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Since Euler's original gyro-dynamic analysis nearly two and a half centuries ago, the use of multi-body dynamics (MBD) has spread widely in application scope from large displacement rigid body dynamics to infinitesimal amplitude elastodynamics. In some cases, MBD has become a multi-physics multi-scale analysis, comprising contact mechanics, tribo-dynamics, terramechanics, thermodynamics, biomechanics, etc. It is an essential part of all analyses in many engineering disciplines, including vehicle engineering. This paper provides an overview of historical developments with emphasis on vehicle development and investigation of observed phenomena, including noise, vibration and harshness. The approach undertaken is comprehensive and provides a uniquely focused perspective, one which has not hitherto been reported in the literature. [ABSTRACT FROM AUTHOR]

MEF2C is a critical transcription factor in neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome (MHS), a severe form of autism spectrum disorder (ASD)/intellectual disability (ID). Despite prior animal studies of MEF2C heterozygosity to mimic MHS, MHS-specific mutations have not been investigated previously, particularly in a human context as hiPSCs afford. Here, for the first time, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found that decreased neurogenesis was accompanied by activation of a micro-(mi)RNA-mediated gliogenesis pathway. We also demonstrate network-level hyperexcitability in MHS neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory (E/I) imbalance. Notably, the predominantly extrasynaptic (e)NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes. During neurodevelopment, MEF2C regulates many ASD-associated gene networks, suggesting that treatment of MHS deficits may possibly help other forms of ASD as well., (© 2024. The Author(s).)

Competing Interests: The authors declare that they have no conflict of interest.

In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild-type and AD mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), evidence is found for compromised mitochondrial energy in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). Isotope-labeled metabolic flux experiments revealed a major block in activity in the tricarboxylic acid (TCA) cycle at the α-ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme-A synthetase step, metabolizing α-ketoglutarate to succinate. Associated with this block, aberrant protein S-nitrosylation of αKGDH subunits inhibited their enzyme function. This aberrant S-nitrosylation is documented not only in AD-hiN but also in postmortem human AD brains versus controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S-nitrosothiols and chemoselective-enrichment of S-nitrosoproteins. Treatment with dimethyl succinate, a cell-permeable derivative of a TCA substrate downstream to the block, resulted in partial rescue of mitochondrial bioenergetic function as well as reversal of synapse loss in AD-hiN. These findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Economic policies for managing agricultural water use are often complicated by the challenge of using water prices as an efficient economic tool when other non-economic concerns are involved in the decision-making process. This study aims to analyse the impact of water pricing policies on preserving agricultural water resources in Iran. This study applies a system dynamics approach to simulate the system performance and behaviour of stakeholders and the economic implications. Our finding shows that water pricing policies will likely fail due to low water price elasticity and if there are lack of institutional and physical infrastructure, alternative professions, manufacturing technology, education, and training opportunities. The results also illustrate how agricultural water price increase (AWPI) fails to reduce water consumption in the absence of an adequate institutional arrangement. Also, it shows how the lack of advanced institutional infrastructure in the presence of physical infrastructure enhances pervasive overuse and destructive competition among stakeholders by increasing the area under cultivation. In the discussion, the paper portrays a way out of the decision-making body by following AWPI effects on water conservation in the agricultural sector as the most significant water consumer. It investigates the absence and subsequent presence of specific institutional conditions and evaluates training and enhancing farmers' skills and alternative career source with higher income and technology as the architecture of good environmental governance. Finally, it concludes that a series of inclusive measures must be considered to increase the elasticity of the water price. These measures must stimulate farmers towards pursuing the goals of global sustainable development and enhancing social welfare., (© 2023. Springer Nature Limited.)

