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Perilla seed oil, derived from a regional plant native to northern Thailand, undergoes cold‐pressing to analyze its bioactive components, notably alpha‐linolenic acid (ALA). ALA, constituting approximately 61% of the oil, serves as a precursor for therapeutic omega‐3 fatty acids, EPA and DHA, with neurodegenerative disease benefits and anti‐inflammatory responses. This study administered different concentrations of perilla seed oil to male C57BL/6 mice, categorized as low dose (LP 5% w/w), middle dose (MP 10% w/w), and high dose (HP 20% w/w), along with a fish oil (FP 10% w/w) diet. An experimental group received soybean oil (5% w/w). Over 42 days, these diets were administered while inducing Parkinson's disease (PD) with rotenone injections. Mice on a high perilla seed oil dose exhibited decreased Cox‐2 expression in the colon, suppressed Iba‐1 microglia activation, reduced alpha‐synuclein accumulation in the colon and hippocampus, prevented dopaminergic cell death in the substantia nigra, and improved motor and non‐motor symptoms. Mice on a middle dose showed maintenance of diverse gut microbiota, with an increased abundance of short‐chain fatty acid (SCFA)‐producing bacteria (Bifidobacteria, Lactobacillus, and Faecalibacteria). A reduction in bacteria correlated with PD (Turicibacter, Ruminococcus, and Akkermansia) was observed. Results suggest the potential therapeutic efficacy of high perilla seed oil doses in mitigating both intestinal and neurological aspects linked to the gut–brain axis in PD. [ABSTRACT FROM AUTHOR]

The Fawn-hooded rat has long been used as a model for various peripheral and central disorders and the data available indicate that the social behavior of this strain may be compromised. However, a thorough description of the Fawn-hooded rat is unavailable in this regard. The objective of the present study was to investigate various aspects of the Fawn-hooded rat's social behavior in depth. Our results show that several facets of socio-communicational behavior are impaired in the RjIbm(m):FH strain, including defective ultrasonic vocalizations in pups upon maternal deprivation, reduced social play in adolescence and impaired social novelty discrimination in adulthood. In addition, Fawn-hooded rats exhibited heightened tactile sensitivity and hyperactivity. The defects observed were comparable to those induced by prenatal valproate exposure, a widely utilized model of autism spectrum disorder. Further on, the pro-social drug R-baclofen (0.25–1 mg/kg) reversed the autistic-like defects observed in Fawn-hooded rats, specifically the deficiency in ultrasonic vocalization, tactile sensitivity and social novelty discrimination endpoints. In conclusion, the asocial, hypersensitive and hyperactive phenotype as well as the responsivity to R-baclofen indicate this variant of the Fawn-hooded rat strain may serve as a model of autism spectrum disorder and could be useful in the identification of novel drug candidates. [ABSTRACT FROM AUTHOR]

Precise forecasting of solar power is crucial for the development of sustainable energy systems. Contemporary forecasting approaches often fail to adequately consider the crucial role of weather factors in photovoltaic (PV) power generation and encounter issues such as gradient explosion or disappearance when dealing with extensive time-series data. To overcome these challenges, this research presents a cutting-edge, multi-stage forecasting method called D-Informer. This method skillfully merges the differential transformation algorithm with the Informer model, leveraging a detailed array of meteorological variables and historical PV power generation records. The D-Informer model exhibits remarkable superiority over competing models across multiple performance metrics, achieving on average a 67.64% reduction in mean squared error (MSE), a 49.58% decrease in mean absolute error (MAE), and a 43.43% reduction in root mean square error (RMSE). Moreover, it attained an R² value as high as 0.9917 during the winter season, highlighting its precision and dependability. This significant advancement can be primarily attributed to the incorporation of a multi-head self-attention mechanism, which greatly enhances the model's ability to identify complex interactions among diverse input variables, and the inclusion of weather variables, enriching the model's input data and strengthening its predictive accuracy in time series analysis. Additionally, the experimental results confirm the effectiveness of the proposed approach. [ABSTRACT FROM AUTHOR]

