Association of dietary and nutritional factors with cognitive decline, dementia, and depressive symptomatology in older individuals according to a neurogenesis-centred biological susceptibility to brain ageing.

Hippocampal neurogenesis (HN) occurs throughout the life course and is important for memory and mood. Declining with age, HN plays a pivotal role in cognitive decline (CD), dementia, and late-life depression, such that altered HN could represent a neurobiological susceptibility to these conditions. Pertinently, dietary patterns (e.g., Mediterranean diet) and/or individual nutrients (e.g., vitamin D, omega 3) can modify HN, but also modify risk for CD, dementia, and depression. Therefore, the interaction between diet/nutrition and HN may alter risk trajectories for these ageing-related brain conditions. Using a subsample (n = 371) of the Three-City cohort-where older adults provided information on diet and blood biobanking at baseline and were assessed for CD, dementia, and depressive symptomatology across 12 years-we tested for interactions between food consumption, nutrient intake, and nutritional biomarker concentrations and neurogenesis-centred susceptibility status (defined by baseline readouts of hippocampal progenitor cell integrity, cell death, and differentiation) on CD, Alzheimer's disease (AD), vascular and other dementias (VoD), and depressive symptomatology, using multivariable-adjusted logistic regression models. Increased plasma lycopene concentrations (OR [95% CI] = 1.07 [1.01, 1.14]), higher red meat (OR [95% CI] = 1.10 [1.03, 1.19]), and lower poultry consumption (OR [95% CI] = 0.93 [0.87, 0.99]) were associated with an increased risk for AD in individuals with a neurogenesis-centred susceptibility. Increased vitamin D consumption (OR [95% CI] = 1.05 [1.01, 1.11]) and plasma γ-tocopherol concentrations (OR [95% CI] = 1.08 [1.01, 1.18]) were associated with increased risk for VoD and depressive symptomatology, respectively, but only in susceptible individuals. This research highlights an important role for diet/nutrition in modifying dementia and depression risk in individuals with a neurogenesis-centred susceptibility.

Comparing the efficacy of combined versus single immune cell adaptive therapy targeting colorectal cancer.

PURPOSE: Colorectal cancer (CRC) is the most frequent cancer with limited therapeutic achievements. Recently, adoptive cellular immunotherapy has been developed as an antitumor therapy. However, its efficacy has not been tested in CRC. This study investigated the ability of an immune cell cocktail of dendritic cells (DCs), T cells, and natural killer (NK) cells to overcome immunological hurdles and improve the therapeutic efficacy of cell therapy for CRC. METHODS: CRC lysate-pulsed monocyte-derived DCs (Mo-DCs), CRC antigen-specifically expanded T cells (CTL), and in vitro-expanded NK cells were cultured from patient peripheral blood mononuclear cells (PBMC). The ability of the combined immune cells to kill autologous tumor cells was investigated by co-culturing the combined immune cells with patient-derived tumor cells. RESULTS: The Mo-DCs produced expressed T cell co-stimulating molecules like CD80, CD86, human leukocyte antigen (HLA)-DR and HLA-ABC, at high levels and were capable of activating naive T cells. The expanded T cells were predominantly CD8 T cells with high levels of CD8 effector memory cells and low levels of regulatory T cells. The NK cells expressed high levels of activating receptors and were capable of killing other cancer cell lines (K562 and HT29). The immune cell cocktail demonstrated a higher ability to kill autologous tumor cells than single types. An in vivo preclinical study confirmed the safety of the combined immune cell adaptive therapy showing no therapy-related death or general toxicity symptoms. CONCLUSION: The results suggested that combined immune cell adaptive therapy could overcome the limited efficacy of cell immunotherapy.

Mucoadhesive chitosan microcapsules for controlled gastrointestinal delivery and oral bioavailability enhancement of low molecular weight peptides.

