Evidence For Mechanism Research Articles

Commentary: Understanding IARC's PFOA and PFOS carcinogenicity assessments.

In November 2023, the International Agency for Research on Cancer (IARC) classified PFOA as "carcinogenic to humans" (Group 1) and PFOS as "possibly carcinogenic to humans" (Group 2B). We evaluated these classifications, considering the epidemiology, experimental animal, and mechanistic evidence. It is our opinion that the IARC Working Group overstated the available evidence for the carcinogenicity of PFOA and PFOS. Epidemiology studies have shown weak and inconsistent associations across studies. Studies reporting increased incidences of tumors in experimental animals exposed to PFOA or PFOS had statistically significant results that were driven by the presence of benign adenomas. The IARC Working Group used the key characteristics of carcinogens (KCCs, which comprise 10 chemical and/or biological properties of known human carcinogens) approach to upgrade the carcinogenicity classifications for PFOA and PFOS from initially lower classifications that were based on the strength of the epidemiology and experimental animal evidence. However, this is not a robust assessment of mechanistic evidence, as it fails to consider the quality, external validity, and relevance of the evidence. Rather than use the KCCs as a checklist of potential carcinogenic mechanisms, IARC should use a rigorous method to evaluate the plausibility and human relevance of mechanistic evidence.

Methodological advances in gastrointestinal tract physiology measurements: relevance to nutritional studies.

The gastrointestinal (GI) tract plays a critical role in nutrition and the pathophysiology of disease, and there is an increasing variety of methodologies available for the assessment of various aspects of GI physiology. Advancements in assessment methods, including techniques to study gut motility, fermentation, permeability, and microbiota composition, have provided researchers with powerful tools to investigate the impact of diet on GI tract physiology and the microbiota-gut-brain axis. Mechanistic evidence from reverse translational studies, which apply findings from human studies to preclinical models in a "bedside-to-bench" approach, have also enhanced our understanding of the bidirectional interactions and candidate signalling molecules among the diet-gut-brain relationship. Interpreting data from these advanced techniques and study designs requires a thorough understanding of their principles, applications, and limitations. This review aims to summarise the methodological advances in GI tract physiology measurements and their application in nutritional studies, focusing on gut motility, fermentation, and permeability. We will present examples of how these techniques have been utilised in recent research, discuss their advantages and limitations, and provide insights on their use and interpretation in research. Understanding the capabilities and limitations of these tools is crucial for designing robust studies and elucidating the complex interplay between diet and the GI tract. The scope of this review encompasses recent advancements in GI tract assessment methodologies and their implications for nutritional research, providing a comprehensive overview for researchers in the field.

Prospective observational study and mechanistic evidence showing lipolysis of circulating triglycerides worsens hypertriglyceridemic acute pancreatitis.

While most hypertriglyceridemia is asymptomatic, hypertriglyceridemia-associated acute pancreatitis (HTG-AP) can be more severe than other AP etiologies. The reasons underlying this are unclear. We thus studied whether lipolytic generation of non-esterified fatty acids (NEFA) from circulating triglycerides (TGs) could worsen clinical outcomes. Admission serum TGs, NEFA compositions and concentrations were analyzed prospectively in 269 patients with AP. These and demographics, clinical outcomes were compared between HTGAP (TGs >500mg/dL; American Heart Association 2018 guidelines) and other AP etiologies. Serum NEFAs were correlated with the serum triglyceride fatty acids (TGFAs) alone, and with the product of TGFA x serum lipase (NEFA-TGFA x lipase). Studies in mice, rats were done to understand the role of HTG lipolysis in organ failure and to interpret the NEFA-TGFA correlations. HTG-AP patients had higher serum NEFAs and TGs and more severe AP (19% vs. 7% p<0.03) than other etiologies. Correlations of long-chain unsaturated NEFA with corresponding TGFAs increased with TG concentrations up to 500mg/dL and declined thereafter. However, NEFA-TGFA x lipase correlations got stronger with TGs >500mg/dL. AP, and intravenous lipase infusion in rodents caused lipolysis of circulating TGs to NEFA. This led to multi-system organ failure, which was prevented by pancreatic triglyceride lipase deletion, or lipase inhibition. HTG-AP is made severe by the NEFAs generated form intravascular lipolysis of circulating TGs. Strategies that prevent TG lipolysis may be effective in improving clinical outcomes of HTG-AP. Not applicable. This project was supported by Grant numbers RO1DK092460, R01DK119646 from the NIDDK, PR191945 under W81XWH-20-1-0400 from the DOD (VPS), and R01AA031257 from the NIAAA (VPS).