Repetitive stereotyped behaviors are core symptoms of autism spectrum disorders (ASD) and fragile X syndrome (FXS), the prevalent genetic cause of intellectual disability and autism. The nigrostriatal dopamine (DA) circuit rules movement and creation of habits and sequential behaviors; therefore, its dysregulation could promote autistic repetitive behaviors. Nevertheless, inspection of substantia nigra pars compacta (SNpc) DA neurons in ASD models has been overlooked and specific evidence of their altered activity in ASD and FXS is absent. Here, we show that hyperactivity of SNpc DA neurons is an early feature of FXS. The underlying mechanism relies on an interplay between metabotropic glutamate receptor 1 (mGluR1) and ErbB tyrosine kinases, receptors for the neurotrophic and differentiation factors known as neuregulins. Up-regulation of ErbB4 and ErbB2 in nigral DA neurons drives neuronal hyperactivity and repetitive behaviors of the FXS mouse, concurrently rescued by ErbB inhibition. In conclusion, beyond providing the first evidence that nigral DA neuron hyperactivity is a signature of FXS and nigral mGluR1 and ErbB4/2 play a relevant role in FXS etiology, we demonstrate that inhibiting ErbB is a valuable pharmacological approach to attenuate stereotyped repetitive behaviors, thus opening an avenue toward innovative therapies for ASD and FXS treatment., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Huntington's disease (HD) is a neurodegenerative disorder that affects mainly the central nervous system (CNS) by inducing progressive deterioration in both its structure and function. In recent years, there has been growing interest in the impact of HD on peripheral tissue function. Herein, we used the R6/2 mouse model of HD to investigate the influence of the disease on adrenal gland functioning. A transcriptomic analysis conducted using a well-established quantitative method, an Affymetrix array, revealed changes in gene expression in the R6/2 model compared to genetic background controls. For the first time, we identified disruptions in cholesterol and sterol metabolism, blood coagulation, and xenobiotic metabolism in HD adrenal glands. This study showed that the disrupted expression of these genes may contribute to the underlying mechanisms of Huntington's disease. Our findings may contribute to developing a better understanding of Huntington's disease progression and aid in the development of novel diagnostic or therapeutic approaches. [ABSTRACT FROM AUTHOR]

Synthetic data generation offers a promising solution to enhance the usefulness of Electronic Healthcare Records (EHR) by generating realistic de-identified data. However, the existing literature primarily focuses on the quality of synthetic health data, neglecting the crucial aspect of fairness in downstream predictions. Consequently, models trained on synthetic EHR have faced criticism for producing biased outcomes in target tasks. These biases can arise from either spurious correlations between features or the failure of models to accurately represent sub-groups. To address these concerns, we present Bias-transforming Generative Adversarial Networks (Bt-GAN), a GAN-based synthetic data generator specifically designed for the healthcare domain. In order to tackle spurious correlations (i), we propose an information-constrained Data Generation Process (DGP) that enables the generator to learn a fair deterministic transformation based on a well-defined notion of algorithmic fairness. To overcome the challenge of capturing exact sub-group representations (ii), we incentivize the generator to preserve sub-group densities through score-based weighted sampling. This approach compels the generator to learn from underrepresented regions of the data manifold. To evaluate the effectiveness of our proposed method, we conduct extensive experiments using the Medical Information Mart for Intensive Care (MIMIC-III) database. Our results demonstrate that Bt-GAN achieves state-of-the-art accuracy while significantly improving fairness and minimizing bias amplification. Furthermore, we perform an in-depth explainability analysis to provide additional evidence supporting the validity of our study. In conclusion, our research introduces a novel and professional approach to addressing the limitations of synthetic data generation in the healthcare domain. By incorporating fairness considerations and leveraging advanced techniques such as GANs, we pave the way for more reliable and unbiased predictions in healthcare applications. [ABSTRACT FROM AUTHOR]

A form of dementia distinct from healthy cognitive aging, Alzheimer's disease (AD) is a complex multi-stage disease that currently afflicts over 50 million people worldwide. Unfortunately, previous therapeutic strategies developed from murine models emulating different aspects of AD pathogenesis were limited. Consequently, researchers are now developing models that express several aspects of pathogenesis that better reflect the clinical situation in humans. As such, this review seeks to provide insight regarding current applications of mammalian models in AD research by addressing recent developments and characterizations of prominent transgenic models and their contributions to pathogenesis as well as discuss the advantages, limitations, and application of emerging models that better capture genetic heterogeneity and mixed pathologies observed in the clinical situation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a common age-related neurodegenerative disease in the central nervous system and is the primary cause of dementia. It is clinically characterized by the memory impairment, aphasia, apraxia, agnosia, visuospatial and executive dysfunction, behavioral changes, and so on. Incidence of this disease was bound up with age, genetic factors, cardiovascular and cerebrovascular dysfunction, and other basic diseases, but the exact etiology has not been clarified. MicroRNAs (miRNAs) are small endogenous non-coding RNAs that were involved in the regulation of post-transcriptional gene expression. miRNAs have been extensively studied as noninvasive potential biomarkers for disease due to their relative stability in bodily fluids. In addition, they play a significant role in the physiological and pathological processes of various neurological disorders, including stroke, AD, and Parkinson's disease. MiR-155, as an important pro-inflammatory mediator of neuroinflammation, was reported to participate in the progression of β-amyloid peptide and tau via regulating immunity and inflammation. In this review, we put emphasis on the effects of miR-155 on AD and explore the underlying biological mechanisms which could provide a novel approach for diagnosis and treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most prevalent dementia, affecting a large number of populations. Despite being under scrutiny for decades, an effective therapeutic option is still not available., Methods and Results: This study explores the therapeutic role of a nootropic herb Bacopa monnieri (BM) in AD-like pathological conditions produced by injecting preformed amyloid-β 42 (Aβ 42 ) fibril bilaterally into hippocampus of Wistar rats, and ethanolic extract of BM is orally administered for 4 weeks. Assessment of behavioral changes reveals that BM treatment ameliorates Aβ 42 -induced cognitive impairment and compromised explorative behavior. Supplementation of BM also reduces oxidative stress biomarkers, proinflammatory cytokines, and cholinesterase activity in the AD rats. Additionally, BM treatment restores Bcl-2-associated X protein (Bax)/ B-cell lymphoma 2 (Bcl-2) imbalance, increases neurotrophic factors expression, and prevents neurodegeneration validated by quantifying Nissl-positive hippocampal neurons. Interestingly, BM administration eliminates amyloid plaques in the hippocampal region and normalizes the Aβ 42 -induced increase in phospho-tau and total tau expression. Mechanistic investigations reveal that BM interacts with glycogen synthase kinase (GSK-3β) and restores Wnt/β-catenin signaling., Conclusion: BM has been used in diet as a nootropic herb for several centuries. This study highlights the anti-Alzheimer activity of BM from the behavioral to the molecular level by modulating mitochondrial dysfunction, and GSK-3β mediates the Wnt/β-catenin signaling pathway., (© 2023 Wiley‐VCH GmbH.)

