increase the expression of this protein and are also discussed.

Leveraging electronic health records and knowledge networks for Alzheimer’s disease prediction and sex-specific biological insights

Identification of Alzheimer’s disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.

Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis.

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (β = 0.23, P = 0.024) and lower indices of cortical remyelination (β = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.