Synthesis of 1,3,5-trisubstituted 1,2,4-triazoles enabled by a gold-catalyzed three-component reaction

Valuable fully substituted 1,2,4-triazoles are obtained via a gold-catalyzed three-component reaction involving ethyl diazoacetate, aryldiazonium salts, and nitriles. The reaction proceeds under mild conditions, is regioselective, and allows the introduction of mono- and di-substituted aryl rings at the ortho, meta, and para positions. Mechanistic evidence suggests the participation of Au(III) species as the active catalysts.

Front Cover: A Cytochrome P450 TxtE Model System with Mechanistic and Theoretical Evidence for a Heme Peroxynitrite Active Species

Front Cover: A Cytochrome P450 TxtE Model System with Mechanistic and Theoretical Evidence for a Heme Peroxynitrite Active Species

Front Cover: A Cytochrome P450 TxtE Model System with Mechanistic and Theoretical Evidence for a Heme Peroxynitrite Active Species

Front Cover: A Cytochrome P450 TxtE Model System with Mechanistic and Theoretical Evidence for a Heme Peroxynitrite Active Species

A Cytochrome P450 TxtE Model System with Mechanistic and Theoretical Evidence for a Heme Peroxynitrite Active Species

AbstractThe cytochrome P450 homolog, TxtE, efficiently catalyzes the direct and regioselective aromatic nitration of the indolyl moiety of L‐tryptophan to 4‐nitro‐L‐tryptophan, using nitric oxide (NO) and dioxygen (O2) as co‐substrates. Pathways for such direct and selective nitration of heteroaromatic motifs present platforms for engineering new nitration biocatalysts for pharmacologically beneficial targets, among a medley of other pivotal industrial applications. Precise mechanistic details concerning this pathway are only weakly understood, albeit a heme iron(III)‐peroxynitrite active species has been postulated. To shed light on this unique reaction landscape, we investigated the indole nitration pathway of a series of biomimetic ferric heme superoxide mimics, [(Por)FeIII(O2−⋅)], in the presence of NO. Therein, our model systems gave rise to three distinct nitroindole products, including 4‐nitroindole, the product analogous to that obtained with TxtE. Moreover, 15N and 18O isotope labeling studies, along with meticulously designed control experiments lend credence to a heme peroxynitrite active nitrating agent, drawing close similarities to the tryptophan nitration mechanism of TxtE. All organic and inorganic reaction components have been fully characterized using spectroscopic methods. Theoretical investigation into several mechanistic possibilities deem a unique indolyl radical based reaction pathway as the most energetically favorable, products of which, are in excellent agreement with experimental findings.

Policy Actions Required to Improve Nutrition for Brain Health.

Brain health is a pressing global concern. Poor diet quality is a recognized major environmental risk factor for brain disorders and one of the few that is modifiable. There is substantial evidence that nutrition impacts brain development and brain health across the life course. So why then is the full potential of nutrition not utilized to improve brain function? This commentary, which is based on discussions of the European Brain Research Area BRAINFOOD cluster, aims to highlight the most urgent research priorities concerning the evidence base in the area of nutrition and brain health and identifies 3 major issues that need to be addressed: (1) increase causal and mechanistic evidence on the link between nutrition and brain health, (2) produce effective messages/education concerning the role of food for brain health, and (3) provide funding to support collaborative working across diverse stakeholders.