The aging of populations is a global phenomenon that follows a possible increase in the incidence of neurodegenerative diseases. Alzheimer's, Parkinson's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington's diseases are some neurodegenerative disorders that aging could initiate or aggravate. Recent research has indicated that intestinal microbiota dysbiosis can trigger metabolism and brain functioning, contributing to the etiopathogenesis of those neurodegenerative diseases. The intestinal microbiota and its metabolites show significant functions in various aspects, such as the immune system modulation (development and maturation), the maintenance of the intestinal barrier integrity, the modulation of neuromuscular functions in the intestine, and the facilitation of essential metabolic processes for both the microbiota and humans. The primary evidence supporting the connection between intestinal microbiota and its metabolites with neurodegenerative diseases are epidemiological observations and animal models experimentation. This paper reviews up-to-date evidence on the correlation between the microbiota-gut-brain axis and neurodegenerative diseases, with a specially focus on gut metabolites. Dysbiosis can increase inflammatory cytokines and bacterial metabolites, altering intestinal and blood-brain barrier permeability and causing neuroinflammation, thus facilitating the pathogenesis of neurodegenerative diseases. Clinical data supporting this evidence still needs to be improved. Most of the works found are descriptive and associated with the presence of phyla or species of bacteria with neurodegenerative diseases. Despite the limitations of recent research, the potential for elucidating clinical questions that have thus far eluded clarification within prevailing pathophysiological frameworks of health and disease is promising through investigation of the interplay between the host and microbiota., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: This work aims to evaluate demand forecasting models to determine if using exogenous factors and machine learning techniques helps improve performance compared to univariate statistical models, allowing manufacturing companies to manage demand better. Design/methodology/approach: We implemented a multivariate Auto-Regressive Moving Average with eXogenous input (ARMAX) statistical model and a Neural Network-ARMAX (NN-ARMAX) hybrid model for forecasting. Later, we compared both to a standard univariate statistical model to forecast the demand for electrical products in a Colombian manufacturing company. Findings: The outcomes demonstrated that the NN-ARMAX model outperformed the other two. Indeed, demand management improved with the reduction of overstock and out-of-stock products. Research limitations/implications: The findings and conclusions in this work are limited to Colombian manufacturing companies that sell electrical products to the construction industry. Moreover, the experts from the company that provided us with the data also selected the external factors based on their own experiences, i.e., we might have disregarded potential factors. Practical implications: This work suggests that a model using neural networks and including exogenous variables can improve demand forecasting accuracy, promoting this approach in manufacturing companies dealing with demand planning issues. Originality/value: The findings in this work demonstrate the convenience of using the proposed hybrid model to improve demand forecasting accuracy and thus provide a reliable basis for its implementation in supply chain planning for the electrical/construction sector in Colombian manufacturing companies. [ABSTRACT FROM AUTHOR]

Introduction: Autism spectrum disorder (ASD) is a persistent neurodevelopmental condition characterized by two core behavioral symptoms: impaired social communication and interaction, as well as stereotypic, repetitive behavior. No distinct cause of ASD is known so far; however, excitatory/inhibitory imbalance and a disturbed serotoninergic transmission have been identified as prominent candidates responsible for ASD etiology. Methods: The GABAB receptor agonist R-Baclofen and the selective agonist for the 5HT7 serotonin receptor LP-211 have been reported to correct social deficits and repetitive behaviors in mouse models of ASD. To evaluate the efficacy of these compounds in more details, we treated BTBR TC Itpr3tf/J and B6.129P2-Fmr1tm1Cgr/J mice acutely with R-Baclofen or LP-211 and evaluated the behavior of animals in a series of tests. Results: BTBR mice showed motor deficits, elevated anxiety, and highly repetitive behavior of self-grooming. Fmr1-KO mice exhibited decreased anxiety and hyperactivity. Additionally, Fmr1-KO mice's ultrasonic vocalizations were impaired suggesting a reduced social interest and communication of this strain. Acute LP-211 administration did not affect the behavioral abnormalities observed in BTBR mice but improved repetitive behavior in Fmr1-KO mice and showed a trend to change anxiety of this strain. Acute R-Baclofen treatment improved repetitive behavior only in Fmr1-KO mice. Conclusion: Our results add value to the current available data on these mouse models and the respective compounds. Yet, additional studies are needed to further test R-Baclofen and LP-211 as potential treatments for ASD therapy. [ABSTRACT FROM AUTHOR]

