A comparison study of pathological features and drug efficacy between Drosophila models of C9orf72 ALS/FTD.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a complex genetic basis, presenting both in familial and sporadic forms. The hexanucleotide (G4C2) repeat expansion in the C9orf72 gene, which triggers distinct pathogenic mechanisms, has been identified as a major contributor to familial and sporadic Amyotrophic lateral sclerosis cases. Animal models have proven pivotal in understanding these mechanisms; however, discrepancies between models due to variable transgene sequence, expression levels, and toxicity profiles complicate the translation of findings. Herein, we provide a systematic comparison of 7 publicly available Drosophila transgenes modeling the G4C2 expansion under uniform conditions, evaluating variations in their toxicity profiles. Further, we tested 3 previously characterized disease-modifying drugs in selected lines to uncover discrepancies among the tested strains. Our study not only deepens our understanding of the C9orf72 G4C2 mutations but also presents a framework for comparing constructs with minute structural differences. This work may be used to inform experimental designs to better model disease mechanisms and help guide the development of targeted interventions for neurodegenerative diseases, thus bridging the gap between model-based research and therapeutic application.

Bacterial filamentation as a mechanism for cell-to-cell spread within an animal host.

Intracellular pathogens are challenged with limited space and resources while replicating in a single host cell. Mechanisms for direct invasion of neighboring host cells have been discovered in cell culture, but we lack an understanding of how bacteria directly spread between host cells in vivo. Here, we describe the discovery of intracellular bacteria that use filamentation for spreading between the intestinal epithelial cells of a natural host, the rhabditid nematode Oscheius tipulae. The bacteria, which belong to the new species Bordetella atropi, can infect the nematodes following a fecal-oral route, and reduce host life span and fecundity. Filamentation requires UDP-glucose biosynthesis and sensing, a highly conserved pathway that is used by other bacteria to detect rich conditions and inhibit cell division. Our results indicate that B. atropi uses a pathway that normally regulates bacterial cell size to trigger filamentation inside host cells, thus facilitating cell-to-cell dissemination.

The Perspectives of Early Diagnosis of Schizophrenia Through the Detection of Epigenomics-Based Biomarkers in iPSC-Derived Neurons.

The lack of early diagnostic biomarkers for schizophrenia greatly limits treatment options that deliver therapeutic agents to affected cells at a timely manner. While previous schizophrenia biomarker research has identified various biological signals that are correlated with certain diseases, their reliability and practicality as an early diagnostic tool remains unclear. In this article, we discuss the use of atypical epigenetic and/or consequent transcriptional alterations (ETAs) as biomarkers of early-stage schizophrenia. Furthermore, we review the viability of discovering and applying these biomarkers through the use of cutting-edge technologies such as human induced pluripotent stem cell (iPSC)-derived neurons, brain models, and single-cell level analyses.

The Relationship of Intra-Individual Release Variability with Distance and Shooting Performance in Basketball.

The aim of this study was to investigate the role of release parameter changes within individuals (intra-individual) on basketball shooting performance across both free throws and three-point shots, and identify whether any velocity dependence exists. Twelve male basketball players were recorded shooting seventy-five three-point shots (6.75 m) and fifty free throws (4.19 m). Ball release parameters were estimated by combining an analytic trajectory model including drag, a least squares estimator, and gradient-based release distance compensation. Intra-individual release velocity standard deviations (SD) were found to be significantly smaller across all distances ([0.05-0.13 m/s] when compared to statistics reported by other studies [0.2-0.8 m/s]). Despite an increase in lower body motion and a 24% increase in release velocity (p < 0.001) as shooting distance increased, no increases in intra-individual release velocity or angle SD were observed indicating velocity-dependent changes in release parameters were absent. Shooting performance was found to be strongly correlated to the release velocity SD (r = -0.96, p < 0.001, for three-point shots, and r = -0.88, p < 0.001, for free throws). Release angle SD (1.2 ± 0.24 deg, for three-point shots, and 1.3 ± 0.26 deg, for free throws) showed no increase with distance and unrelated to performance. These findings suggest that velocity-dependent factors have minimal contribution to shooting strategies and an individual's ability to control release velocity at any distance is a primary factor in determining their shooting performance.

Pesticide Residues and Risk Assessment from Monitoring Programs in the Largest Production Area of Leafy Vegetables in South Korea: A 15-Year Study.

