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Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration with typical survival of only 2–5 years from diagnosis. The causes of ALS are multifactorial: known genetic mutations account for only around 70% of cases of familial ALS and 15% of sporadic cases, and heritability estimates range from 8% to 61%, indicating additional causes beyond genetics. Consequently, interest has grown in environmental contributions to ALS risk and progression. The gene–time–environment hypothesis posits that ALS onset occurs through an interaction of genes with environmental exposures during ageing. An alternative hypothesis, the multistep model of ALS, suggests that several hits, at least some of which could be environmental, are required to trigger disease onset, even in the presence of highly penetrant ALS-associated mutations. Studies have sought to characterize the ALS exposome — the lifetime accumulation of environmental exposures that increase disease risk and affect progression. Identifying the full scope of environmental toxicants that enhance ALS risk raises the prospect of preventing disease by eliminating or mitigating exposures. In this Review, we summarize the evidence for an ALS exposome, discussing the strengths and limitations of epidemiological studies that have identified contributions from various sources. We also consider potential mechanisms of exposure-mediated toxicity and suggest future directions for ALS exposome research. The amyotrophic lateral sclerosis exposome is the lifetime accumulation of environmental exposures that increase disease risk and affect progression. This Review summarizes the literature that has sought to characterize aspects of the amyotrophic lateral sclerosis exposome and considers potential mechanisms of exposure-induced toxicity. Key points: Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration, with both genetic and environmental factors contributing to the risk and rate of disease progression. The gene–time–environment hypothesis of ALS posits that disease arises from an interaction of genetic burden with environmental burden over the life course. The multistep model of ALS posits that multiple 'hits', some of which are presumed to be environmental in origin, trigger disease onset, even in carriers of highly penetrant mutations. Epidemiological studies suggest potential contributions to the ALS exposome from pesticides, occupational exposures, sports and physical activity, metals, air pollution, trauma, electromagnetic fields, the gut microbiome, diet and lifestyle factors. The mechanisms underlying the effects of environmental factors on ALS risk remain incompletely understood but might involve neurotoxicity from specific environmental toxins, microbiome-mediated changes, epigenetic restructuring, systemic and central inflammation and excitotoxicity. Most studies of the ALS exposome have a retrospective design using questionnaires and are, therefore, prone to recall bias and other limitations. Future studies will require prospective, longitudinal designs that include quantification of exposures in biosamples in addition to questionnaires. [ABSTRACT FROM AUTHOR]

Significance: Reactive oxygen species (ROS) contribute to multiple aspects of peripheral nervous system (PNS) biology ranging from physiological processes (e.g., axonal outgrowth and regeneration) to pathophysiology (e.g., nerve degeneration). Although ROS are derived from multiple sources, NADPH oxidase (Nox) family members are dedicated to ROS generation. Noxs are expressed in the PNS, and their overexpression is associated with detrimental effects on nerve function and contributes, at least in part, to peripheral neuropathies. Recent Advances: Of the seven members, studies mostly focused on Nox1, Nox2, and Nox4, which are expressed in the PNS in a cell-specific manner. We have also recently identified human Nox5 in sural nerve biopsies. When maintained at homeostatic levels, Noxs regulate several aspects of peripheral nerve health, most notably neurite outgrowth and axonal regeneration following nerve lesion. While Nox2 and Nox4 dysregulation is a major source of oxidative stress in PNS disorders, including neuropathic pain and diabetic peripheral neuropathy, recent evidence also implicates Nox1 and Nox5. Critical Issues: Although there is compelling evidence for a direct role of Noxs on nerve function, little is known about their subcellular localization, intercellular regulation, and interaction. These, together with redox signaling, are considered crucial components of nerve redox status. In addition, the lack of isoform-specific inhibitors limits conclusions about the physiological role of Noxs in the PNS and their therapeutic potential in peripheral neuropathies. Future Directions: Future research using isoform-specific genetic and pharmacological approaches are therefore needed to better understand the significance of Nox enzymes in PNS (patho) physiology. Antioxid. Redox Signal. 37, 613–630. [ABSTRACT FROM AUTHOR]