Green energy is very important for developing new cities with high energy consumption, in addition to helping environment preservation. Integrating solar energy into a grid is very challenging and requires precise forecasting of energy production. Recent advances in Artificial Intelligence have been very promising. Particularly, Deep Learning technologies have achieved great results in short-term time-series forecasting. Thus, it is very suitable to use these techniques for solar energy production forecasting. In this work, a combination of a Convolutional Neural Network (CNN), a Long Short-Term Memory (LSTM) network, and a Transformer was used for solar energy production forecasting. Besides, a clustering technique was applied for the correlation analysis of the input data. Relevant features in the historical data were selected using a self-organizing map. The hybrid CNN-LSTM-Transformer model was used for forecasting. The Fingrid open dataset was used for training and evaluating the proposed model. The experimental results demonstrated the efficiency of the proposed model in solar energy production forecasting. Compared to existing models and other combinations, such as LSTM-CNN, the proposed CNN-LSTM-Transformer model achieved the highest accuracy. The achieved results show that the proposed model can be used as a trusted forecasting technique that facilitates the integration of solar energy into grids. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175Δneo mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a currently incurable neurogenerative disorder and is typically characterized by progressive movement disorder (including chorea), cognitive deficits (culminating in dementia), psychiatric abnormalities (the most common of which is depression), and peripheral symptoms (including gastrointestinal dysfunction). There are currently no approved disease-modifying therapies available for HD, with death usually occurring approximately 10-25 years after onset, but some therapies hold promising potential. HD subjects are often burdened by chronic diarrhea, constipation, esophageal and gastric inflammation, and a susceptibility to diabetes. Our understanding of the microbiota-gut-brain axis in HD is in its infancy and growing evidence from preclinical and clinical studies suggests a role of gut microbial population imbalance (gut dysbiosis) in HD pathophysiology. The gut and the brain can communicate through the enteric nervous system, immune system, vagus nerve, and microbiota-derived-metabolites including short-chain fatty acids, bile acids, and branched-chain amino acids. This review summarizes supporting evidence demonstrating the alterations in bacterial and fungal composition that may be associated with HD. We focus on mechanisms through which gut dysbiosis may compromise brain and gut health, thus triggering neuroinflammatory responses, and further highlight outcomes of attempts to modulate the gut microbiota as promising therapeutic strategies for HD. Ultimately, we discuss the dearth of data and the need for more longitudinal and translational studies in this nascent field. We suggest future directions to improve our understanding of the association between gut microbes and the pathogenesis of HD, and other 'brain and body disorders'., (© 2024 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The dysregulation of striatal gene expression and function is linked to multiple diseases, including Huntington's disease (HD), Parkinson's disease, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neurons in the striatum and are critical to motor control. The transcription factor, Bcl11b (also known as Ctip2), is required for striatal development, but the function of Bcl11b in adult MSNs in vivo has not been investigated. We conditionally deleted Bcl11b specifically in postnatal MSNs and performed a transcriptomic and behavioral analysis on these mice. Multiple enrichment analyses showed that the D9-Cre-Bcl11btm1.1Leid transcriptional profile was similar to the HD gene expression in mouse and human data sets. A Gene Ontology enrichment analysis linked D9-Cre-Bcl11btm1.1Leid to calcium, synapse organization, specifically including the dopaminergic synapse, protein dephosphorylation, and HDAC-signaling, commonly dysregulated pathways in HD. D9-Cre-Bcl11btm1.1Leid mice had decreased DARPP-32/Ppp1r1b in MSNs and behavioral deficits, demonstrating the dysregulation of a subtype of the dopamine D2 receptor expressing MSNs. Finally, in human HD isogenic MSNs, the mislocalization of BCL11B into nuclear aggregates points to a mechanism for BCL11B loss of function in HD. Our results suggest that BCL11B is important for the function and maintenance of mature MSNs and Bcl11b loss of function drives, in part, the transcriptomic and functional changes in HD. [ABSTRACT FROM AUTHOR]