Leafy vegetables are widely consumed in South Korea, especially in the form of kimchi and namul (seasoned vegetables) and are used for wrapping meat. Therefore, the management of pesticide residues in leafy vegetables is very important. A total of 17,977 samples (49 leafy vegetables) were mainly collected in the largest production area of leafy vegetables (Gwangju Metropolitan City and Chonnam Province) in South Korea. They were analyzed within the government's monitoring programs (Gwangju Metropolitan City) of pesticide residues between 2005 and 2019. Pesticide residues were found in 2815 samples (15.7%), and 426 samples (2.4%) from among these exceeded the specified maximum residue limits (MRLs). Samples exceeding the MRLs were mostly detected in spinach, ssamchoo (brassica lee ssp. namai), crown daisy, lettuce, and perilla leaves. Azoxystrobin, dimethomorph, and procymidone were the most frequently detected pesticides. However, procymidone, diniconazole, and lufenuron were found to most frequently exceed the MRLs. The rate of MRLs exceeding has been managed below the average (2.4%) more recently than in the past in this area. Further, leafy vegetables with the most violations of the MRLs in our study in South Korea were not harmful to health by a risk assessment (the range of the hazard index was 0.001-7.6%).

An Inexpensive Cardiovascular Flow Simulator for Cardiac Catheterization Procedure Using a Pulmonary Artery Catheter.

Cardiac catheterization associated with central vein cannulation can involve potential thrombotic and infectious complications due to multiple cannulation trials or improper placement. To minimize the risks, medical simulators are used for training. Simulators are also employed to test medical devices such as catheters before performing animal tests because they are more cost-effective and still reveal necessary improvements. However, commercial simulators are expensive, simplified for their purpose, and provide limited access sites. Inexpensive and anatomical cardiovascular simulators with central venous access for cannulation are sparse. Here, we developed an anatomically and physiologically accurate cardiovascular flow simulator to help train medical professionals and test medical devices. Our simulator includes an anatomical right atrium/ventricle, femoral and radial access sites, and considers the variability of arm position. It simulates physiological pulsatile blood flow with a setting for constant flow from 3 to 6 L/min and mimics physiological temperature (37°C). We demonstrated simulation by inserting a catheter into the system at radial/femoral access sites, passing it through the vasculature, and advancing it into the heart. We expect that our simulator can be used as an educational tool for cardiac catheterization as well as a testing tool that will allow for design iteration before moving to animal trials.

Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3.

Cytoplasmic accumulation of TDP-43 in motor neurons is the most prominent pathological feature in amyotrophic lateral sclerosis (ALS). A feedback cycle between nucleocytoplasmic transport (NCT) defect and TDP-43 aggregation was shown to contribute to accumulation of TDP-43 in the cytoplasm. However, little is known about cellular factors that can control the activity of NCT, thereby affecting TDP-43 accumulation in the cytoplasm. Here, we identified via FRAP and optogenetics cytosolic calcium as a key cellular factor controlling NCT of TDP-43. Dynamic and reversible changes in TDP-43 localization were observed in Drosophila sensory neurons during development. Genetic and immunohistochemical analyses identified the cytosolic calcium-Calpain-A-Importin α3 pathway as a regulatory mechanism underlying NCT of TDP-43. In C9orf72 ALS fly models, upregulation of the pathway activity by increasing cytosolic calcium reduced cytoplasmic accumulation of TDP-43 and mitigated behavioral defects. Together, these results suggest the calcium-Calpain-A-Importin α3 pathway as a potential therapeutic target of ALS.

NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases.

Dendrite pathology is frequently observed in various neurodegenerative diseases (NDs). Although previous studies identified several pathogenic mediators of dendrite defects that act through loss of function in NDs, the underlying pathogenic mechanisms remain largely unexplored. Here, our search for additional pathogenic contributors to dendrite defects in NDs identifies Relish/NF-κB as a novel gain-of-toxicity-based mediator of dendrite defects in animal models for polyglutamine (polyQ) diseases and amyotrophic lateral sclerosis (ALS). In a Drosophila model for polyQ diseases, polyQ-induced dendrite defects require Dredd/Caspase-8-mediated endoproteolytic cleavage of Relish to generate the N-terminal fragment, Rel68, and subsequent Charon-mediated nuclear localization of Rel68. Rel68 alone induced neuronal toxicity causing dendrite and behavioral defects, and we identify two novel transcriptional targets, Tup and Pros, that mediate Rel68-induced neuronal toxicity. Finally, we show that Rel68-induced toxicity also contributes to dendrite and behavioral defects in a Drosophila model for ALS. Collectively, our data propose disinhibition of latent toxicity of Relish/NF-κB as a novel pathogenic mechanism underlying dendrite pathology in NDs.

Ataxin-2 Dysregulation Triggers a Compensatory Fragile X Mental Retardation Protein Decrease in Drosophila C4da Neurons.