Pediatric neuropathy attributed to metabolic dysfunction is a well‐known complication in children and youth with type 1 diabetes. Moreover, the rise of obesity and in particular of type 2 diabetes may cause an uptick in pediatric neuropathy incidence. However, despite the anticipated increase in neuropathy incidence, pathogenic insights and strategies to prevent or manage neuropathy in the setting of diabetes and obesity in children and youth remain unknown. Data from adult studies and available youth cohort studies are providing an initial understanding of potential diagnostic, management, and preventative measures in early life. This review discusses the current state of knowledge emanating from these efforts, with particular emphasis on the prevalence, clinical presentation, diagnostic approaches and considerations, and risk factors of neuropathy in type 1 and type 2 diabetes in children and youth. Also highlighted are current management strategies and recommendations for neuropathy in children and youth with diabetes. This knowledge, along with continued and sustained emphasis on identifying and eliminating modifiable risk factors, completing randomized controlled trials to assess effectiveness of strategies like weight loss and exercise, and enhancing awareness to support early detection and prevention, are pertinent to addressing the rising incidence of neuropathy associated with diabetes and obesity in children and youth. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has infected >22.7 million and led to the deaths of 795,000 people worldwide. Patients with diabetes are highly susceptible to COVID-19–induced adverse outcomes and complications. The COVID-19 pandemic is superimposing on the preexisting diabetes pandemic to create large and significantly vulnerable populations of patients with COVID-19 and diabetes. This article provides an overview of the clinical evidence on the poorer clinical outcomes of COVID-19 infection in patients with diabetes versus patients without diabetes, including in specific patient populations, such as children, pregnant women, and racial and ethnic minorities. It also draws parallels between COVID-19 and diabetes pathology and suggests that preexisting complications or pathologies in patients with diabetes might aggravate infection course. Finally, this article outlines the prospects for long-term sequelae after COVID-19 for vulnerable populations of patients with diabetes. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has infected >22.7 million and led to the deaths of 795,000 people worldwide. Patients with diabetes are highly susceptible to COVID-19-induced adverse outcomes and complications. The COVID-19 pandemic is superimposing on the preexisting diabetes pandemic to create large and significantly vulnerable populations of patients with COVID-19 and diabetes. This article provides an overview of the clinical evidence on the poorer clinical outcomes of COVID-19 infection in patients with diabetes versus patients without diabetes, including in specific patient populations, such as children, pregnant women, and racial and ethnic minorities. It also draws parallels between COVID-19 and diabetes pathology and suggests that preexisting complications or pathologies in patients with diabetes might aggravate infection course. Finally, this article outlines the prospects for long-term sequelae after COVID-19 for vulnerable populations of patients with diabetes. [ABSTRACT FROM AUTHOR]

The article discusses metabolite-based detection of aspergillosis. The metabolite-based diagnostic tools for aspergillosis include detection of gliotoxin, changes to the host's metabolome in serum, and siderophore uptake. Also explored are the advantages and diasadvantages of the metabolite-based methods, aspergillosis diagnosis based on metabolomics, and aspergillosis diagnosis based on volatile organic compounds.

The world faces a pandemic-level prevalence of type 2 diabetes. In parallel with this massive burden of metabolic disease is the growing prevalence of dementia as the population ages. The two health issues are intertwined. The Lancet Commission on dementia prevention, intervention, and care was convened to tackle the growing global concern of dementia by identifying risk factors. It concluded, along with other studies, that diabetes as well as obesity and the metabolic syndrome more broadly, which are frequently comorbid, raise the risk of developing dementia. Type 2 diabetes is a modifiable risk factor; however, it is uncertain whether anti-diabetic drugs mitigate risk of developing dementia. Reasons are manifold but constitute a critical knowledge gap in the field. This review outlines studies of type 2 diabetes on risk of dementia, illustrating key concepts. Moreover, it identifies knowledge gaps, reviews strategies to help fill these gaps, and concludes with a series of recommendations to mitigate risk and advance understanding of type 2 diabetes and dementia. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic is responsible for 267 million infections and over 5 million deaths globally. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA beta-coronavirus, which causes a systemic inflammatory response, multi-organ damage, and respiratory failure requiring intubation in serious cases. SARS-CoV-2 can also trigger neurological conditions and syndromes, which can be long-lasting and potentially irreversible. Since COVID-19 infections continue to mount, the burden of SARS-CoV-2-induced neurologic sequalae will rise in parallel. Therefore, understanding the spectrum of neurological clinical presentations in SARS-CoV-2 is needed to manage COVID-19 patients, facilitate diagnosis, and expedite earlier treatment to improve outcomes. Furthermore, a deeper knowledge of the neurological SARS-CoV-2 pathomechanisms could uncover potential therapeutic targets to prevent or mitigate neurologic damage secondary to COVID-19 infection. Evidence indicates a multifaceted pathology involving viral neurotropism and direct neuroinvasion along with cytokine storm and neuroinflammation leading to nerve injury. Importantly, pathological processes in neural tissue are non-cell autonomous and occur through a concerted breakdown in neuron-glia homeostasis, spanning neuron axonal damage, astrogliosis, microgliosis, and impaired neuron-glia communication. A clearer mechanistic and molecular picture of neurological pathology in SARS-CoV-2 may lead to effective therapies that prevent or mitigate neural damage in patients contracting and developing severe COVID-19 infection. [ABSTRACT FROM AUTHOR]