A bioactive compound, collagen peptide (CP), is widely used for biological activities such as anti-photoaging and antioxidant effects, with increased oral bioavailability because of its low molecular weight and high hydrophilicity. However, controlling release time and increasing retention time in the digestive tract for a more convenient oral administration is still a challenge. We developed CP-loaded chitosan (CS) microcapsules via strong and rapid ionic gelation using a highly negative phytic acid (PA) crosslinker. The platform enhanced the oral bioavailability of CP with controlled gastrointestinal delivery by utilizing the mucoadhesiveness and tight junction-opening properties of CS. CS and CP concentrations varied from 1.5 to 3.5% and 0-30%, respectively, for optimal and stable microcapsule synthesis. The physicochemical properties, in vitro release profile with intestinal permeability, in vivo oral bioavailability, in vivo biodistribution, anti-photoaging effect, and antioxidant effect of optimized CS microcapsules were analyzed to investigate the impact of controlling parameters. The structure of CS microcapsules was tuned by PA diffused gradient ionic cross-linking degree, resulting in a controlled CP release region in the gastrointestinal tract. The optimized microcapsules increased Cmax, AUC, and tmax by 1.5-, 3.4-, and 8.0-fold, respectively. Furthermore, CP in microcapsules showed anti-photoaging effects by downregulating matrix metalloproteinases-1 via antioxidant effects. According to our knowledge, this is the first study to microencapsulate CP for oral bioavailability enhancement. The peptide delivery method employed is simple, economical, and can be applied to customize bioactive compound administration.

Diagnostic Performance of Artificial Intelligence-Based Computer-Aided Detection Software for Automated Breast Ultrasound.

RATIONALE AND OBJECTIVES: This study aimed to evaluate the diagnostic performance of radiologists following the utilization of artificial intelligence (AI)-based computer-aided detection software (CAD) in detecting suspicious lesions in automated breast ultrasounds (ABUS). MATERIALS AND METHODS: ABUS-detected 262 breast lesions (histopathological verification; January 2020 to December 2022) were included. Two radiologists reviewed the images and assigned a Breast Imaging Reporting and Data System (BI-RADS) category. ABUS images were classified as positive or negative using AI-CAD. The BI-RADS category was readjusted in four ways: the radiologists modified the BI-RADS category using the AI results (AI-aided 1), upgraded or downgraded based on AI results (AI-aided 2), only upgraded for positive results (AI-aided 3), or only downgraded for negative results (AI-aided 4). The AI-aided diagnostic performances were compared to radiologists. The AI-CAD-positive and AI-CAD-negative cancer characteristics were compared. RESULTS: For 262 lesions (145 malignant and 117 benign) in 231 women (mean age, 52.2 years), the area under the receiver operator characteristic curve (AUC) of radiologists was 0.870 (95% confidence interval [CI], 0.832-0.908). The AUC significantly improved to 0.919 (95% CI, 0.890-0.947; P = 0.001) using AI-aided 1, whereas it improved without significance to 0.884 (95% CI, 0.844-0.923), 0.890 (95% CI, 0.852-0.929), and 0.890 (95% CI, 0.853-0.928) using AI-aided 2, 3, and 4, respectively. AI-CAD-negative cancers were smaller, less frequently exhibited retraction phenomenon, and had lower BI-RADS category. Among nonmass lesions, AI-CAD-negative cancers showed no posterior shadowing. CONCLUSION: AI-CAD implementation significantly improved the radiologists' diagnostic performance and may serve as a valuable diagnostic tool.

Humidity Sensors Based on Cellulose Nanofiber Fabricated on a Three-Dimensional (3D) Curved Surface.

Traditional printed electronics processes have recently been utilized within 3D-printed structures where components and interconnects are introduced during manufacturing disruptions. The dielectric performance of 3D-printed materials has a low-resolution problem, and many technologies have been proposed for direct printing on a 3D curved surface or structure. This paper reports a humidity sensor fabricated with a 3D-printed electrode and cellulose nanofibers on a curved surface. The electrode part of an interdigital electrode (IDE) sensor is printed on a flat glass substrate and a 3D-curved glass substrate using a double blanket reverse offset. Subsequently, a cellulose nanofiber emulsion is coated onto the IDE pattern as a sensing layer with a dispenser. The electrical impedance of the sensor is measured with the relative humidity (RH) changes between 10% and 90% RH. The sensor demonstrates a high repeatability and sensitivity, even on a 3D curved substrate. This technology provides a promising method to integrate humidity sensors and 3D deformable surfaces.

