Search Results (496)

Signalling between the ER and mitochondria regulates a number of key cellular functions that are damaged in frontotemporal dementia and related amyotrophic lateral sclerosis (FTD/ALS). This signalling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ER–mitochondria “tethering” proteins. A number of studies have shown that mutant genes which cause familial FTD/ALS disrupt the VAPB-PTPIP51 tethers and that this involves activation of GSK3β. TDP43 is one such mutant and altered TDP43 metabolism is central to FTD/ALS pathogenesis. Loss of Sigma-1 receptor function is also seen in FTD/ALS and there is evidence that Sigma-1 receptor agonists can repair damaged ER–mitochondria signalling. However, the underlying mechanisms are not properly understood. In this study, we show that the reference Sigma-1 receptor agonist PRE-084 stimulates VAPB-PTPIP51 binding and rescues FTD/ALS mutant TDP43-induced disruption to the VAPB-PTPIP51 interaction and linked ER–mitochondria Ca²⁺ delivery. We also show that these effects involve inhibition of the kinase GSK3β, a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that ANAVEX2-73, a further Sigma-1 receptor agonist which is in clinical trials for Alzheimer’s disease, also stimulates VAPB-PTPIP51 binding via GSK3β inhibition. Our findings provide novel insights into the mechanisms by which Sigma-1 receptor agonists influence defective ER–mitochondria signalling in FTD/ALS. Full article

TDP-43 proteinopathies, encompassing amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE), represent a heterogeneous spectrum of devastating neurodegenerative disorders. For decades, the diverse clinical presentations of these diseases have complicated antemortem diagnosis and hindered the development of disease-modifying therapies. However, recent breakthroughs in basic science are beginning to address these clinical barriers, although substantial hurdles to practical clinical application remain. Structural elucidation via cryo-electron microscopy (Cryo-EM) has shattered the single-protein amyloid dogma by revealing that TDP-43 can form hetero-amyloid filaments with ANXA11, thereby providing a molecular basis for pathological strain diversity. Concurrently, the pathogenic focus has shifted toward nuclear loss of function, which triggers a systemic “RNA crisis” characterized by aberrant alternative polyadenylation (APA) and cryptic exon inclusion (e.g., STMN2, UNC13A). Crucially, this metabolic collapse is profoundly exacerbated by patient-specific genetic risk factors, acting synergistically in a “two-hit” model of neurodegeneration. To translate these findings to the clinic, next-generation diagnostic tools are emerging. Integrating neuron-derived extracellular vesicle (EV) isolation with Seed Amplification Assays (SAAs) holds promise to help overcome the structural camouflage that limits current PET imaging, potentially offering ultra-sensitive, functional strain identification in biofluids. While these structural and diagnostic milestones provide a strong foundation for precision medicine, major challenges in assay standardization and clinical validation must be addressed. Advanced therapeutic strategies—namely, splice-switching antisense oligonucleotides (ASOs) that directly restore RNA metabolism, combined with the targeted suppression of neuronal hyperexcitability—are now entering clinical trials. This review synthesizes how decoding the structural and RNA-metabolic complexities of TDP-43 is paving a promising pathway from bench to bedside, while critically discussing current translational limitations. Full article

The textile dyeing and printing (TDP) industry in Zhejiang Province faces significant pressure to reduce conventional pollutants and carbon emissions. Dyeing and finishing (DF) are key links in energy consumption and pollutant emissions in the TDP industry. However, the trade-offs between pollution reduction and carbon mitigation remain poorly understood. This study evaluated five synergistic technology pathways using a hybrid life cycle assessment (LCA) approach. The pathways included low-carbon energy substitution, waste heat recovery, advanced wastewater treatment, intelligent process control, and integrated application. The IMPACT 2002+ method was used to quantify 7 environmental impact categories. The results showed that no single technology pathway achieved optimal performance across all categories. Scenario 3 (advanced wastewater treatment) reduced eutrophication potential by 54.97% but increased global warming potential by 18.00%. Scenario 5 (integrated application) achieved the best overall performance. It reduced non-renewable energy consumption by 30.90%, global warming potential by 32.69%, acidification potential by 26.08%, and eutrophication potential by 40.00%. The synergy coefficient of Scenario 5 was 1.08, indicating strong pollution-reduction synergy. Extrapolation to the provincial level showed reductions of 40% for COD, 39.76% for ammonia nitrogen, 40.78% for SO₂, 10.67% for NOx, and 14% for VOCs. These findings demonstrate that systematic technology integration can resolve the trade-offs inherent in individual pollution control measures under the conditions evaluated in this Zhejiang-based case study. This study provides scientific guidance for technology selection and policy formulation in the DF industry. Full article