The development of a cure for Alzheimer’sdisease (AD) hasbeen impeded by an inability to pinpoint the root cause of this disorder.Although numerous potential pathological factors have been indicated,acting either individually or mutually, the molecular mechanisms leadingto disease onset and progression have not been clear. Amyloid-β(Aβ), generated from proteolytic processing of the amyloid precursorprotein (APP), and its aggregated forms, particularly oligomers, aresuggested as key pathological features in AD-affected brains. Historically,highly concentrated metals are found colocalized within Aβ plaques.Metal binding to Aβ (metal–Aβ) generates/stabilizespotentially toxic Aβ oligomers, and produces reactive oxygenspecies (ROS) in vitro (redox active metal ions; plausible contributionto oxidative stress). Consequently, clarification of the relationshipbetween Aβ, metal ions, and toxicity, including oxidative stressvia metal–Aβ, can lead to a deeper understanding of ADdevelopment. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease lacking effective treatments. This is due, in part, to a complex and incompletely understood pathophysiology. To shed light, we conducted untargeted metabolomics on plasma from two independent cross-sectional ALS cohorts versus control participants to identify recurrent dysregulated metabolic pathways. Untargeted metabolomics was performed on plasma from two ALS cohorts (cohort 1, n = 125; cohort 2, n = 225) and healthy controls (cohort 1, n = 71; cohort 2, n = 104). Individual differential metabolites in ALS cases versus controls were assessed by Wilcoxon, adjusted logistic regression and partial least squares-discriminant analysis, while group lasso explored sub-pathway level differences. Adjustment parameters included age, sex and body mass index. Metabolomics pathway enrichment analysis was performed on metabolites selected using the above methods. Additionally, we conducted a sex sensitivity analysis due to sex imbalance in the cohort 2 control arm. Finally, a data-driven approach, differential network enrichment analysis (DNEA), was performed on a combined dataset to further identify important ALS metabolic pathways. Cohort 2 ALS participants were slightly older than the controls (64.0 versus 62.0 years, P = 0.009). Cohort 2 controls were over-represented in females (68%, P < 0.001). The most concordant cohort 1 and 2 pathways centred heavily on lipid sub-pathways, including complex and signalling lipid species and metabolic intermediates. There were differences in sub-pathways that were enriched in ALS females versus males, including in lipid sub-pathways. Finally, DNEA of the merged metabolite dataset of both ALS and control cohorts identified nine significant subnetworks; three centred on lipids and two encompassed a range of sub-pathways. In our analysis, we saw consistent and important shared metabolic sub-pathways in both ALS cohorts, particularly in lipids, further supporting their importance as ALS pathomechanisms and therapeutics targets. [ABSTRACT FROM AUTHOR]

Evolutionary links between type 1 blue copper (T1 Cu), type 2 red copper (T2 Cu), and purple CuA cupredoxins have been proposed, but the structural features and mechanism responsible for such links as well as for assembly of CuA sites in vivo are poorly understood, even though recent evidence demonstrated that the Cu(II) oxidation state plays an important role in this process. In this study, we examined the kinetics of Cu(II) incorporation into the CuA site of a biosynthetic CuA model, CuA azurin (CuAAZ) and found that both T1 Cu and T2 Cu intermediates form on the path to final CuA reconstitution in a pH-dependent manner, with slower kinetics and greater accumulation of the intermediates as the pH is raised from 5.0 to 7.0. While these results are similar to those observed previously in the native CuA center of nitrous oxide reductase, the faster kinetics of copper incorporation into CuAAz allowed us to use lower copper equivalents to reveal a new pathway of copper incorporation, including a novel intermediate that has not been reported in cupredoxins before, with intense electronic absorption maxima at ∼410 and 760 nm. We discovered that this new intermediate underwent reduction to Cu(I), and proposed that it is a Cu(II)-dithiolate species. Oxygen-dependence studies demonstrated that the T1 Cu species only formed in the presence of molecular oxygen, suggesting the T1 Cu intermediate is a one-electron oxidation product of a Cu(I) species. By studying CuAAZ variants where the Cys and His ligands are mutated, we have identffied the T2 Cu intermediate as a capture complex with Cys116 and the T1 Cu intermediate as a complex with Cys112 and His120. These results led to a unified mechanism of copper incorporation and new insights regarding the evolutionary link between all cupredoxin sites as well as the in vivo assembly of CuA centers. [ABSTRACT FROM AUTHOR]

CuA is a binuclear copper center that functions as an electron transfer agent, cycling between a reduced Cu(I)Cu(I) state and an oxidized mixed-valence Cu(+1.5)···Cu(+1.5) state. The copper ions are bridged by two cysteine thiolate ligands and form a copper–copper bond, the first reported of its kind in Nature. Such a “diamond-core” Cu2S(Cys)2 structure allows an unpaired electron to be completely delocalized over the two copper ions and contributes to its highly efficient electron transfer properties. This review provides accounts of how the CuA center was structurally characterized and highlights its salient spectroscopic properties. In the process, it introduces the CuA center in four different systems—native protein systems, soluble protein truncates of native proteins, synthetic models using organic molecules, and biosynthetic models using proteins as ligands—with a greater emphasis on biosynthetic models of CuA, especially on new, deeper insights gained from their studies. [ABSTRACT FROM AUTHOR]