Dendrites require precise and timely delivery of protein substrates to distal areas to ensure the correct morphology and function of neurons. Many of these protein substrates are supplied in the form of ribonucleoprotein (RNP) complex consisting of RNA-binding proteins (RBPs) and mRNAs, which are subsequently translated in distal dendritic areas. It remains elusive, however, whether key RBPs supply mRNA according to local demands individually or in a coordinated manner. In this study, we investigated how Drosophila sensory neurons respond to the dysregulation of a disease-associated RBP, Ataxin-2 (ATX2), which leads to dendritic defects. We found that ATX2 plays a crucial role in spacing dendritic branches for the optimal dendritic receptive fields in Drosophila class IV dendritic arborization (C4da) neurons, where both expression level and subcellular location of ATX2 contribute significantly to this effect. We showed that translational upregulation through the expression of eukaryotic translation initiation factor 4E (eIF4E) further enhanced the ATX2-induced dendritic phenotypes. Additionally, we found that the expression level of another disease-associated RBP, fragile X mental retardation protein (FMRP), decreased in both cell bodies and dendrites when neurons were faced with aberrant upregulation of ATX2. Finally, we revealed that the PAM2 motif of ATX2, which mediates its interaction with poly(A)-binding protein (PABP), is potentially necessary for the decrease of FMRP in certain neuronal stress conditions. Collectively, our data suggest that dysregulation of RBPs triggers a compensatory regulation of other functionally-overlapping RBPs to minimize RBP dysregulation-associated aberrations that hinder neuronal homeostasis in dendrites.

Dietary Antioxidants and the Mitochondrial Quality Control: Their Potential Roles in Parkinson's Disease Treatment.

Advances in medicine and dietary standards over recent decades have remarkably increased human life expectancy. Unfortunately, the chance of developing age-related diseases, including neurodegenerative diseases (NDDs), increases with increased life expectancy. High metabolic demands of neurons are met by mitochondria, damage of which is thought to contribute to the development of many NDDs including Parkinson's disease (PD). Mitochondrial damage is closely associated with the abnormal production of reactive oxygen species (ROS), which are widely known to be toxic in various cellular environments, including NDD contexts. Thus, ways to prevent or slow mitochondrial dysfunction are needed for the treatment of these NDDs. In this review, we first detail how ROS are associated with mitochondrial dysfunction and review the cellular mechanisms, such as the mitochondrial quality control (MQC) system, by which neurons defend against both abnormal production of ROS and the subsequent accumulation of damaged mitochondria. We next highlight previous studies that link mitochondrial dysfunction with PD and how dietary antioxidants might provide reinforcement of the MQC system. Finally, we discuss how aging plays a role in mitochondrial dysfunction and PD before considering how healthy aging through proper diet and exercise may be salutary.

The Mechanisms of Nuclear Proteotoxicity in Polyglutamine Spinocerebellar Ataxias.

Polyglutamine (polyQ) spinocerebellar ataxias (SCAs) are the most prevalent subset of SCAs and share the aberrant expansion of Q-encoding CAG repeats within the coding sequences of disease-responsible genes as their common genetic cause. These polyQ SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) are inherited neurodegenerative diseases characterized by the progressive atrophy of the cerebellum and connected regions of the nervous system, which leads to loss of fine muscle movement coordination. Upon the expansion of polyQ repeats, the mutated proteins typically accumulate disproportionately in the neuronal nucleus, where they sequester various target molecules, including transcription factors and other nuclear proteins. However, it is not yet clearly understood how CAG repeat expansion takes place or how expanded polyQ proteins accumulate in the nucleus. In this article, we review the current knowledge on the molecular and cellular bases of nuclear proteotoxicity of polyQ proteins in SCAs and present our perspectives on the remaining issues surrounding these diseases.

Discovery of new epigenomics-based biomarkers and the early diagnosis of neurodegenerative diseases.

Treatment options for many neurodegenerative diseases are limited due to the lack of early diagnostic procedures that allow timely delivery of therapeutic agents to affected neurons prior to cell death. While notable advances have been made in neurodegenerative disease biomarkers, whether or not the biomarkers discovered to date are useful for early diagnosis remains an open question. Additionally, the reliability of these biomarkers has been disappointing, due in part to the large dissimilarities between the tissues traditionally used to source biomarkers and primarily diseased neurons. In this article, we review the potential viability of atypical epigenetic and/or consequent transcriptional alterations (ETAs) as biomarkers of early-stage neurodegenerative disease, and present our perspectives on the discovery and practical use of such biomarkers in patient-derived neural samples using single-cell level analyses, thereby greatly enhancing the reliability of biomarker application.