Tauopathies including Alzheimer's disease (AD) are neurodegenerative disorders accompanied by the conversion of functional forms of the microtubule associated protein Tau into non-functional aggregates. A variety of post-translational modifications (PTMs) on Tau precede or accompany the conversion, placing them in position to modulate Tau function as well as its propensity to aggregate. Although Tau PTMs can be characterized by their sites of modification, their total stoichiometry when summed over all sites also is an important metric of their potential impact on function. Here we provide a protocol for rapidly producing recombinant Tau with enzyme-specific PTMs at high stoichiometry in vitro and demonstrate its utility in the context of hyperphosphorylation. Additionally, protocols for estimating phosphorylation and methylation stoichiometry on Tau proteins isolated from any source are presented. Together these methods support experimentation on Tau PTM function over a wide range of experimental conditions., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases. Efficient replacement: Cell therapies have the potential of being an effective approach for treating neurodegenerative conditions. However, the need for local delivery and the poor distribution of the transplanted cells hinder the development of effective treatments. Here, Shibuya et al. developed an efficient microglia replacement approach in rodents using circulation-derived myeloid cells (CDMCs). The cells broadly incorporated in the brain and generated microglia-like cells more efficiently than bone marrow transplant. In a mouse model of progressive neurodegeneration, CDMC-mediated microglia replacement reduced cell loss and brain inflammation, improved motor behavior, and extended life span. The results suggest that this approach might be therapeutic in multiple neurological conditions. [ABSTRACT FROM AUTHOR]

Background: Anti-IgLON5 disease is a rare late-onset neurological disease associated with autoantibodies against IgLON5, neuronal accumulation of phosphorylated Tau protein (p-Tau), and sleep, respiratory, and motor alterations. Purpose: We performed a pilot study of whether the neuropathological and clinical features of anti-IgLON5 disease may be recapitulated in mice with chronic intracerebroventricular infusion of human anti-IgLON5 disease IgG (Pt-IgG). Methods: Humanized transgenic hTau mice expressing human Tau protein and wild-type (WT) control mice were infused intracerebroventricularly with Pt-IgG or with antibodies from a control subject for 14 days. The sleep, respiratory, and motor phenotype was evaluated at the end of the antibody infusion and at least 30 days thereafter, followed by immunohistochemical assessment of p-Tau deposition. Results: In female hTau and WT mice infused with Pt-IgG, we found reproducible trends of diffuse neuronal cytoplasmic p-Tau deposits in the brainstem and hippocampus, increased ventilatory period during sleep, and decreased inter-lick interval during wakefulness. These findings were not replicated on male hTau mice. Conclusion: The results of our pilot study suggest, but do not prove, that chronic ICV infusion of mice with Pt-IgG may elicit neuropathological, respiratory, and motor alterations. These results should be considered as preliminary until replicated in larger studies taking account of potential sex differences in mice. [ABSTRACT FROM AUTHOR]

Neurogenerative disorders, such as Alzheimer's disease (AD), represent a growing public health challenge in aging societies. Tauopathies, a subset of neurodegenerative disorders that includes AD, are characterized by accumulation of fibrillar and hyperphosphorylated forms of microtubule-associated protein tau with coincident mitochondrial abnormalities and neuronal dysfunction. Although, in vitro , tau impairs axonal transport altering mitochondrial distribution, clear in vivo mechanisms associating tau and mitochondrial dysfunction remain obscure. Herein, we investigated the effects of human tau on brain mitochondria in vivo using transgenic htau mice at ages preceding and coinciding with onset of tauopathy. Subcellular proteomics combined with bioenergetic assessment revealed pathologic forms of tau preferentially associate with synaptic over non-synaptic mitochondria coinciding with changes in bioenergetics, reminiscent of an aged synaptic mitochondrial phenotype in wild-type mice. While mitochondrial content was unaltered, mitochondrial maximal respiration was impaired in synaptosomes from htau mice. Further, mitochondria-associated tau was determined to be outer membrane-associated using the trypsin protection assay and carbonate extraction. These findings reveal non-mutant human tau accumulation at the synapse has deleterious effects on mitochondria, which likely contributes to synaptic dysfunction observed in the context of tauopathy. [ABSTRACT FROM AUTHOR]

Olfactory dysfunction is a common symptom in patients with neurodegenerative disorders, including Huntington's disease (HD). Understanding its pathophysiology is important in establishing a preventive and therapeutic plan. In this literature review, we cover the physiology of olfaction, its role in neurodegeneration, and its characteristics in patients with HD. In the general population, olfactory dysfunction is present in 3.8–5.8%and the prevalence increases significantly in those older than 80 years. For HD, data regarding prevalence rates are lacking and the scales used have been inconsistent or have been restructured due to concerns about cross-cultural understanding. Pathogenic huntingtin deposits have been found in the olfactory bulb of individuals with HD, although no studies have correlated this with the grade of olfactory impairment. Olfactory dysfunction is present in both premanifest and manifest patients with HD, showing a progressive decline over time with more severe deficits at advanced stages. No specific treatment for olfactory impairment in HD has been proposed; identifying and avoiding potential medications that cause olfactory dysfunction, as well as general safety recommendations remain the basis of the therapeutic strategy. [ABSTRACT FROM AUTHOR]