The cupredoxin fold is an important motif in numerous proteins that are central to several critical cellular processes ranging from aerobic and anaerobic respiration to catalysis and iron homeostasis. Three types of copper sites have been found to date within cupredoxin folds: blue type 1 (T1) copper, red type 2 (T2) copper, and purple CuA. Although as much as 90% sequence difference has been observed among some members of this superfamily of proteins that span several kingdoms, sequence alignment and phylogenic trees strongly suggest an evolutionary link and common ancestry. However, experimental evidence for such a link has been lacking. We report herein the observation of pH-dependent transformation between blue T1 copper, red T2 copper, and the native purple CuA centers of nitrous oxide reductase (N2OR) from Paracoccus denitrificans. The blue and red copper centers form initially before they are transformed into purple CuA center. This transformation process is pH-dependent, with lower pH resulting in fewer trapped T1 and T2 coppers and faster transition to purple CuA. These observations suggest that the purple CuA site contains the essential elements of T1 and T2 copper centers and that the CuA center is preferentially formed at low pH. Therefore, this work provides an underlying link between the various cupredoxin copper sites and possible experimental evidence in vitro for the evolutionary relationship between the cupredoxin proteins. The findings also lend physiological relevance to cupredoxin site biosynthesis. [ABSTRACT FROM AUTHOR]

Abstract: A double mutant of CuA azurin was prepared in which both bridging cysteine thiolate ligands of the binuclear CuA center were replaced by serine. The copper binding properties of this protein were investigated, and shown to be pH dependent. At lower pH (5.2±0.1), the protein binds one copper per protein molecule as demonstrated by electrospray ionization mass spectrometry. Copper titrations resulted in electronic absorptions at 730nm (peak) and ca. 330nm (shoulder) in the UV–Vis spectrum. EPR data show a four line pattern with hyperfine A ∥ =150G and g ∥ and g ⊥ values 2.32 and 2.03, characteristic of a type II (T2) copper. Superhyperfines to two nitrogen atoms were also observed. At higher pH (8.5±0.1), the protein binds upto two copper atoms per protein molecule, and copper titrations exhibit a blue transition at 595nm in the UV–Vis spectrum. The EPR data are consistent with two monomeric sites very similar to one another having hyperfines A ∥ =182 and 150G, g ∥ =2.24 and 2.22 and a similar g ⊥ value of 2.01. These results indicate that both bridging cysteines play a critical role in the CuA center, and replacing them with serines is not enough to maintain the symmetrical diamond core structure or the characteristic electronic and functional properties of the CuA center. [Copyright &y& Elsevier]

Examines the properties of the dimeric polyoxotungstates. Crystallization of the dimeric polyoxotungstates in the triclinic system; Components of the polyanions; Electrochemical properties of the iron-containing complexes.

Type 2 diabetes (T2D) is a complex chronic metabolic disorder characterized by hyperglycemia because of insulin resistance. Diabetes with chronic hyperglycemia may alter brain metabolism, including brain glucose and neurotransmitter levels; however, detailed, longitudinal studies of metabolic alterations in T2D are lacking. To shed insight, here, we characterized the consequences of poorly controlled hyperglycemia on neurochemical profiles that reflect metabolic alterations of the brain in both humans and animal models of T2D. Using in vivo 1 H magnetic resonance spectroscopy, we quantified 12 metabolites cross-sectionally in T2D patients and 20 metabolites longitudinally in T2D db/db mice versus db+ controls. We found significantly elevated brain glucose (91%, p< 0.001), taurine (22%, p= 0.02), glucose+taurine (56%, p< 0.001), myo-inositol (12%, p= 0.02), and choline-containing compounds (10%, p= 0.01) in T2D patients versus age- and sex-matched controls, findings consistent with measures in T2D db/db versus control db+ littermates. In mice, hippocampal and striatal neurochemical alterations in brain glucose, ascorbate, creatine, phosphocreatine, γ-aminobutyric acid, glutamate, glutamine, glutathione, glycerophosphorylcholine, lactate, myo-inositol, and taurine persisted in db/db mice with chronic disease progression from 16 to 48 weeks of age, which were distinct from control db+ mice. Overall, our study demonstrates the utility of 1 H magnetic resonance spectroscopy as a non-invasive tool for characterizing and monitoring brain metabolic changes with T2D progression. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex, multifactorial, neurodegenerative disease that poses tremendous difficulties in pinpointing its precise etiology. A toolkit, which specifically targets and modulates suggested key players, may elucidate their roles in disease onset and progression. We report high-resolution insights on the activity of a small molecule (L2-NO) which exhibits reactivity toward Cu(II)-amyloid-β (Aβ) over Zn(II)-Aβ. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a complex, fatal neurodegenerative disease. Disease pathophysiology is incompletely understood but evidence suggests gut dysbiosis occurs in ALS, linked to impaired gastrointestinal integrity, immune system dysregulation and altered metabolism. Gut microbiome and plasma metabolome have been separately investigated in ALS, but little is known about gut microbe-plasma metabolite correlations, which could identify robust disease biomarkers and potentially shed mechanistic insight. Here, gut microbiome changes were longitudinally profiled in ALS and correlated to plasma metabolome. Gut microbial structure at the phylum level differed in ALS versus control participants, with differential abundance of several distinct genera. Unsupervised clustering of microbe and metabolite levels identified modules, which differed significantly in ALS versus control participants. Network analysis found several prominent amplicon sequence variants strongly linked to a group of metabolites, primarily lipids. Similarly, identifying the features that contributed most to case versus control separation pinpointed several bacteria correlated to metabolites, predominantly lipids. Mendelian randomization indicated possible causality from specific lipids related to fatty acid and acylcarnitine metabolism. Overall, the results suggest ALS cases and controls differ in their gut microbiome, which correlates with plasma metabolites, particularly lipids, through specific genera. These findings have the potential to identify robust disease biomarkers and shed mechanistic insight into ALS. [ABSTRACT FROM AUTHOR]