A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in activity inhibition assessed by carbon-labeled metabolic flux experiments. This inhibition principally affects α-ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing α-ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death. Our evidence indicates that aberrant S-nitrosylation of TCA cycle enzymes contributes to this bioenergetic failure., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Incomplete knowledge of the molecular basis of colorectal cancer, with subsequent limitations in early diagnosis and effective treatment, has contributed to this form of malignancy becoming the second most common cause of cancer-related death worldwide. With the advances in high-throughput profiling techniques and the availability of public data sets such as The Cancer Genome Atlas Program (TCGA), a broad range of coding transcripts have been profiled and their underlying modes of action have been mapped. However, there is still a huge gap in our understanding of noncoding RNA dysregulation. To this end, we used a bioinformatics approach to shortlist and evaluate yet-to be-profiled long noncoding RNAs (lncRNAs) in colorectal cancer. We analysed the TCGA RNA-seq data and followed this by validating the expression patterns using a qPCR technique. Analysing in-house clinical samples, the real-time PCR method revealed that the shortlisted lncRNAs, that is MER1 Repeat Containing Imprinted Transcript 1 (MIMT1) and Non-Protein Coding RNA 1550 (LINC01550), were down-regulated in colorectal cancer tumours compared with the paired adjacent normal tissues. Mechanistically, the in silico results suggest that LINC01550 could form a complex competitive endogenous RNA (ceRNA) network leading to the subsequent regulation of colorectal cancer-related genes, such as CUGBP Elav-Like Family Member (CELF2), Polypyrimidine Tract Binding Protein 1 (PTBP1) and ELAV Like RNA Binding Protein 1 (ELAV1). The findings of this work indicate that MIMT1 and LINC01550 could be novel tumour suppressor genes that can be studied further to assess their roles in regulating the cancer signalling pathway(s)., (© 2023 Company of the International Journal of Experimental Pathology (CIJEP).)

Introduction: Accurate landmark identification is a prerequisite for accurate and reliable biomedical image analysis. Orthodontic study models are valuable tools for diagnosis, treatment planning, and maintaining complete records. The purpose of this study was to evaluate the reliability and validity of a software program (Align Technology, Inc) as a tool for automatic landmark location., Methods: Using digital intraoral scans of 10 dental arches, 4 calibrated human judges independently located cusp tips and interproximal contacts. The same landmarks were automatically identified by the software. Intraclass correlation coefficient (Cronbach α), absolute mean errors, and regression analysis were calculated. In addition, Bland-Altman 95% confidence limits were also applied to the data to graphically display agreement on landmark identification between the human judges and the software., Results: The intraclass correlation coefficient between the software and the human judges' average for the x-, y-, and z-coordinates for all landmarks was excellent, at 1.0, 1.0, and 0.98, respectively. The regression analysis and Bland-Altman plots show no systematic errors for agreement on landmark identification between the human judges and the software., Conclusions: Landmark location was nearly identical between the software and the human judges, making the methods interchangeable., (Copyright © 2022. Published by Elsevier Inc.)

Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins, such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown. Here, we used cell-based models, including human induced pluripotent stem cell-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathologic pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular buildup of misfolded proteins, with consequent secretion resulting in cell-to-cell spread. Thus, our data show that pathologic protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of individual neurons, but also for α-syn release and spread of disease throughout the nervous system. SIGNIFICANCE STATEMENT In Parkinson's disease and Lewy body dementia, dysfunctional autophagy contributes to accumulation and spread of aggregated α-synuclein. Here, we provide evidence that protein S-nitrosylation of p62 inhibits autophagic flux, contributing to α-synuclein aggregation and spread., (Copyright © 2022 the authors.)

Cell surface proteins (CSPs) are an important type of protein in different essential cell functions. This study aimed to distinguish overexpressed CSPs in colorectal cancer to investigate their biomarker, prognosis, and drug resistance potential. Raw data of three datasets including 1187 samples was downloaded then normalization and differential expression were performed. By the combination of the cancer genome atlas (TCGA) clinical data, survival analysis was carried out. Information of all CSPs was collected from cell surface protein atlas. The role of each candidate gene expression was investigated in drug resistance by CCEL and GDSC data from PharmacoGX. CRC samples including 30 tumor samples and adjacent normal were used to confirm data by RT-qPCR. Outcomes showed that 66 CSPs overexpressed in three datasets, and 146 CSPs expression associated with poor prognosis features in TCGA data that TIMP1 and QSOX2 can associate with poor patient survival independently. High-risk patients illustrated more fatality than low-risk patients based on the risk score calculated by the expression level of these genes. Receiver operating characteristic curve analysis showed that 39 CSPs as perfect biomarkers for diagnosis in CRC. Furthermore, QSOX2 and TIMP1 expression levels increased in tumor samples compared to adjacent normal samples. The Drug resistance analysis demonstrated ADAM12 and COL1A2 up-regulation among 66 overexpressed CSPs caused resistance to Venetoclax and Cyclophosphamide with a high estimate, respectively. Many CSPs are deregulated in CRC, and can be valuable candidates as biomarkers for diagnosis, prognosis, and drug resistance., (Copyright © 2021. Published by Elsevier Inc.)