There has been a significant push in recent years to deploy fundamental knowledge and methods of photochemistry toward biological ends. Photoreactive groups have enabled chemists to activate biological function using the concept of photocaging. By granting spatiotemporal control over protein activation, these photocaging methods are fundamental in understanding biological processes. Peptides and proteins are an important group of photocaging targets that present conceptual and technical challenges, requiring precise chemoselectivity in complex polyfunctional environments. This review focuses on recent advances in photocaging techniques and methodologies, as well as their use in living systems. Photocaging methods include genetic and chemical approaches that require a deep understanding of structure–function relationships based on subtle changes in primary structure. Successful implementation of these ideas can shed light on important spatiotemporal aspects of living systems. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) still depicts an incurable and devastating disease. Drug development efforts are mostly based on superoxide dismutase 1 gene (SOD1)-G93A mice that present a very strong and early phenotype, allowing only a short time window for intervention. An alternative mouse model is available, that is based on the same founder line but has a reduced SOD1-G93A copy number, resulting in a weaker and delayed phenotype. To be able to use these SOD1-G93A/low mice for drug testing, we performed a characterization of ALS-typical pathologies. All analyses were performed compared to non-transgenic (ntg) littermates of the same sex and age. In vivo analysis of SOD1-G93A/low mice was performed by weekly body weight measurements, analysis of the survival rate, and measurement of the muscle strength of 24–30 weeks old female and male SOD1-G93A/low mice. Immunofluorescent labeling of SOD1, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba1) protein was performed in the cervical, thoracic, and lumbar ventral horn of the spinal cord of 24–30 weeks old male and female SOD1-G93A/low mice. The musculus gastrocnemius of male SOD1-G93A/low mice was labeled with fluorophore-conjugated α-bungarotoxin and antibodies against phosphorylated neurofilaments. Fluorescent labeling was detected and quantified by macro-based image analysis. Although SOD1 protein levels were highly increased in both sexes and all age groups, levels strongly peaked in 30 weeks old male SOD1-G93A/low mice. Astrocytosis and activated microglia in the spinal cord ventral horn and phosphorylated neurofilaments in the motor unit of the musculus gastrocnemius progressively increased, while muscle strength progressively decreased in male SOD1-G93A/low mice. In female SOD1-G93A/low mice, only activated microglia increased progressively, while muscle strength was constantly reduced starting at 26 weeks. These differences result in a shorter survival time of male SOD1-G93A/low mice of about 3 weeks compared to female animals. The results suggest that male SOD1-G93A/low mice present a stronger pathology and are, therefore, better suitable to evaluate the efficacy of new drugs against ALS as most pathological features are developing progressively paralleled by a survival time that allows treatment to start before symptom onset. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exposure to secondhand smoke (SHS) is a risk factor for developing sporadic forms of sporadic dementia. A human tau (htau) mouse model is available that exhibits age-dependent tau dysregulation, neurofibrillary tangles, neuronal loss, neuroinflammation, and oxidative stress starting at an early age (3–4 months) and in which tau dysregulation and neuronal loss correlate with synaptic dysfunction and cognitive decline. OBJECTIVE: The goal of this study was to assess the effects of chronic SHS exposure (10 months' exposure to ~30 mg/m³) on behavioral and cognitive function, metabolism, and neuropathology in mice. METHODS: Wild-type (WT) and htau female and male mice were exposed to SHS (90% side stream, 10% main stream) using the SCIREQ® inExposeâ„¢ system or air control for 168 min per day, for 312 d, 7 d per week. The exposures continued during the days of behavioral and cognitive testing. In addition to behavioral and cognitive performance and neuropathology, the lungs of mice were examined for pathology and alterations in gene expression. RESULTS: Mice exposed to chronic SHS exposure showed the following genotype-dependent responses: a) lower body weights in WT, but not htau, mice; b) less spontaneous alternation in WT, but not htau, mice in the Y maze; c) faster swim speeds of WT, but not htau, mice in the water maze; d) lower activity levels of WT and htau mice in the open field; e) lower expression of brain PHF1, TTCM1, IGF1b, and HSP90 protein levels in WT male, but not female, mice; and f) more profound effects on hippocampal metabolic pathways in WT male than female mice and more profound effects in WT than htau mice. DISCUSSION: The brain of WT mice, in particular WT male mice, might be especially susceptible to the effects of chronic SHS exposure. In WT males, independent pathways involving ascorbate, flavin adenine dinucleotide, or palmitoleic acid might contribute to the hippocampal injury following chronic SHS exposure. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a major public health crisis due to devastating cognitive symptoms, a lack of curative treatments, and increasing prevalence. Most cases are sporadic (>95% of cases) after the age of 65 years, implicating an important role of environmental factors in disease pathogenesis. Environmental neurotoxicants have been implicated in neurodegenerative disorders including Parkinson's Disease and AD. Animal models of AD and in vitro studies have shed light on potential neuropathological mechanisms, yet the biochemical and molecular underpinnings of AD‐relevant environmental neurotoxicity remain poorly understood. Beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1) is a potentially critical pathogenic target of environmentally induced neurotoxicity. BACE1 clearly has a critical role in AD pathophysiology: It is required for amyloid beta production and expression and activity of BACE1 are increased in the AD brain. Though the literature on BACE1 in response to environmental insults is limited, current studies, along with extensive AD neurobiology literature suggest that BACE1 deserves attention as an important neurotoxic target. Here, we critically review research on environmental neurotoxicants such as metals, pesticides, herbicides, fungicides, polyfluoroalkyl substances, heterocyclic aromatic amines, advanced glycation end products, and acrolein that modulate BACE1 and potential mechanisms of action. Though more research is needed to clearly understand whether BACE1 is a critical mediator of AD‐relevant neurotoxicity, available reports provide convincing evidence that BACE1 is altered by environmental risk factors associated with AD pathology, implying that BACE1 inhibition and its use as a biomarker should be considered in AD management and research. [ABSTRACT FROM AUTHOR]