The metabolic syndrome (MetS) and Alzheimer's disease share several pathological features, including insulin resistance, abnormal protein processing, mitochondrial dysfunction and elevated inflammation and oxidative stress. The MetS constitutes elevated fasting glucose, obesity, dyslipidaemia and hypertension and increases the risk of developing Alzheimer's disease, but the precise mechanism remains elusive. Insulin resistance, which develops froma diet rich in sugars and saturated fatty acids, such as palmitate, is shared by the MetS and Alzheimer's disease. Extracellular vesicles (EVs) are also a point of convergence, with altered dynamics in both the MetS and Alzheimer's disease. However, the role of palmitate- and glucose-induced insulin resistance in the brain and its potential link through EVs to Alzheimer's disease is unknown. We demonstrate that palmitate and high glucose induce insulin resistance and amyloid precursor protein phosphorylation in primary rat embryonic cortical neurons and human cortical stem cells. Palmitate also triggers insulin resistance in oligodendrocytes, the supportive glia of the brain. Palmitate and glucose enhance amyloid precursor protein secretion from cortical neurons via EVs, which induce tau phosphorylation when added to naïve neurons. Additionally, EVs from palmitatetreated oligodendrocytes enhance insulin resistance in recipient neurons.Overall, our findings suggest a novel theory underlying the increased risk of Alzheimer's disease inMetS mediated by EVs, which spreadAlzheimer's pathology and insulin resistance. [ABSTRACT FROM AUTHOR]

Objective: Brain organoids are miniaturized in vitro brain models generated from pluripotent stem cells, which resemble full‐sized brain more closely than conventional two‐dimensional cell cultures. Although brain organoids mimic the human brain's cell‐to‐cell network interactions, they generally fail to faithfully recapitulate cell‐to‐matrix interactions. Here, an engineered framework, called an engineered extracellular matrix (EECM), was developed to provide support and cell‐to‐matrix interactions to developing brain organoids. Methods: We generated brain organoids using EECMs comprised of human fibrillar fibronectin supported by a highly porous polymer scaffold. The resultant brain organoids were characterized by immunofluorescence microscopy, transcriptomics, and proteomics of the cerebrospinal fluid (CSF) compartment. Results: The interstitial matrix‐mimicking EECM enhanced neurogenesis, glial maturation, and neuronal diversity from human embryonic stem cells versus conventional protein matrix (Matrigel). Additionally, EECMs supported long‐term culture, which promoted large‐volume organoids containing over 250 μL of CSF. Proteomics analysis of the CSF found it superseded previous brain organoids in protein diversity, as indicated by 280 proteins spanning 500 gene ontology pathways shared with adult CSF. Interpretation: Engineered EECM matrices represent a major advancement in neural engineering as they have the potential to significantly enhance the structural, cellular, and functional diversity that can be achieved in advanced brain models. [ABSTRACT FROM AUTHOR]

The article discusses the Dissect-O-Matic, a fictional tool that dissects, blocks, stains, and mounts biological samples, automatically preparing them for microscopy imaging.

A letter to the editor is presented in response to a challenge to young scientists by "Science" in the October 2014 issue to name and describe a course that would have better prepared them for their science careers.