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder strongly associated with mitochondrial dysfunction and impaired proteostasis. Mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), contribute to disease pathogenesis through cytoplasmic mislocalization and aggregation. Among these, the ALS-linked TDP-43^G376D mutation has been previously associated with oxidative stress, mitochondrial fragmentation, and impaired oxidative phosphorylation. Here, we investigated the impact of TDP-43^G376D on Mitochondrial Quality Control (MQC) pathways using patient-derived dermal fibroblasts carrying the mutation at early and advanced disease stages, complemented by HEK293T and Neuro2a cellular models expressing mutant TDP-43. We show that TDP-43^G376D impairs mitophagic flux, as evidenced by reduced delivery of damaged mitochondria to lysosomes. This was accompanied by pronounced disruption of mitochondrial cristae architecture and accumulation of mitochondrial DNA damage, indicating compromised mitochondrial genome integrity. Furthermore, TDP-43^G376D induces sustained activation of the mitochondrial Unfolded Protein Response (UPR^mt), consistent with persistent mitochondrial stress, while selectively impairing the sirtuin-dependent antioxidant branch. In parallel, activation of the Endoplasmic Reticulum UPR (UPR^ER) was observed, indicating a coordinated engagement of cellular stress pathways. Collectively, our findings identify coordinated alterations in multiple MQC pathways associated with TDP-43^G376D rather than isolated mitochondrial defects, supporting further investigation of these pathways in larger and disease-relevant ALS models. Full article

TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA binding activity using synthetic UU-rich RNA probes. We analyzed 1080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 functional activity was elevated in ALS (mean 390 a.u.) versus controls (302 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); a 366 a.u. threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal in serum likely reflects increased extracellular release of probe-competent TDP-43 species during cell death and exosomal shedding, rather than restored intracellular nuclear splicing function. This assay provides a proof-of-concept platform for the direct functional measurement of probe-competent TDP-43 species in serum. While it demonstrates moderate group-level discrimination, individual diagnostic performance requires prospective validation. The assay may support exploratory applications in genotype stratification and progression monitoring in future clinical studies. Full article

Misfolded TAR DNA-binding protein 43 (TDP-43) is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), have shown promise in detecting misfolded TDP-43 in cerebrospinal fluid (CSF) and olfactory mucosa, technically accessible methodologies are urgently required for widespread clinical application. We developed a streamlined, non-immunoprecipitation-based TDP-43 RT-QuIC assay to assess seeding activity in brain tissue and CSF. We evaluated its diagnostic performance using CSF from patients with TDP-43 proteinopathies and control subjects, and further examined its association with neurofilament light chain (NfL) and tau-related biomarkers. In CSF analysis, the assay demonstrated positive seeding activity in 70% (21/30) of patients with ALS and dementia, 50% (5/10) of patients with FTLD, and 40% (8/20) of patients with ALS alone. The assay exhibited excellent specificity, yielding negative results in >99% (199/200) of control samples, including those with autoimmune or electrophysiological abnormalities. Furthermore, CSF analysis demonstrated significantly higher NfL levels in TDP-43 SAA-positive cases compared to SAA-negative cases (p < 0.0008). The highest NfL concentrations were observed in the SAA-positive ALS with dementia and ALS cohorts, contrasting with lower levels in FTLD. Tau-related biomarkers exhibited no significant differences between the groups. Our streamlined, non-immunoprecipitation TDP-43 RT-QuIC assay provides highly specific detection of pathological TDP-43 seeding activity. While the assay detects the underlying TDP-43 proteinopathy rather than distinguishing between ALS and FTLD clinical phenotypes, its technical simplicity and combined utility with NfL measurements offer a robust, scalable framework for biomarker development. This approach provides a practical foundation for future multi-center validation and international standardization efforts. Full article

Drosophila melanogaster (D. melanogaster), or fruit flies, are a commonly used model organism in the study of neurodegenerative diseases (NDs). Their short lifespan, low cost, genetic tractability, and conserved signaling and developmental pathways make them ideal for studying NDs and associated biochemical pathways. Further, flies offer the advantage of high-throughput exploratory drug and genetic screening without stringent ethical constraints. Therefore, D. melanogaster serves as an ideal organism for preliminary drug screening before transitioning to toxicity and efficacy studies in vertebrate models. Following the recent plan by the United States FDA (US FDA) and the National Institutes of Health (NIH) to progressively phase out preclinical drug testing in vertebrate animals and introduce New Approach Methodologies (NAMs), D. melanogaster has the potential to become part of the conventional drug testing pipeline in the future. This literature review focuses on the use of D. melanogaster models as a powerful, low-cost model organism to study superoxide dismutase 1 (SOD1)- and TAR DNA-binding protein 43 (TDP-43)-linked Amyotrophic Lateral Sclerosis (ALS), as well as previous efforts to screen drugs in SOD1- and TDP-43-expressing Drosophila models. Full article