Acute lymphoblastic leukemia (ALL) is one of the most frequent hematological malignancies in children, representing approximately 25 % of all pediatric cancers. Despite striking advances in ALL treatments, a small population of patients does not still respond to chemotherapy, raising the number of deaths in children. ABC transporters are one of the major causes of multidrug resistance (MDR) in cancers and overexpression of ABCA3 is directly associated with increased chemo-resistance in pediatric ALL. Here, we aimed to identify the microRNAs (miRNAs) which may regulate the expression of ABCA3 in childhood ALL. Bone marrow samples from a total of 50 ALLs and 59 controls were collected and after in silico and literature search, miR-324-3p and miR-508-5p were nominated from a list of putative miRNAs targeting ABCA3. Our qPCR analysis showed a low expression profile of selected miRNAs in pediatric ALL patients compared with non-cancer controls. Furthermore, we found that both miR-324-3p and miR-508-5p were significantly differentially expressed between patients with positive and negative minimal residual disease (MRD + vs MRD-) after one year of chemotherapy while only miR-508-5p was underexpressed in relapsed ALL patients. Additionally, a negative correlation was identified between the expression of these two miRNAs and ABCA3, supporting the regulatory effect of them on drug resistance through interacting with ABCA3. Overall, we suggested miR-324-3p and miR-508-5p as potential diagnostic and drug-resistant biomarkers in pediatric ALL. Moreover, our findings presented miR-508-5p to behave as a promising relapsed indicator in childhood ALL which can be applied in the development of novel therapeutic strategies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Patients with heart failure are one of the high-risk groups for coronary artery. Distance education of self-care behaviors can be effective in preventing the disease. The aim of this study was to investigate the effect of social networks in explaining the awareness of cardiovascular patients' self-care behaviors toward COVID-19., Materials and Methods: In the present survey study, 227 patients with a history of heart failure were selected from Shahid Rajaei Hospital in Tehran by the available sampling method (May to July 2020). Data collection tools were the standard European Self-Care Behavior Questionnaire for heart failure and the Dorty Elizabeth Orem self-care model. Data were analyzed using SPSS Version 22., Results: The results of the Pearson correlation coefficient showed a positive and relatively strong linear relationship between the variable of the degree of persistence in the use of networks with the eight dimensions of self-care behavior except psychological emotion control ( r = -0.39, P = 0.315). Furthermore, a significant weak inverse relationship between the dimension of "cooperation with physicians and treatment staff" ( r = -0.22, P = 0.129). Moreover, psychological support ( r = -0/034, P = 0.446) was observed with the use of networks. Multivariate regression analysis revealed that the type of activity and participation in networks has a greater share and effect in increasing the score of self-care behavior of 0.55., Conclusions: Since the use of networks has a positive effect on patients' self-care behavior, the use of these networks is recommended as a community-based approach in the health system and to improve health and health outcomes., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Advanced Biomedical Research.)