Introduction/Aims: Body mass index (BMI) is linked to amyotrophic lateral sclerosis (ALS) risk and prognosis, but additional research is needed. The aim of this study was to identify whether and when historical changes in BMI occurred in ALS participants, how these longer term trajectories associated with survival, and whether metabolomic profiles provided insight into potential mechanisms. Methods: ALS and control participants self‐reported body height and weight 10 (reference) and 5 years earlier, and at study entry (diagnosis for ALS participants). Generalized estimating equations evaluated differences in BMI trajectories between cases and controls. ALS survival was evaluated by BMI trajectory group using accelerated failure time models. BMI trajectories and survival associations were explored using published metabolomic profiling and correlation networks. Results: Ten‐year BMI trends differed between ALS and controls, with BMI loss in the 5 years before diagnosis despite BMI gains 10 to 5 years beforehand in both groups. An overall 10‐year drop in BMI associated with a 27.1% decrease in ALS survival (P =.010). Metabolomic networks in ALS participants showed dysregulation in sphingomyelin, bile acid, and plasmalogen subpathways. Discussion: ALS participants lost weight in the 5‐year period before enrollment. BMI trajectories had three distinct groups and the group with significant weight loss in the past 10 years had the worst survival. Participants with a high BMI and increase in weight in the 10 years before symptom onset also had shorter survival. Certain metabolomics profiles were associated with the BMI trajectories. Replicating these findings in prospective cohorts is warranted. See Editorial on pages 191‐192 in this issue [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis is a fatal CNS neurodegenerative disease. Despite intensive research, current management of amyotrophic lateral sclerosis remains suboptimal from diagnosis to prognosis. Recognition of the phenotypic heterogeneity of amyotrophic lateral sclerosis, global CNS dysfunction, genetic architecture, and development of novel diagnostic criteria is clarifying the spectrum of clinical presentation and facilitating diagnosis. Insights into the pathophysiology of amyotrophic lateral sclerosis, identification of disease biomarkers and modifiable risks, along with new predictive models, scales, and scoring systems, and a clinical trial pipeline of mechanism-based therapies, are changing the prognostic landscape. Although most recent advances have yet to translate into patient benefit, the idea of amyotrophic lateral sclerosis as a complex syndrome is already having tangible effects in the clinic. This Seminar will outline these insights and discuss the status of the management of amyotrophic lateral sclerosis for the general neurologist, along with future prospects that could improve care and outcomes for patients with amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) occurs in up to half of individuals with type 1 or type 2 diabetes. DPN results from the distal-to-proximal loss of peripheral nerve function, leading to physical disability and sometimes pain, with the consequent lowering of quality of life. Early diagnosis improves clinical outcomes, but many patients still develop neuropathy. Hyperglycaemia is a risk factor and glycaemic control prevents DPN development in type 1 diabetes. However, glycaemic control has modest or no benefit in individuals with type 2 diabetes, probably because they usually have comorbidities. Among them, the metabolic syndrome is a major risk factor for DPN. The pathophysiology of DPN is complex, but mechanisms converge on a unifying theme of bioenergetic failure in the peripheral nerves due to their unique anatomy. Current clinical management focuses on controlling diabetes, the metabolic syndrome, and pain, but remains suboptimal for most patients. Thus, research is ongoing to improve early diagnosis and prognosis, to identify molecular mechanisms that could lead to therapeutic targets, and to investigate lifestyle interventions to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective: The serum lipidomic profile associated with neuropathy in type 2 diabetes is not well understood. Obesity and dyslipidemia are known neuropathy risk factors, suggesting lipid profiles early during type 2 diabetes may identify individuals who develop neuropathy later in the disease course. This retrospective cohort study examined lipidomic profiles 10 years prior to type 2 diabetic neuropathy assessment. Methods: Participants comprised members of the Gila River Indian community with type 2 diabetes (n = 69) with available stored serum samples and neuropathy assessment 10 years later using the combined Michigan Neuropathy Screening Instrument (MNSI) examination and questionnaire scores. A combined MNSI index was calculated from examination and questionnaire scores. Serum lipids (435 species from 18 classes) were quantified by mass spectrometry. Results: The cohort included 17 males and 52 females with a mean age of 45 years (SD = 9 years). Participants were stratified as with (high MNSI index score > 2.5407) versus without neuropathy (low MNSI index score ≤ 2.5407). Significantly decreased medium-chain acylcarnitines and increased total free fatty acids, independent of chain length and saturation, in serum at baseline associated with incident peripheral neuropathy at follow-up, that is, participants had high MNSI index scores, independent of covariates. Participants with neuropathy also had decreased phosphatidylcholines and increased lysophosphatidylcholines at baseline, independent of chain length and saturation. The abundance of other lipid classes did not differ significantly by neuropathy status. Interpretation: Abundance differences in circulating acylcarnitines, free fatty acids, phosphatidylcholines, and lysophosphatidylcholines 10 years prior to neuropathy assessment are associated with neuropathy status in type 2 diabetes. [ABSTRACT FROM AUTHOR]

During mammalian neocortex development, nascent pyramidal neurons migrate along radial glial cells and overtake earlier-born neurons to terminate at the front of the developing cortical plate (CP), leading to the outward expansion of the CP border. While much has been learned about the cellular and molecular mechanisms that underlie the migration of pyramidal neurons, how migrating neurons bypass the preceding neurons at the end of migration to reach their final positions remains poorly understood. Here, we report that Down syndrome cell adhesion molecule (DSCAM) is required for migrating neurons to bypass their postmigratory predecessors during the expansion of the upper cortical layers. DSCAM is a type I transmembrane cell adhesion molecule. It has been linked to Down syndrome through its location on Chromosome 21 trisomy and to autism spectrum disorders through loss-of-function mutations. Ex vivo time-lapse imaging demonstrates that DSCAM is required for migrating neurons to bypass their postmigratory predecessors, crossing the CP border to expand the upper cortical layers. In DSCAM-deficient cortices, migrating neurons stop prematurely under the CP border, leading to thinner upper cortical layers with higher neuronal density. We further show that DSCAM weakens cell adhesion mediated by N-cadherin in the upper cortical plate, allowing migrating neurons to traverse the CP border and expand the CP. These findings suggest that DSCAM is required for proper migratory termination and final positioning of nascent pyramidal neurons, which may provide insight into brain disorders that exhibit thinner upper layers of the cerebral cortex without neuronal loss. [ABSTRACT FROM AUTHOR]