The Apollo 16 sample 66095, named "Rusty Rock", is enriched in volatile and moderately volatile elements. The impact melt breccia is characterized by abundant Fe‐rich sulfide and chloride alteration phases, including FeS, ZnS, and FeCl2. These phases have previously been interpreted to be the result of fumarolic alteration of the breccia. Here we present the results of two different experimental approaches, which aim to constrain the temperature conditions and the process under which the "Rusty Rock" alteration formed. The first experimental set‐up assumes that the metals Zn, Cu, and Fe were introduced into the rock by a C‐O‐S‐Cl gas phase, and that the Fe‐rich sulfides and chlorides were deposited from this gas phase. This "gas deposition" experiment suggests that the alteration assemblage formed over the temperature range of 538–638 ± 5°C. The second experimental set‐up simulates a scenario, where Fe metal particles in the lunar rock react with a Zn‐C‐O‐S‐Cl gas phase at six different temperatures between 396 ± 5°C and 1,005 ± 5°C. This latter "metal reaction" experiment resulted in the formation of sulfide and chloride coatings on the Fe metal chips. The "Rusty Rock" alteration phases FeCl2 and (Zn,Fe)S were abundantly present in the coating of the Fe metal chip reacted at 580 ± 10°C. Both experiments lead to results which are in agreement, providing a temperature of 580 ± 50°C for the fumarolic alteration on the Moon, as observed in the Apollo 16 "Rusty Rock". Plain Language Summary: The Apollo 16 sample 66095, colloquially named "Rusty Rock", is an unusual lunar rock which is enriched in volatile elements such as sulfur and chlorine. We investigate two processes by which sulfides and chlorides may form in a lunar fumarolic system, by conducting experiments in evacuated silica glass tubes at reducing conditions. First, we assume that metals and volatiles (Zn, Cu, Fe, S, and Cl) are all deposited from a gas phase (gas deposition experiments), and second, we assume that Fe metal is already present in the rock and that the Fe altered by the introduction of a Zn‐S‐Cl‐bearing gas phase (metal reaction experiment). In both experimental setups we observe the formation of "Rusty Rock" alteration phases FeCl2 and (Zn, Fe)S at 580 ± 50°C, constraining the temperature of fumarolic alteration recorded in the Apollo 16 sample 66095. Hence, our experiments confirm that the characteristic S‐ and Cl‐rich minerals found in the lunar "Rusty Rock" were formed by a lunar fumarole. More broadly, lunar metal deposits may be associated with ancient fumarolic processes. Key points: Experiments constrain the temperature of fumarolic Apollo 16 "Rusty Rock" alteration to 580 ± 50°CThe phase assemblage of FeCl2 and (Zn,Fe)S constrains the composition of the fumarolic gas at 600°CGas deposition and gas‐solid metal reaction experiments reproduce the "Rusty Rock" alteration phases FeCl2 and (Zn, Fe)S [ABSTRACT FROM AUTHOR]

To evaluate the therapeutic effects of Chinese herbal medicine (CHM) for Alzheimer's disease (AD), we evaluated five CHMs in oligomeric A β 2 5 − 3 5 -treated mouse primary hippocampal neuronal cultures. The aqueous extract from the root of Pueraria lobata (Puerariae Radix; PR) showed better neuroprotective effects than did the other four CHM aqueous extracts, including Gardenia jasminoides, Eleutherococcus senticosus, Rhodiola rosea, and Panax, in the primary culture treated with saline or oligomeric A β 2 5 − 3 5 . Furthermore, the neuroprotective effects of aqueous extract of PR were also better than its well-known active compound, puerarin, against the neurotoxicity of oligomeric A β 2 5 − 3 5 in a primary culture. For in vivo experiments, C57BL/6J male mice that received direct infusion of soluble oligomeric A β 2 5 − 3 5 into the bilateral hippocampal CA1 subregion were used as an alternative AD mouse model. The effects and molecular mechanisms of chronic systemic administration of PR aqueous extract were evaluated in the alternative AD model. PR aqueous extract prevented anxiety and cognitive impairment in mice associated with a decrease in the levels of A β deposition, tau protein phosphorylation, inflammation, loss of noradrenergic, and serotonergic neurons and an increase in the levels of synaptophysin and insulin degrading enzyme (IDE) against the toxicity of oligomeric A β 2 5 − 3 5 . Furthermore, no obvious damage to the liver and kidney was detected after chronic systemic administration of PR aqueous extract. Therefore, using PR could be a safer, more effective therapeutic strategy than using its active compound puerarin to prevent both cognitive and noncognitive dysfunction and related pathological features of AD. [ABSTRACT FROM AUTHOR]