Background: To better manage the COVID-19 pandemic, it is necessary to carefully study information about patients with COVID-19. Objective: To report clinical and epidemiological characteristics of COVID-19 patients in southern Iran., Methods: This cross-sectional retrospective study was conducted based on data extracted from the COVID-19 registry of Hormozgan. Data from patients with confirmed COVID-19 based on CT-scan results or real-time reverse transcriptase-polymerase chain reaction (RT-PCR) results until September 25, 2020, were analyzed for this study (2351 inpatients). We reported demographics, signs and symptoms on admission, comorbidities, and treatments, as well as clinical outcomes, hospital stay, and intensive care unit (ICU) admission., Results: Most of patients were men (1235/2351; 52.5%) and the most common signs and symptoms included cough (1343/2351; 57.1%), shortness of breath (1224/2351; 52.1%) and fever. The most common comorbidities included hypertension (410/2351 (17.4%), diabetes (343/2351; 14.6%) and chronic cardiac disease (282/2351; 12%). Also, 228 patients (9.7%) were hospitalized in the ICU. The mortality rate was 12.5% (295/2351) among all patients and 64.5% (147/228) in ICU wards, respectively. The number of cases with comorbidities including hypertension, chronic cardiac disease, diabetes, chronic neurological disorders, chronic kidney disease, chronic hematologic disease, malignant neoplasm, moderate or severe liver disease, dementia and fauvism in the ICU was significantly higher than the general wards., Conclusion: Most characteristics of our patients were similar to those reported in other studies; however, our patients were younger and suffered from a less severe disease. The mortality rate in the ICU was higher than other studies., (© 2021 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia., Competing Interests: Competing interest statement: S.A.L. and G.H. are coauthors on a published consensus statement review of cell-death criteria along with several dozen other authors who are authorities in this field [N. M. C. Connolly et al., Cell Death Differ. 25, 542–572 (2018)]. That manuscript was published in order to help nonexperts in the field understand and use criteria for various types of cell death. They also published a similar type of review paper together 10 y ago [G. E. Hardingham, S. A. Lipton, Antioxid. Redox Signal. 14, 1421–1424 (2011)]. However, S.A.L. and G.H. have never formally collaborated or worked together on any laboratory-based scientific project, including the current work.

Shape memory alloys (SMAs) have been widely used in civil engineering applications including active and passive control of structures, sensors and actuators and strengthening of reinforced concrete (RC) structures owing to unique features such as the shape memory effect and pseudo-elasticity. Iron-based shape memory alloys (Fe-SMAs) have become popular in recent years. Use of iron-based SMAs for strengthening RC structures has received attention in the recent decade due to the advantages it presents, that is, no ducts or anchor heads are required, friction losses do not occur and no space is needed for a hydraulic device to exert force. Accordingly, Fe-SMAs embedded in a shotcrete layer have been used for pre-stressing RC beams at Empa. The aim of this study is to present an approach to model and analyze the behavior of RC members strengthened and pre-stressed with Fe-SMA rebars embedded in a shotcrete layer. The lack of research on developing finite element models for studying the behavior of concrete structures strengthened by iron-based shape memory alloys is addressed. Three-dimensional finite element models were developed in the commercial finite element code ABAQUS, using the concrete damaged plasticity model to predict the studied beams' load-displacement response. The results of the finite element analyses show a considerably good agreement with the experimental data in terms of the beams' cracking load and ultimate load capacity. The effects of different strengthening parameters, including SMA rebar diameter, steel rebar diameter and pre-stressing force level on the beam behavior, were investigated based on the verified finite element models. The results were compared. The load-displacement response of an 18-m concrete girder strengthened and pre-stressed with iron-based SMA bars was examined by the developed finite element model as a case study.

A higher expression of MALAT1 has been reported in breast cancer. However, more studies are needed to decipher the mechanisms by which this lncRNA imposes its oncogenic effects. In this study, blood and tissue samples were taken from healthy normal and breast cancer subjects. qPCR was used to analyze the gene expression. HRM-PCR method was carried out to genotype the selected samples. Computational analysis was recruited to find novel targets of MALAT1 and miR-143-3p. The data analyses revealed that MALAT1 was up-regulated in breast cancer and could be a distinctive factor to diagnose cancer. The expression of MALAT1 was inversely correlated with miR-143-3p expression in the studied clinical samples. The down-regulation of miR-143-3p was proven in the clinical tumor samples as compared to the healthy controls. A negative correlation of miR-143-3p with its putative target, RALGAPA2 was observed. A functional SNP rs3827693 located within the 3'UTR region of RALGAPA2 mRNA was validated in this study to associate with breast cancer risk. The rs3827693 allele G significantly decreased the breast cancer incidence and augmented the negative correlation between RALGAPA2 and miR-143-3p, presumably through strengthening the interaction between these two transcripts. This study proposed MALAT1 miR-143-3p and miR-143-3p RALGAPA2 axis in breast cancer, whereby the latter can be altered by the clinically functional SNP rs3827693.