Macrophage-mediated interleukin-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation

Abstract Background Postoperative atrial fibrillation (poAF) is self-limited AF that occurs within days after cardiac surgery in one-third of patients. Clinical and preclinical studies have demonstrated that the magnitude of the perioperative increase in systemic inflammation, in particular mediated by interleukin (IL)-6, correlates with poAF risk. However, no studies to-date have mechanistically linked IL-6 signaling to fundamental arrhythmia mechanisms or identified the specific cell types driving postoperative atrial IL-6 signaling. Methods We performed single-cell RNA sequencing (scRNAseq), followed by pseudotime trajectory and cell-cell communication analyses on atrial non-myocytes comparing mice with and without poAF. We followed up our scRNAseq findings with pharmacologic and genetic approaches in mice to validate pathways related to macrophage-mediated IL-6 signaling. We used confocal imaging to assess calcium-signaling mechanisms at the single atrial cardiomyocyte (ACM) level and performed parallel patch-clamp studies in isolated human ACMs as well as biochemical analyses of human atrial tissue to assess the translational relevance of our findings. Results Our scRNAseq results demonstrated macrophages to be the most prominently altered cell type in the atria of mice with poAF. Pseudotime trajectory analyses revealed IL-6 to be one of the top inflammatory pathways implicated in macrophage transcriptional state. Indeed, both macrophage depletion and conditional knockout of IL-6 receptors in macrophages were sufficient to prevent poAF. We found that inhibition of STAT3, which is downstream of the IL-6Ra, with FDA-approved phospho-STAT3 inhibitor TTI-101 prevented poAF in mice. Lastly, we demonstrate that enhanced STAT3 activity in poAF promotes arrhythmogenic Ca2+ sparks and waves through ryanodine receptor-2 dysfunction, and that CaMKII inhibition is sufficient to ameliorate Ca2+ mishandling at the single atrial myocyte level. Conclusions Taken together, we use an integrated approach incorporating mouse and human biochemical, functional, and single-cell sequencing data to demonstrate that infiltrating atrial macrophages are fundamentally required for poAF. IL-6 was found to be a critical pathway upregulated in poAF leading to downstream ryanodine receptor-2 dysfunction and atrial arrhythmogenesis. Our findings portend significant therapeutic utility by providing robust mechanistic evidence that targeting the IL-6 axis may be used for poAF prevention and treatment in a clinically amenable timeframe.

Shifting interactions between ectomycorrhizae, plants and insect herbivores in a CO2‐enriched world

Abstract Increasing atmospheric CO2 concentrations are changing how plants interact with their biotic mutualists and antagonists, but few syntheses consider how the three‐way interactions between mycorrhizae, plants and herbivores will shift under rising CO2. We summarise the mechanisms by which ectomycorrhizal (EcM)‐associated plants, their mycorrhizae and insect herbivores interact with each other under current conditions and evaluate a set of expectations for how these interactions might shift under higher CO2. We then outline priorities for future work on EcM–plant–herbivore interactions as atmospheric CO2 continues to rise. EcM colonisation has variable but often positive effects on herbivory, while herbivory has consistently negative impacts on EcM colonisation. Mechanistic evidence suggests that the positive EcM effect on herbivory will strengthen and the negative impact of herbivory on EcM will be ameliorated under higher CO2. Synthesis: While more empirical evidence on fungal–plant–herbivore interactions is needed in EcM systems, our synthesis suggests that EcM associations may play an under‐recognised role in dictating future terrestrial carbon capture by mediating herbivory and the ability of plants to compensate for herbivory as atmospheric CO2 continues to rise.

Low conduction velocity is a key factor for localisation of reentrant drivers for atrial fibrillation