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by progressive motor neuron (MN) degeneration and severe skeletal muscle atrophy. Despite extensive research, the mechanisms driving disease onset and progression remain incompletely understood. While MN loss is a defining feature of ALS, increasing evidence indicates that mitochondrial dysfunction contributes to disease pathogenesis. Here, we investigated the hypothesis that Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp-1, may exert neuroprotective properties in the SOD1^G93A mouse model of ALS. Treatment was initiated prior to symptomatic onset to assess its potential disease-modifying effects. Mdivi-1 administration resulted in partial preservation of spinal MNs, however, this benefit did not translate into functional improvement. Moreover, treated animals exhibited exacerbated muscle atrophy, increased cytoplasmic localization of TDP-43 in MNs and compromised synaptic plasticity. Drp-1 expression was reduced in SOD1 mice and further decreased following Mdivi-1 treatment, suggesting that mitochondrial dynamics may already be compromised in this model. Overall, our results also highlight possible off-target effects of Mdivi-1 and point to a context-dependent role of mitochondrial dynamics in ALS. Full article

Owing to its efficient energy recovery capability, the pump as turbine (PAT) has attracted considerable attention and has been widely applied in micro hydropower systems. However, under off-design conditions, large-scale helical vortex ropes are readily induced in the draft tube, causing severe hydraulic losses and flow instability. Because existing theoretical models do not account for the slip effect at the impeller outlet, this study combines vortex dynamics theory with numerical simulation and introduces a correction coefficient to develop a Burgers vortex-based analytical wake vortex model for a PAT with splitter blades. The model is verified by its ability to predict the peak tangential velocity and radial decay trend of the vortex core. In addition, the influence of draft tube configuration on vortex rope evolution is revealed using the Liutex vortex identification method and enstrophy analysis. The results show that the geometric curvature of the elbow draft tube induces vortex rope breakup and high energy dissipation. Finally, entropy production theory is used to quantitatively evaluate the vortex suppression benefit and hydraulic loss caused by deflector plates. The results indicate that the transverse deflector plate (TDP) provides a significantly better suppression effect than the longitudinal deflector plate (LDP) by disrupting the circumferential continuity of the vortex rope. Although increasing the insertion depth of the deflector plate improves vortex suppression, it induces non-negligible local high-entropy production on the upstream-facing surface (US). This study clarifies the physical mechanism of wake vortices in a PAT with splitter blades and provides theoretical guidance for efficient PAT operation and wake vortex control. Full article

Accurate prediction of chiller energy consumption is crucial for the efficient operation and intelligent management of heating, ventilation, and air conditioning (HVAC) systems in large buildings. However, such prediction remains challenging due to the multi-scale temporal coupling and nonstationary dynamics of chiller systems. Therefore, an IMVMD-MADNet hybrid framework integrating Improved Multivariate Variational Mode Decomposition (IMVMD) and a Multi-scale Aggregation Decomposition Network (MADNet) is proposed for chiller energy consumption prediction. To avoid information leakage and capture multi-scale features, a rolling local decomposition strategy with adaptive mode selection is employed. First, IMVMD performs stepwise decomposition within a sliding window, and the optimal number of modes is determined using envelope entropy. Then, sample entropy is used to reconstruct the multivariate modes into high-, medium-, and low-frequency components. Subsequently, a dual-branch MADNet combining wavelet-domain time-frequency modeling (WDP) and time-domain causal dependency modeling (TDP) predicts each component, and the results are aggregated to generate the final prediction. Bayesian optimization is employed to optimize the key hyperparameters. One year of real industrial chiller data from a plant in Huizhou, China, is used to evaluate the proposed model against 11 forecasting models. Results show that the dual-branch architecture outperforms single-branch models. The proposed model achieves the best performance across all forecasting horizons, with its advantage becoming more pronounced as the forecasting horizon increases, demonstrating stable predictive performance under the same-plant setting. Full article

The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA–tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies. Full article

To address the issue of low-frequency oscillations in active power and frequency caused by parameter mismatches among multiple grid-forming energy-storage converters in islanded microgrids—where the fixed damping coefficient of conventional VSG control fails to simultaneously achieve satisfactory dynamic response and steady-state accuracy—this paper proposes a VSG control strategy enhanced by cooperative transient damping. The strategy first introduces active power feedback transient damping (TDP) into the active power loop. Although TDP can effectively suppress low-frequency oscillations in active power, it provides insufficient suppression for frequency oscillations induced by angular frequency coupling. Therefore, angular frequency feedback compensation is further incorporated, forming an active power-angular frequency two-degree-of-freedom architecture. This design flexibly adjusts the system damping without compromising steady-state performance, achieving cooperative suppression of both types of oscillations. Simulation and experimental results demonstrate that the proposed strategy significantly suppresses low-frequency oscillations in active power and frequency, effectively improving both the dynamic response performance and steady-state accuracy of the system. Full article