Human Alzheimer's disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, the underlying mechanism for this excessive excitability remains incompletely understood. To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In the AD hiPSC-derived neurons/organoids, we found increased excitatory bursting activity, which could be explained in part by a decrease in neurite length. AD hiPSC-derived neurons also displayed increased sodium current density and increased excitatory and decreased inhibitory synaptic activity. Our findings establish hiPSC-derived AD neuronal cultures and organoids as a relevant model of early AD pathophysiology and provide mechanistic insight into the observed hyperexcitability., Competing Interests: SG, ND, DT, XZ, YW, MM, RA, MT, SL No competing interests declared, (© 2019, Ghatak et al.)

Fluid media such as water and ethylene glycol are usually quite poor conductors of heat. Nanoparticles can improve the thermal properties of fluids in a remarkable manner. Despite a plethora of experimental and theoretical studies, the underlying physics of heat transport in nanofluids is not yet well understood. Furthermore, the link between nanoscale energy transport and bulk properties of nanofluids is not fully established. This paper presents a thermal conductivity model, encapsulating solid-liquid interfacial thermal resistance, particle shape factor and the variation of thermal conductivity across a physisorbed fluidic layer on a nanoparticle surface. The developed model for thermal conductivity integrates the interfacial Kapitza resistance, the characteristics of a nanolayer, convective diffusion and surface energy with capillary condensation. In addition, the thickness of the nanolayer is predicted using the Brunauer-Emmett-Teller (BET) isotherms and micro/nano-menisci generated pressures of condensation. Such a comprehensive model for thermal conductivity of nanoparticles and systematic study has not hitherto been reported in the literature. The thermal conductivity model is evaluated using experimental data available in open literature., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Parkinson's disease (PD) is a debilitating neurodegenerative disorder, for which people above the age of 60 show an increased risk. Although there has been great advancement in understanding the disease-related abnormalities in brain circuitry and development of symptomatic treatments, a cure for PD remains elusive. The discovery of PD associated gene mutations and environmental toxins have yielded animal models of the disease. These models could recapitulate several key aspects of PD, and provide more insights into the disease pathogenesis. They have also revealed novel aspects of the disease mechanism including noncell autonomous events and spreading of pathogenic protein species across the brain. Nevertheless, none of these models so far can comprehensively represent all aspects of the human disease. While the field is still searching for the perfect model system, recent developments in stem cell biology have provided a new dimension to modelling PD, especially doing it in a patient-specific manner. In the current review, we attempt to summarize the key findings in the areas discussed above, and highlight how the core PD pathology distinguishes itself from other neurodegenerative disorders while also resembling them in many aspects.