The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders. Diagnosis early in the disease course can improve outcomes as timely interventions can slow disease progression. An evolving awareness of disease genotypes and phenotypes and new diagnostic criteria, such as the recent Gold Coast criteria, could expedite diagnosis. Improved prognosis, such as that achieved with the survival model from the European Network for the Cure of ALS, could inform the patient and their family about disease course and improve end-of-life planning. Novel staging and scoring systems can help monitor disease progression and might potentially serve as clinical trial outcomes. Lastly, new tools, such as fluid biomarkers, imaging modalities, and neuromuscular electrophysiological measurements, might increase diagnostic and prognostic accuracy. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. The discovery of genes associated with amyotrophic lateral sclerosis, commencing with SOD1 in 1993, started fairly gradually. Recent advances in genetic technology have led to the rapid identification of multiple new genes associated with the disease, and to a new understanding of oligogenic and polygenic disease risk. The overlap of genes associated with amyotrophic lateral sclerosis with those of other neurodegenerative diseases is shedding light on the phenotypic spectrum of neurodegeneration, leading to a better understanding of genotype-phenotype correlations. A deepening knowledge of the genetic architecture is allowing the characterisation of the molecular steps caused by various mutations that converge on recurrent dysregulated pathways. Of crucial relevance, mutations associated with amyotrophic lateral sclerosis are amenable to novel gene-based therapeutic options, an approach in use for other neurological illnesses. Lastly, the exposome-the summation of lifetime environmental exposures-has emerged as an influential component for amyotrophic lateral sclerosis through the gene-time-environment hypothesis. Our improved understanding of all these aspects will lead to long-awaited therapies and the identification of modifiable risks factors. [ABSTRACT FROM AUTHOR]

Highlights: [•] A triple resonance experiment that correlates ELDOR-detected NMR signals is described. [•] Theory and simulations to account for the cross peaks is presented. [•] Negative cross peaks appear between nuclear frequencies belonging to different M S manifolds. [•] Positive cross peaks are produced by of off resonance effects and nuclear relaxation. [•] Experiment is demonstrated on 14N of a nitroxide and 33S and 14N of Cu(II) type one center of Azurin. [ABSTRACT FROM AUTHOR]

Focuses on the interaction of the lacunary [alpha-XW[sub 9]O[sub 33]][sup 9- (X = arsenic (As)[sup III], antimony (Sb)[sup III]) with Cu[sup 2=] and Zn[sup 2+] ions in neutral, aqueous medium which leads to the formation of dimeric polyoxoanions. Selenium and tellurium analogues of the copper-containing heteropolyanions; Result of the reaction of [alpha-AsW[sub 9]O[sub 33]][sup 9-] with Zn, Co, and Mn ions.

Objective: The global rise in type 2 diabetes is associated with a concomitant increase in diabetic complications. Diabetic polyneuropathy is the most frequent type 2 diabetes complication and is associated with poor outcomes. The metabolic syndrome has emerged as a major risk factor for diabetic polyneuropathy; however, the metabolites associated with the metabolic syndrome that correlate with diabetic polyneuropathy are unknown. Methods: We conducted a global metabolomics analysis on plasma samples from a subcohort of participants from the Danish arm of Anglo‐Danish‐Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION‐Denmark) with and without diabetic polyneuropathy versus lean control participants. Results: Compared to lean controls, type 2 diabetes participants had significantly higher HbA1c (p = 0.0028), BMI (p = 0.0004), and waist circumference (p = 0.0001), but lower total cholesterol (p = 0.0001). Out of 991 total metabolites, we identified 15 plasma metabolites that differed in type 2 diabetes participants by diabetic polyneuropathy status, including metabolites belonging to energy, lipid, and xenobiotic pathways, among others. Additionally, these metabolites correlated with alterations in plasma lipid metabolites in type 2 diabetes participants based on neuropathy status. Further evaluating all plasma lipid metabolites identified a shift in abundance, chain length, and saturation of free fatty acids in type 2 diabetes participants. Importantly, the presence of diabetic polyneuropathy impacted the abundance of plasma complex lipids, including acylcarnitines and sphingolipids. Interpretation: Our explorative study suggests that diabetic polyneuropathy in type 2 diabetes is associated with novel alterations in plasma metabolites related to lipid metabolism. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia in vitro demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis in vivo. We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca2+ levels and increased mitochondrial lengthening and expression of PGC1a, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca2+ levels and impairs impulse conduction within the saphenous nerve in prediabetic PN. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by an imbalance between production and clearance of amyloid-β (Aβ) species. Aβ peptides can transform structurally from monomers into β-stranded fibrils via multiple oligomeric states. Among the various Aβ species, structured oligomers are proposed to be more toxic than fibrils; however, the identification of Aβ oligomers has been challenging due to their heterogeneous and metastable nature. Multiple techniques have recently helped us gain a better understanding of oligomers' assembly details and structural properties. Moreover, some progress on elucidating the mechanisms of oligomer-triggered toxicity has been made. Based on the collection of current findings, there is growing consensus that control of toxic Aβ oligomers could be a valid approach to regulate Aβ-associated toxicity, which could advance development of new diagnostics and therapeutics for amyloid-related diseases. In this review, we summarize the recent understanding of Aβ oligomers' assembly, structural properties, and toxicity, along with inhibitors against Aβ aggregation, including oligomerization. [ABSTRACT FROM AUTHOR]