Abstract Background Atrial Fibrillation (AF) is a prevalent cardiac arrhythmia globally, associated with heightened risks of stroke, dementia, and heart failure. Catheter ablation, the sole curative therapy for AF, yields suboptimal success rates for persistent AF cases. Understanding the mechanisms and dynamics of AF remains challenging, hindering treatment advancements. Novel ablation strategies aimed at targeting substrates harbouring AF reentrant drivers (RD), such as low-voltage ablation and rotor-based ablation, have yet to demonstrate superiority over the gold standard ablation strategy – pulmonary vein isolation. Purpose The purpose of the study is to integrate in-silico 3D left atrial (LA) simulations and explainable artificial intelligence (AI) to pinpoint key factors for RD localisation in persistent AF, aiming to improve the mechanistic understanding of AF and help develop a more effective ablation strategy. Methods 3D LA models were derived from magnetic resonance images of 41 patients and combined with atrial cell electrophysiology models. Persistent AF was initiated in each patient-specific LA model with fast pacing, and five functional features (action potential duration (APD), conduction velocity (CV), wavelength, APD spatial gradient, CV spatial gradient, and wavelength spatial gradient) and three structural features (fibrotic density, fibrotic entropy, and image intensity ratio) were evaluated. A random forest AI model was trained to classify phase singularities corresponding to the RDs (PS-RD) in five distinct tissue classes (total LA tissue, healthy tissue, fibrotic border zone, dense fibrotic tissue, and PS-RD tissue) based on the functional and structural features. Shapley additive explanations (SHAP) analysis was then used to find the most influential feature in the AI model’s decision process. Results Simulations of the patient-specific LA models revealed that RDs were typically localised in regions with the lowest atrial CV, which often coincided with patches of dense fibrotic tissue. In a five-fold cross-validation, the random forest AI model achieved high accuracy in classifying PS-RD regions: a mean ROC AUC of 0.99 ± 0.010, a mean F1 score of 0.86 ± 0.034, a mean recall of 0.95 ± 0.058, and a mean precision score of 0.79 ± 0.085. The further SHAP analysis revealed that low CV was the key determinant in classifying the PS-RD regions. Conclusion Our study combined AF computational modelling and explainable AI to identify the key factors in RD localisation. Both the computational and AI models concluded that low CV was the most important determinant in localising RDs. These findings provide mechanistic evidence for the efficacy of ablation strategies that target low CV atrial areas for persistent AF patients.

Trophoblast-specific overexpression of adiponectin receptor 2 causes fetal growth restriction in pregnant mice.

Maternal obesity in pregnancy is strongly associated with complications such as fetal overgrowth and infants of obese mothers have an increased risk to develop obesity, diabetes, and cardiovascular disease later in life. However, the underlying mechanisms are not well established. Circulating levels of adiponectin are low in obese pregnant women and maternal circulating adiponectin is negatively associated with birth weight. We have reported that normalizing maternal adiponectin in obese pregnant mice prevents placental dysfunction, fetal overgrowth, and programming of offspring cardio-metabolic disease. However, the mechanistic link between maternal adiponectin, placental function, and fetal growth remains to be established. We hypothesized that trophoblast-specific overexpression of the adiponectin receptor 2 (Adipor2) in healthy pregnant mice inhibits placental mTORC1 signaling and nutrient transport, resulting in fetal growth restriction. Using lentiviral transduction of blastocysts with a mammalian gene expression lentiviral vector for up-regulation of Adipor2 (Adipor2-OX), we achieved a ~ 3-fold increase in placenta Adipor2 mRNA levels and a 2-fold increase of the ADIPOR2 protein in the trophoblast plasma membrane. Placenta-specific Adipor2-OX increased placental peroxisome proliferator-activated receptor-α phosphorylation, ceramide synthase expression and ceramide concentrations. Furthermore, Adipor2-OX inhibited placental mTORC1 signaling and reduced invivo placental transport of glucose and amino acids. Lastly, Adipor2-OX reduced fetal weight by 11%. These data provide mechanistic evidence that placental Adipor2 signaling directly affects fetal growth. We propose that low circulating adiponectin in maternal obesity causes fetal overgrowth and programs the offspring for cardio-metabolic disease mediated by a direct effect on placental function.

Crocus sativus (saffron) and age-related macular degeneration.

Age-related macular degeneration (ARMD) leads to impaired vision and potential blindness. Globally, it accounts for approximately 9% of vision loss cases, and a projected 288 million individuals will be affected by 2040. Current treatments have limitations such as variable effectiveness, high costs, and potential side effects. Additionally, atrophic ARMD management remains challenging. As saffron has shown promising neuroprotective and antioxidant effects by potentially delaying disease progression, this study aims to review the mechanistic, pre-clinical, and clinical evidence of the effects, safety, and tolerability of saffron in ARMD treatment. The Scale for the Assessment of Narrative Review Articles was applied in this narrative review. To find relevant literature, the syntax "(saffron OR crocus) AND (retin* OR "geographic atrophy" OR "choroidal neovascular*" OR "macular degeneration")" was searched in PubMed/MEDLINE. Pre-clinical and clinical original investigations of the effects of saffron in ARMD along with the eligible studies cited in their reference lists were identified and included. Saffron and its active compounds, crocin and crocetin, have shown promising results in improving visual function and delaying ARMD progression. Several clinical studies have found that daily supplementation with 20-50 mg of saffron or 5-15 mg of crocin for 3-12 months significantly improved best-corrected visual acuity, contrast sensitivity, and retinal function as measured by electroretinogram and microperimetry, with benefits observed in both dry and wet forms of ARMD. The effects were independent of genetic risk factors and maintained during the follow-up periods, suggesting the potential role of saffron as a long-term treatment option. Saffron reduces ARMD progression via anti-angiogenic, neuroprotective, and antioxidant mechanisms. Moreover, saffron is safe and well tolerated. Although further research is needed to confirm long-term safety and efficacy, current evidence supports the use of saffron or crocin supplements as a safe and tolerable adjunct therapy for ARMD management.