Mutations in PARK6 (PINK1) and PARK2 (Parkin) are linked to rare familial cases of Parkinson's disease (PD). Mutations in these genes result in pathological dysregulation of mitophagy, contributing to neurodegeneration. Here, we report that environmental factors causing a specific posttranslational modification on PINK1 can mimic these genetic mutations. We describe a molecular mechanism for impairment of mitophagy via formation of S-nitrosylated PINK1 (SNO-PINK1). Mitochondrial insults simulating age- or environmental-related stress lead to increased SNO-PINK1, inhibiting its kinase activity. SNO-PINK1 decreases Parkin translocation to mitochondrial membranes, disrupting mitophagy in cell lines and human-iPSC-derived neurons. We find levels of SNO-PINK1 in brains of α-synuclein transgenic PD mice similar to those in cell-based models, indicating the pathophysiological relevance of our findings. Importantly, SNO-PINK1-mediated deficits in mitophagy contribute to neuronal cell death. These results reveal a direct molecular link between nitrosative stress, SNO-PINK1 formation, and mitophagic dysfunction that contributes to the pathogenesis of PD., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent studies have pointed to protein S-nitrosylation as a critical regulator of cellular redox homeostasis. For example, S-nitrosylation of peroxiredoxin-2 (Prx2), a peroxidase widely expressed in mammalian neurons, inhibits both enzymatic activity and protective function against oxidative stress. Here, using in vitro and in vivo approaches, we identify a role and reaction mechanism of the reductase sulfiredoxin (Srxn1) as an enzyme that denitrosylates (thus removing -SNO) from Prx2 in an ATP-dependent manner. Accordingly, by decreasing S-nitrosylated Prx2 (SNO-Prx2), overexpression of Srxn1 protects dopaminergic neural cells and human-induced pluripotent stem cell (hiPSC)-derived neurons from NO-induced hypersensitivity to oxidative stress. The pathophysiological relevance of this observation is suggested by our finding that SNO-Prx2 is dramatically increased in murine and human Parkinson's disease (PD) brains. Our findings therefore suggest that Srxn1 may represent a therapeutic target for neurodegenerative disorders such as PD that involve nitrosative/oxidative stress., Competing Interests: The authors declare no conflict of interest.

Metabolic syndrome (MetS) and Type 2 diabetes mellitus (T2DM) increase risk for Alzheimer's disease (AD). The molecular mechanism for this association remains poorly defined. Here we report in human and rodent tissues that elevated glucose, as found in MetS/T2DM, and oligomeric β-amyloid (Aβ) peptide, thought to be a key mediator of AD, coordinately increase neuronal Ca(2+) and nitric oxide (NO) in an NMDA receptor-dependent manner. The increase in NO results in S-nitrosylation of insulin-degrading enzyme (IDE) and dynamin-related protein 1 (Drp1), thus inhibiting insulin and Aβ catabolism as well as hyperactivating mitochondrial fission machinery. Consequent elevation in Aβ levels and compromise in mitochondrial bioenergetics result in dysfunctional synaptic plasticity and synapse loss in cortical and hippocampal neurons. The NMDA receptor antagonist memantine attenuates these effects. Our studies show that redox-mediated posttranslational modification of brain proteins link Aβ and hyperglycaemia to cognitive dysfunction in MetS/T2DM and AD.

Cyanide is a life-threatening, bioterrorist agent, preventing cellular respiration by inhibiting cytochrome c oxidase, resulting in cardiopulmonary failure, hypoxic brain injury, and death within minutes. However, even after treatment with various antidotes to protect cytochrome oxidase, cyanide intoxication in humans can induce a delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Additional mechanisms are thought to underlie cyanide-induced neuronal damage, including generation of reactive oxygen species. This may account for the fact that antioxidants prevent some aspects of cyanide-induced neuronal damage. Here, as a potential preemptive countermeasure against a bioterrorist attack with cyanide, we tested the CNS protective effect of carnosic acid (CA), a pro-electrophilic compound found in the herb rosemary. CA crosses the blood-brain barrier to up-regulate endogenous antioxidant enzymes via activation of the Nrf2 transcriptional pathway. We demonstrate that CA exerts neuroprotective effects on cyanide-induced brain damage in cultured rodent and human-induced pluripotent stem cell-derived neurons in vitro, and in vivo in various brain areas of a non-Swiss albino mouse model of cyanide poisoning that simulates damage observed in the human brain. Cyanide, a potential bioterrorist agent, can produce a chronic delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Here, cyanide poisoning treated with the proelectrophillic compound carnosic acid, results in reduced neuronal cell death in both in vitro and in vivo models through activation of the Nrf2/ARE transcriptional pathway. Carnosic acid is therefore a potential treatment for the toxic central nervous system (CNS) effects of cyanide poisoning. ARE, antioxidant responsive element; Nrf2 (NFE2L2, Nuclear factor (erythroid-derived 2)-like 2)., (© 2015 International Society for Neurochemistry.)