Systemic Immune Modulation Induced by Ephedrine in Obese-Diabetes (db/db) Mice.

Immune-modulatory effects in obese-diabetes (db/db) mice were observed to understand the possible mechanism(s) of ephedrine-induced unfavorable responses. The ephedrine doses were selected based on the FDA report (NTP Tech Rep Ser NO 307; CAS# 134-72-5), which showed the non-toxic dose for B6C3F1 mice. In db/db mice, higher doses (6 and 12 mg/mouse) of ephedrine significantly harmed the liver and lung morphology, including fatty liver with multiple blood vessel engorgement, alveolar wall thickening, and inflammatory response in the lung. The immune micro-environment of db/db mice was an inflammatory state with suppressed adaptive cellular immunity. After the administration of ephedrine, significant deterioration of NK activity was observed with lowered gene transcription of klrk1 encoding NKG2D, and of ccl8, a NK cell targeting chemokine. Suppressed cellular immunity in db/db mice was lowered ever further by single ephedrine treatment, as was evidenced by mitogen-induced T or B cell proliferations. These observations demonstrate that at the non-toxic doses in normal B6C3F1 mice, ephedrine clearly suppressed systemic immunity of db/db mice. The data suggest that the immune micro-environment of obese individuals is fragile and susceptible to ephedrine-related pathologic response, and this may be a prelude to the induction of obesity-related secondary immunological disorders.

A Mediterranean Diet-Based Metabolomic Score and Cognitive Decline in Older Adults: A Case-Control Analysis Nested within the Three-City Cohort Study.

SCOPE: Evidence on the Mediterranean diet (MD) and age-related cognitive decline (CD) is still inconclusive partly due to self-reported dietary assessment. The aim of the current study is to develop an MD- metabolomic score (MDMS) and investigate its association with CD in community-dwelling older adults. METHODS AND RESULTS: This study includes participants from the Three-City Study from the Bordeaux (n = 418) and Dijon (n = 422) cohorts who are free of dementia at baseline. Repeated measures of cognition over 12 years are collected. An MDMS is designed based on serum biomarkers related to MD key food groups and using a targeted metabolomics platform. Associations with CD are investigated through conditional logistic regression (matched on age, sex, and education level) in both sample sets. The MDMS is found to be inversely associated with CD (odds ratio [OR] [95% confidence interval (CI)] = 0.90 [0.80-1.00]; p = 0.048) in the Bordeaux (discovery) cohort. Results are comparable in the Dijon (validation) cohort, with a trend toward significance (OR [95% CI] = 0.91 [0.83-1.01]; p = 0.084). CONCLUSIONS: A greater adherence to the MD, here assessed by a serum MDMS, is associated with lower odds of CD in older adults.

Nucleotide-binding leucine-rich repeat network underlies nonhost resistance of pepper against the Irish potato famine pathogen Phytophthora infestans.

Nonhost resistance (NHR) is a robust plant immune response against non-adapted pathogens. A number of nucleotide-binding leucine-rich repeat (NLR) proteins that recognize non-adapted pathogens have been identified, although the underlying molecular mechanisms driving robustness of NHR are still unknown. Here, we screened 57 effectors of the potato late blight pathogen Phytophthora infestans in nonhost pepper (Capsicum annuum) to identify avirulence effector candidates. Selected effectors were tested against 436 genome-wide cloned pepper NLRs, and we identified multiple functional NLRs that recognize P. infestans effectors and confer disease resistance in the Nicotiana benthamiana as a surrogate system. The identified NLRs were homologous to known NLRs derived from wild potatoes that recognize P. infestans effectors such as Avr2, Avrblb1, Avrblb2, and Avrvnt1. The identified CaRpi-blb2 is a homologue of Rpi-blb2, recognizes Avrblb2 family effectors, exhibits feature of lineage-specifically evolved gene in microsynteny and phylogenetic analyses, and requires pepper-specific NRC (NLR required for cell death)-type helper NLR for proper function. Moreover, CaRpi-blb2-mediated hypersensitive response and blight resistance were more tolerant to suppression by the PITG_15 278 than those mediated by Rpi-blb2. Combined results indicate that pepper has stacked multiple NLRs recognizing effectors of non-adapted P. infestans, and these NLRs could be more tolerant to pathogen-mediated immune suppression than NLRs derived from the host plants. Our study suggests that NLRs derived from nonhost plants have potential as untapped resources to develop crops with durable resistance against fast-evolving pathogens by stacking the network of nonhost NLRs into susceptible host plants.