Novel mechanistic understanding that Lactiplantibacillus plantarum is more capable of improving the ensiling performance of wheat straw silage than xylanase by driving certain key metabolites

Microbial and enzyme additives can improve silage performance, but there is limited comparative research on the effects of microbial and enzyme additives on improving silage fermentation quality, and the underlying microbial and metabolic pathways remain unclear. This study investigated the effects without inoculants (CK treatment) or with Lactiplantibacillus plantarum (LP treatment), xylanase (XY treatment) and their combination (LPXY treatment) on the fermentation quality, as well as on the microbial communities and metabolite profiles of the wheat straw silage. The results demonstrated that the LP treatment has a better effect on improving the fermentation quality of wheat straw silage compared to other treatments, as evidenced by markedly (p < 0.05) decreased the pH (4.06), acid and neutral fiber (ANF, NDF, 23.43 and 31.69%DM), and increased the lactic acid (LA, 965.89 mg/L) and acetic acid (AA, 656.10 mg/L) concentrations. After the fermentation process, the LP treatment significantly (p < 0.05) enhanced the abundance of Lactobacillus, reduced bacterial Shannon (p < 0.05) and increased some key metabolites content. The structural equation models (SEMs) and Pearson’s correlation results proved that the LP treatment improved the wheat straw silage fermentation quality via increasing the abundance of Lactobacillus, decreasing the diversity of bacterial community and enriching the content of certain key metabolites. The present study provides mechanistic evidence that Lactiplantibacillus plantarum additive is superior to xylanase additive and their combination on improving fermentation quality of wheat straw silage, that is, by enriching certain key metabolites to increase AA and LA concentrations, providing a reference for the cross study of silage feed fermentation microbiome and metabolome.Graphical

Is there dietary macronutrient malabsorption in children with environmental enteropathy?

Assessing the digestive and absorptive capacity of the gastro-intestinal tract (GIT) using minimally- or non-invasive methods, particularly in children, has been difficult owing to the complex physiology and variability in functional measurements. However, measuring GIT function is increasingly important with the emerging relevance of childhood environmental enteropathy (EE) as a mediating factor in linear growth faltering, severe acute malnutrition, poor oral vaccine uptake and impaired cognition. In EE, sub-optimal nutrient digestion and absorption (malabsorption) forms the critical link to the conditions mentioned above. The present narrative review discusses probable mechanisms that can cause malabsorption of macronutrients, along with mechanistic and experimental evidence, in children (if not, in adults) with EE. The strengths and limitations of the human experimental studies are examined in relation to a battery of existing and potential tests that are used to measure malabsorption. From the available studies conducted in children, lactose and fat malabsorption are more likely to occur in EE. Breath tests (non-invasive) measuring carbohydrate (13C-starch/sucrose/lactose), fat (13C-mixed triglyceride) and dipeptide (benzoyl-L-tyrosyl-L-1-13C-alanine) malabsorption with modifications to the existing protocols seem suitable for use in children with EE. Future research should focus on understanding the degree of macronutrient malabsorption using these tests, in different settings, and link them to functional outcomes (such as growth, muscle strength, cognition).