Neural transplantation is a promising strategy for restoring dopaminergic dysfunction and modifying disease progression in Parkinson's disease (PD). Human embryonic stem cells (hESCs) are a potential resource in this regard because of their ability to provide a virtually limitless supply of homogenous dopaminergic progenitors and neurons of appropriate lineage. The recent advances in developing robust cell culture protocols for directed differentiation of hESCs to near pure populations of ventral mesencephalic (A9-type) dopaminergic neurons has heightened the prospects for PD cell therapy. Here, we focus our review on current state-of-the-art techniques for harnessing hESC-based strategies toward development of a stem cell therapeutic for PD. Importantly, we also briefly describe a novel genetic-programming approach that may address many of the key challenges that remain in the field and that may hasten clinical translation., (© 2014 Wiley Periodicals, Inc.)

Parkinson's disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived stem cell model of PD allowing comparison of A53T α-synuclein (α-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T α-syn A9 DA neurons (hNs). We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2C-PGC1α transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1α pathway as a therapeutic target to combat PD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Mutations in the store-operated Ca²⁺ entry pore protein ORAI1 have been reported to cause myopathies in human patients but the mechanism involved is not known. Cardiomyocytes express ORAI1 but its role in heart function is also unknown. Using reverse genetics in zebrafish, we demonstrated that inactivation of the highly conserved zebrafish orthologue of ORAI1 resulted in severe heart failure, reduced ventricular systolic function, bradycardia and skeletal muscle weakness. Electron microscopy of Orai1-deficient myocytes revealed progressive skeletal muscle instability with loss of myofiber integrity and ultrastructural abnormalities of the z-disc in both skeletal and cardiac muscle. Isolated Orai1-deficient cardiomyocytes showed loss of the calcineurin-associated protein calsarcin from the z-discs. Furthermore, we found mechanosignal transduction was affected in Orai1-depleted hearts, indicating an essential role for ORAI1 in establishing the cardiac signaling transduction machinery at the z-disc. Our findings identify ORAI1 as an important regulator of cardiac and skeletal muscle function and provide evidence linking ORAI1-mediated calcium signaling to sarcomere integrity and cardiomyocyte function.

Cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signalling pathways dependent on extracellular calcium (Ca(2+)) influx that control normal and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the present study is to determine the role of the Ca(2+) release-activated Ca(2+) (CRAC) channel Orai1 and stromal interaction molecule 1 (Stim1) in postnatal cardiomyocyte store operated Ca(2+) entry (SOCE) and impact on normal and hypertrophic postnatal cardiomyocyte growth. Employing a combination of siRNA-mediated gene silencing, cultured neonatal rat ventricular cardiomyocytes together with indirect immunofluorescence, epifluorescent Ca(2+) imaging and site-specific protein phosphorylation and real-time mRNA expression analysis, we show for the first time that both Orai1 and Stim1 are present in cardiomyocytes and required for SOCE due to intracellular Ca(2+) store depletion by thapsigargin. Stim1-KD but not Orai1-KD significantly decreased diastolic Ca(2+) levels and caffeine-releasable Ca(2+) from the sarcoplasmic reticulum (SR). Conversely, Orai1-KD but not Stim1-KD significantly diminished basal NRCM cell size, anp and bnp mRNA levels and activity of the calcineurin (CnA) signalling pathway although diminishing both Orai1 and Stim1 proteins similarly attenuated calmodulin kinase II (CamKII) and ERK1/2 activity under basal conditions. Both Orai1- and Stim1-KD completely abrogated phenylephrine (PE) mediated hypertrophic NRCM growth and enhanced natriuretic factor expression by inhibiting G(q)-protein conveyed activation of the CamKII and ERK1/2 signalling pathway. Interestingly, only Orai1-KD but not Stim1-KD prevented Gq-mediated CaN-dependent prohypertrophic signalling. This study shows for the first time that both Orai1 and Stim1 have a key role in cardiomyocyte SOCE regulating both normal and hypertrophic postnatal cardiac growth in vitro., ((c) 2010 Elsevier Ltd. All rights reserved.)