Neurodegenerative diseases represent a major and growing global health burden. Although these disorders are often clinically defined by symptoms and affected brain regions, many are mechanistically linked to abnormal protein accumulation, misfolding, impaired proteostasis, RNA dysregulation, mitochondrial dysfunction, and neuroinflammation. In this Perspective article, I discuss major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, prion diseases, spinocerebellar ataxias, and spinal muscular atrophy, through the lens of disease-associated proteins and experimental modeling. I argue that a protein-centered framework provides a useful approach for understanding disease mechanisms and selecting transgenic mouse models, while recognizing that aging, cellular context, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and other disease modifiers also shape neurodegeneration. Transgenic and genetically engineered mouse models have been essential for dissecting the pathogenic roles of amyloid-β, tau, α-synuclein, TDP-43, SOD1, FUS, C9ORF72-associated dipeptide repeat proteins, mutant huntingtin, prion protein, ataxins, and SMN deficiency. However, these models have important limitations, including artificial overexpression, familial mutation bias, species differences, and incomplete representation of aging-related sporadic diseases. Rather than seeking a single “best” model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation. Such an approach may improve mechanistic insight, strengthen translational relevance, and enhance the predictive value of preclinical neurodegenerative disease research. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) represents a compelling pharmacological target for the development of agents designed to circumvent tumor resistance to topoisomerase 1 (TOP1) inhibitors, a major class of clinically relevant antineoplastic drugs. This paper describes the design and synthesis of novel hybrid TDP1 inhibitors combining coumarin and monoterpene moieties via rigid isoxazole and 1,2,3-triazole heterocyclic linkers. The synthesis was accomplished via [3 + 2] cycloaddition of nitrile oxides to alkynes and copper-catalyzed click chemistry. Biological tests have demonstrated the crucial role of linker nature in the activity of the compounds. Isoxazole-linked conjugates showed strong inhibitory effects on TDP1, with IC₅₀ values in the submicromolar to low micromolar range (0.8–3.2 μM). Overall, these values slightly surpassed those of the triazole-linked analogues, whose IC₅₀ values ranged from 1.1 to 23.3 μM. At noncytotoxic doses, compounds 26e and 16b enhanced the sensitivity of human cervical cancer (HeLa) cells to the antitumor agent topotecan, a TOP1 inhibitor, thereby supporting the promise of this structural class as components of combination chemotherapy. Full article

Background/Objectives: Children with congenital long QT syndrome (cLQTS) are at extremely high risk of torsades de pointes (TdP) and sudden cardiac death (SCD). Although the implantable cardioverter-defibrillator (ICD) is a cornerstone in SCD prevention, traditional transvenous ICDs are associated with venous access occupation, lead wear or fracture due to somatic growth, and difficulties with long-term lead revision or extraction. The extravascular ICD, which places the lead in the substernal extravascular space, has the potential to circumvent these lead-related complications. We report the experience of successful extravascular ICD implantation in a young child with drug-refractory cLQTS type 2 (cLQTS2). Methods: The clinical data of a 9-year-old boy with cLQTS2 were retrospectively analyzed. The patient carried a heterozygous KCNH2 variant (c.1810G>A, p.Gly604Ser) and had been on long-term oral propranolol and mexiletine. He presented with a cardiac arrest out of hospital during nocturnal sleep, was transferred to our hospital after successful cardiopulmonary resuscitation, and had TdP captured on ambulatory monitoring. Following multidisciplinary discussion, preoperative chest computed tomography (CT) assessment of the substernal anatomy, and informed consent, extravascular ICD implantation was performed on hospital day 11. The procedure involved the creation of a substernal tunnel via a subxiphoid incision, placement of the defibrillation lead in the anterior mediastinum with lead slack reserved for growth, and positioning of the pulse generator in a left axillary subcutaneous pocket. Intraoperative defibrillation testing succeeded with a single 30 J shock. Results: The postoperative recovery was uneventful without procedure-related complications. At the 2-month follow-up, device parameters were satisfactory and no inappropriate shocks had occurred. The corrected QT interval (QTc) decreased from 563 ms on admission to 522 ms. Ambulatory monitoring detected asymptomatic episodes of non-sustained ventricular tachycardia, but no ventricular fibrillation or syncope was observed. Venous access was fully preserved. Conclusions: In children with drug-refractory cLQTS2, the extravascular ICD provides defibrillation and antitachycardia pacing (ATP) while avoiding transvenous lead complications and preserving venous access. This case shows that with precise preoperative planning and lead redundancy, the device appears feasible and can be implanted without short-term complications in young children. Larger studies with longer follow-up are needed to evaluate long-term device performance. Full article