Autonomic recalibration: A pilot study documenting mechanistic evidence for a trauma-informed manual therapy for chronic pain

Autonomic recalibration: A pilot study documenting mechanistic evidence for a trauma-informed manual therapy for chronic pain

Estrogenic post-menopausal anti-osteoporotic mechanism of Achyranthes aspera L.: Phytochemicals and network pharmacology approaches

Hormone replacement therapy is used to treat postmenopausal syndrome caused by estrogen deficiency, but it has been linked to an increased risk of breast cancer. In India, Achyranthes aspera L. is traditionally used to treat menstrual problems; however, there is a lack of mechanistic evidence of its phytoestrogenicity. Therefore, this study investigated the estrogenic activity of A. aspera on estrogen-responsive MCF-7 breast cancer cells. In a cell proliferation assay, the MeOH fraction (100 μg/mL) exhibited the highest proliferation effect (PE) of 138 % (p < 0.001) and relative proliferation effect (RPE) of 96.5 %, compared to 17β-estradiol (0.01 μM: 143 % PE, p < 0.001; 100 % RPE). The MeOH fraction was shown to upregulate the oestrogen marker genes trefoil factor 1 and progesterone receptor by 20.14–23.94 folds and 10.83–14.83 folds, respectively. Twelve phenolics were identified by LC-MS/MS in the active MeOH fraction, i.e. quinic acid, kaempferol hexoside, kaempferol 3-O-(2″-O-galloyl)-glucoside)-β-D-glucoside, geniposide, 3-O-(6′-O-(9Z,12Z-octadecadienoyl)-β-D-glucopyranosyl)-stigmast-5,22E-dien-3β-ol, kaempferol-3-O-glucoside (astragalin), 3,30-di-O-methylellagic acid isomer, procyanidin, naringin, propapyriogenin A2, (3β,22E,24R)-23-methylergosta-5,7,22-trien-3-ol and 6-prenylapigenin. Through network pharmacology, the potential effects, and mechanisms of these compounds in osteoporosis were revealed. About 55 target genes were linked to osteoporosis. GO and KEGG enrichment suggest regulation of female reproductive hormone related signaling pathways, which are also associated with estrogen dependent osteoporosis. Molecular docking analysis of the compounds revealed potential interactions with hERα receptor for 3-O-(6′-O-(9Z,12Z-octadecadienoyl)-β-D-glucopyranosyl)-stigmast-5,22E-dien-3β-ol and kaempferol-3-O-glucoside (astragalin) (docking scores of −9.3 and −10.1 kcal/mol, respectively) as compared to 17β-estradiol (−9.3 kcal/mol). These results suggest the estrogenicity of A. aspera via an ERα-associated mechanism and support its traditional usage in the management of menopausal-related problems.

Unlocking choline's potential in Alzheimer's disease: A narrative review exploring the neuroprotective and neurotrophic role of phosphatidylcholine and assessing its impact on memory and learning

Background and aimsGrowing evidence suggests nutritional intervention may influence the development and progression of Alzheimer‘s Disease (AD). Choline, an essential dietary nutrient plays a critical role in neurological development and brain function, however, its effects on AD in humans is unclear. The research aims to investigate mechanistic links between dietary choline intake and cognitive functioning, focusing on the role of phosphatidylcholine (PC) in neuroplasticity and its interaction with amyloid beta (Aβ) peptides in neuron membranes. Additionally, human evidence on potential benefits of PC interventions on AD, cognition and proposed mechanisms are evaluated. MethodsA reproducible systematic literature search was performed using a three-tranche strategy, consisting of a review, mechanism and intervention search. Using PubMed as the main database, 1254 titles and abstracts were screened, 149 papers were read in full and 65 peer-reviewed papers were accepted, critically appraised and analysed in a narrative review. ResultsPredominantly preclinical evidence demonstrated that PC enhances neuroplasticity, a key biological substrate for cognition, by activating intracellular neuronal signalling pathways or through neuron membrane function.Molecular dynamic simulation methods provided mechanistic understanding of the interconnection between neuronal PC content and the potential behaviour and trajectory of Aβ peptide aggregation. The results indicate that the neuronal membrane composition of PC is critical to inhibiting Aβ aggregation and neuronal damage, protecting the neuron from Aβ toxicity. This might provide a foundation for optimising cellular PC which may prove beneficial in the treatment or prevention of neurodegenerative disease.Altered PC metabolism in AD was evidenced in observational studies; however, whether this relationship represents a cause or consequence of AD remains to be determined. Human intervention studies did not produce conclusive evidence supporting its effectiveness in enhancing cognitive function. This lack of consistency primarily stems from methodological constraints within the conducted studies. Human observational research provided the most compelling evidence linking a higher dietary PC intake to reduced risk of dementia and significant improvements in cognitive testing. ConclusionDespite the lack of randomised control trials (RCTs) assessing the efficacy of lecithin/PC to improve cognition in AD patients, there exists promising evidence supporting its neuroprotective and neurotrophic role.This review establishes an evidence-based framework through chains of mechanistic evidence, that may provide potential strategies for enhanced neuroprotection and reduced neurodegeneration caused by AD. Considering the escalating global burden of AD and the current shortcomings in effective treatments, this review together with the limitations and gaps identified in the existing research present valuable insights that emphasise the urgency of more comprehensive research into the relationship between PC and AD.