Dementia is a complex set of disorders affecting normal cognitive function. Recently, several clinical studies have shown that diabetes, obesity, and components of the metabolic syndrome (MetS) are associated with cognitive impairment, including dementias such as Alzheimer's disease. Maintaining normal cognitive function is an intricate process involving coordination of neuron function with multiple brain glia. Well-orchestrated bioenergetics is a central requirement of neurons, which need large amounts of energy but lack significant energy storage capacity. Thus, one of the most important glial functions is to provide metabolic support and ensure an adequate energy supply for neurons. Obesity and metabolic disease dysregulate glial function, leading to a failure to respond to neuron energy demands, which results in neuronal damage. In this review, we outline evidence for links between diabetes, obesity, and MetS components to cognitive impairment. Next, we focus on the metabolic crosstalk between the three major glial cell types, oligodendrocytes, astrocytes, and microglia, with neurons under physiological conditions. Finally, we outline how diabetes, obesity, and MetS components can disrupt glial function, and how this disruption might impair glia-neuron metabolic crosstalk and ultimately promote cognitive impairment. [ABSTRACT FROM AUTHOR]

Summary: Golgi complexes (Golgi) play important roles in the development and function of neurons [1–3]. Not only are Golgi present in the neuronal soma (somal Golgi), they also exist in the dendrites as Golgi outposts [4–7]. Previous studies have shown that Golgi outposts serve as local microtubule-organizing centers [8] and secretory stations in dendrites [6, 9]. It is unknown whether the structure and function of Golgi outposts differ from those of somal Golgi. Here we show in Drosophila that, unlike somal Golgi, the biochemically distinct cis, medial, and trans compartments of Golgi are often disconnected in dendrites in vivo. The Golgi structural protein GM130 is responsible for connecting distinct Golgi compartments in soma and dendritic branch points, and the specific distribution of GM130 determines the compartmental organization of dendritic Golgi in dendritic shafts. We further show that compartmental organization regulates the role of Golgi in acentrosomal microtubule growth in dendrites and in dendritic branching. Our study provides insights into the structure and function of dendritic Golgi outposts as well as the regulation of compartmental organization of Golgi in general. [Copyright &y& Elsevier]

Alzheimer's disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (ML) prototype of a rationally designed molecule obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound ML targets metalfree and metal-bound Aβ (metal-Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)phenol (DAP) and (8- aminoquinolin-2-yl)methanol (1)) for reactivity with Aβ and metal-Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, ML is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity. [ABSTRACT FROM AUTHOR]

Simple Summary: Type 1 and type 2 diabetes can lead to serious health problems that affect many organs including the nerve, the eye, and the kidney. These health problems can be disabling or even life-threatening, and to date, there are no effective therapies that can slow or prevent their development. We studied the effect of empagliflozin, a medication that reduces blood sugar levels and the risk of cardiovascular disease, on the nerve, eye, and kidney in a side-by-side comparison of type 1 and type 2 mouse models. Empagliflozin had no beneficial effects on disease progression in type 2 diabetic mice, but improved nerve function in the type 1 diabetic model, an effect that was accompanied by reduced markers of oxidative injury. These findings support the concept that different mechanisms contribute to nerve damage in type 1 and type 2 diabetes. Our results further support our view that the concept of one therapy will benefit all complications should be abandoned as we pursue more personalized, tissue-specific, diabetes type-specific treatments. Microvascular complications account for the significant morbidity associated with diabetes. Despite tight glycemic control, disease risk remains especially in type 2 diabetes (T2D) patients and no therapy fully prevents nerve, retinal, or renal damage in type 1 diabetes (T1D) or T2D. Therefore, new antidiabetic drug classes are being evaluated for the treatment of microvascular complications. We investigated the effect of empagliflozin (EMPA), an inhibitor of the sodium/glucose cotransporter 2 (SGLT2), on diabetic neuropathy (DPN), retinopathy (DR), and kidney disease (DKD) in streptozotocin-induced T1D and db/db T2D mouse models. EMPA lowered blood glycemia in T1D and T2D models. However, it did not ameliorate any microvascular complications in the T2D model, which was unexpected, given the protective effect of SGLT2 inhibitors on DKD progression in T2D subjects. Although EMPA did not improve DKD in the T1D model, it had a potential modest effect on DR measures and favorably impacted DPN as well as systemic oxidative stress. These results support the concept that glucose-centric treatments are more effective for DPN in T1D versus T2D. This is the first study that provides an evaluation of EMPA treatment on all microvascular complications in a side-by-side comparison in T1D and T2D models. [ABSTRACT FROM AUTHOR]