Recombinant DNA technology and corresponding innovations in molecular biology, chemistry and medicine have led to novel therapeutic biomacromolecules as lead candidates in the pharmaceutical drug development pipelines. While monoclonal antibodies and other proteins provide therapeutic potential beyond the possibilities of small molecule drugs, the concomitant demand for supportive bioanalytical sample testing creates multiple novel challenges. For example, intact macromolecules can usually not be quantified by mass-spectrometry without enzymatic digestion and isotopically labeled internal standards are costly and/or difficult to prepare. Classical ELISA-type immunoassays, on the other hand, often lack the sensitivity required to obtain pharmacokinetics of low dosed drugs or pharmacodynamics of suitable biomarkers. Here we summarize emerging state-of-the-art ligand-binding assay technologies for pharmaceutical sample testing, which reveal enhanced analytical sensitivity over classical ELISA formats. We focus on immuno-PCR, which combines antibody specificity with the extremely sensitive detection of a tethered DNA marker by quantitative PCR, and alternative nucleic acid–based technologies as well as methods based on electrochemiluminescence or single-molecule counting. Using case studies, we discuss advantages and drawbacks of these methods for preclinical and clinical sample testing. [ABSTRACT FROM AUTHOR]

This paper proposes to use a state feedback method to control the Hopf bifurcation for a novel congestion control model, i.e. the exponential random early detection (RED) algorithm with a single link and a single source. The gain parameter of the congestion control model is chosen as the bifurcation parameter. The analysis shows that in the absence of the state feedback controller, the model loses stability via the Hopf bifurcation early, and can maintain a stationary sending rate only in a certain domain of the gain parameter. When applying the state feedback controller to the model, the onset of the undesirable Hopf bifurcation is postponed. Thus, the stability domain is extended, and the model possesses a stable sending rate in a larger parameter range. Furthermore, explicit formulae to determine the properties of the Hopf bifurcation are obtained. Numerical simulations are given to justify the validity of the state feedback controller in bifurcation control. [ABSTRACT FROM AUTHOR]

Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay. Only soluble total tau and phosphorylated tau (ptau at residue Thr181, Ser199, Thr231 and Thr235), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser396 and Ser404 in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The role of hyperphosphorylation of the microtubule-associated protein tau in the pathological processes of several neurodegenerative diseases is becoming better understood. Consequently, development of new compounds capable of preventing tau hyperphosphorylation is an increasingly hot topic. For this reason, dependable in vitro and in vivo models that reflect tau hyperphosphorylation in human diseases are needed. In this study, we generated and validated an in vitro model appropriate to test potential curative and preventive compound effects on tau phosphorylation. For this purpose, a stably transfected SH-SY5Y cell line was constructed over-expressing mutant human tau441 (SH-SY5Y-TMHT441). Analyses of expression levels and tau phosphorylation status in untreated cells confirmed relevance to human diseases. Subsequently, the effect of different established kinase inhibitors on tau phosphorylation (e.g., residues Thr231, Thr181, and Ser396) was examined. It was shown with several methods including immunosorbent assays and mass spectrometry that the phosphorylation pattern of tau in SH-SY5Y-TMHT441 cells can be reliably modulated by these compounds, specifically targeting JNK, GSK-3, CDK1/5, and CK1. These four protein kinases are known to be involved in in vivo tau phosphorylation and are therefore authentic indicators for the suitability of this new cell culture model for tauopathies. [ABSTRACT FROM AUTHOR]

Forecasting shoreline evolution for sandy coasts is important for sustainable coastal management, given the present-day increasing anthropogenic pressures and a changing future climate. Here, we evaluate eight different time-series forecasting methods for predicting future shorelines derived from historic satellite-derived shorelines. Analyzing more than 37,000 transects around the globe, we find that traditional forecast methods altogether with some of the evaluated probabilistic Machine Learning (ML) time-series forecast algorithms, outperform Ordinary Least Squares (OLS) predictions for the majority of the sites. When forecasting seven years ahead, we find that these algorithms generate better predictions than OLS for 54% of the transect sites, producing forecasts with, on average, 29% smaller Mean Squared Error (MSE). Importantly, this advantage is shown to exist over all considered forecast horizons, i.e., from 1 up to 11 years. Although the ML algorithms do not produce significantly better predictions than traditional time-series forecast methods, some proved to be significantly more efficient in terms of computation time. We further provide insight in how these ML algorithms can be improved so that they can be expected to outperform not only OLS regression, but also the traditional time-series forecast methods. These forecasting algorithms can be used by coastal engineers, managers, and scientists to generate future shoreline prediction at a global level and derive conclusions thereof. [ABSTRACT FROM AUTHOR]