Do Vaccines Cause Postural Orthostatic Tachycardia Syndrome? Review of Cases in the National Vaccine Injury Compensation Program

BackgroundThe National Childhood Vaccine Injury Act of 1986 created the National Vaccine Injury Compensation Program (VICP), a no-fault alternative to the traditional tort system. Since 1988, the total compensation paid exceeds $6 billion. Although postural orthostatic tachycardia syndrome (POTS) is a frequent reason for filing a claim, there has been no review of the process and validity of the legal outcomes given current medical information. The purpose of this study was to review vaccine-related POTS and assess the rationale behind decisions made by the court. MethodsWe identified 102 unique cases with POTS. All published reports were reviewed for petitioner's theories supporting vaccine-induced POTS, respondent's counterarguments, the final decision regarding compensation, and the rationale underlying these decisions. The primary goal was to determine which factors went into decisions regarding whether vaccines cause POTS. ResultsIn deciding the cases the Special Masters hearing the cases place a high reliance on expert witnesses for both the petitioners and respondents. Petitioners’ experts frequently implicated vaccines, primarily human papillomavirus vaccine, as causing POTS through autoimmunity induced by molecular mimicry. However, in none of the 102 cases was POTS considered to be directly caused by a vaccine. ConclusionsDespite the lack of epidemiologic or mechanistic evidence indicating that childhood vaccines covered by the VICP result in POTS, these cases continue to be adjudicated, at considerable cost to the government. Unless there is emerging scientific support for implicating vaccines in POTS it is time that the VICP stop considering these cases.

NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.

Pathological disruption of Nucleocytoplasmic Transport (NCT), such as the mis-localization of nuclear pore complex proteins (Nups), nuclear transport receptors, Ran-GTPase, and RanGAP1, are seen in both animal models and in familial and sporadic forms of amyotrophic lateral sclerosis (ALS), frontal temporal dementia and frontal temporal lobar degeneration (FTD\FTLD), and Alzheimer's and Alzheimer's Related Dementias (AD/ADRD). However, the question of whether these alterations represent a primary cause, or a downstream consequence of disease is unclear, and what upstream factors may account for these defects are unknown. Here, we report four key findings that shed light on the upstream causal role of Importin-β-specific nuclear transport defects in disease onset. First, taking advantage of two novel mouse models of NEMF neurodegeneration (NemfR86S and NemfR487G) that recapitulate many cellular and biochemical aspects of neurodegenerative diseases, we find an Importin-β-specific nuclear import block. Second, we observe cytoplasmic mis-localization and aggregation of multiple proteins implicated in the pathogenesis of ALS/FTD and AD/ADRD, including TDP43, Importin-β, RanGap1, and Ran. These findings are further supported by a pathological interaction between Importin-β and the mutant NEMFR86S protein in cytoplasmic accumulations. Third, we identify similar transcriptional dysregulation in key genes associated with neurodegenerative disease. Lastly, we show that even transient pharmaceutical inhibition of Importin-β in both mouse and human neuronal and non-neuronal cells induces key proteinopathies and transcriptional alterations seen in our mouse models and in neurodegeneration. Our convergent results between mouse and human neuronal and non-neuronal cellular biology provide mechanistic evidence that many of the mis-localized proteins and dysregulated transcriptional events seen in multiple neurodegenerative diseases may in fact arise primarily from a primary upstream defect in Importin- β nuclear import. These findings have critical implications for investigating how sporadic forms of neurodegeneration may arise from presently unidentified genetic and environmental perturbations in Importin-β function.