CD8α+ dendritic cells potentiate antitumor and immune activities against murine ovarian cancers.

Dendritic cell (DC)-based immunotherapies have been shown to be a potential treatment option for various cancers; however, the exact strategies in ovarian cancer remain unknown. Here, we report the effectiveness of mouse CD8α+ DCs derived from bone marrow hematopoietic stem cells (BM-HSCs), equivalent to human CD141+ DCs, which have proven to be a highly superior subset. Mono-DCs from monocytes and stem-DCs from HSCs were characterized by CD11c+ CD80+ CD86+ and CD8α+ Clec9a+ expression, respectively. Despite a lower dose compared with Mono-DCs, mice treated with pulsed Stem-DCs showed a reduced amount of ascitic fluid and lower body weights compared with those of vehicle-treated mice. These mice treated with pulsed stem-DCs appeared to have fewer tumor implants, which were usually confined in the epithelium of tumor-invaded organs. All mice treated with DCs showed longer survival than the vehicle group, especially in the medium/high dose pulsed Stem-DC treatment groups. Moreover, the stem-DC-treated group demonstrated a low proportion of myeloid-derived suppressor cells and regulatory T cells, high interleukin-12 and interferon-γ levels, and accumulation of several tumor-infiltrating lymphocytes. Together, these results indicate that mouse CD8α+ DCs derived from BM-HSCs decrease tumor progression and enhance antitumor immune responses against murine ovarian cancer, suggesting that better DC vaccines can be used as an effective immunotherapy in EOC treatment. Further studies are necessary to develop potent DC vaccines using human CD141+ DCs.

Natural overexpression of CAROTENOID CLEAVAGE DIOXYGENASE 4 in tomato alters carotenoid flux.

Carotenoids and apocarotenoids function as pigments and flavor volatiles in plants that enhance consumer appeal and offer health benefits. Tomato (Solanum lycopersicum.) fruit, especially those of wild species, exhibit a high degree of natural variation in carotenoid and apocarotenoid contents. Using positional cloning and an introgression line (IL) of Solanum habrochaites "LA1777', IL8A, we identified carotenoid cleavage dioxygenase 4 (CCD4) as the factor responsible for controlling the dark orange fruit color. CCD4b expression in ripe fruit of IL8A plants was ∼8,000 times greater than that in the wild type, presumably due to 5' cis-regulatory changes. The ShCCD4b-GFP fusion protein localized in the plastid. Phytoene, ζ-carotene, and neurosporene levels increased in ShCCD4b-overexpressing ripe fruit, whereas trans-lycopene, ß-carotene, and lutein levels were reduced, suggestive of feedback regulation in the carotenoid pathway by an unknown apocarotenoid. Solid-phase microextraction-gas chromatography-mass spectrometry analysis showed increased levels of geranylacetone and ß-ionone in ShCCD4b-overexpressing ripe fruit coupled with a ß-cyclocitral deficiency. In carotenoid-accumulating Escherichia coli strains, ShCCD4b cleaved both ζ-carotene and ß-carotene at the C9-C10 (C9'-C10') positions to produce geranylacetone and ß-ionone, respectively. Exogenous ß-cyclocitral decreased carotenoid synthesis in the ripening fruit of tomato and pepper (Capsicum annuum), suggesting feedback inhibition in the pathway. Our findings will be helpful for enhancing the aesthetic and nutritional value of tomato and for understanding the complex regulatory mechanisms of carotenoid and apocarotenoid biogenesis.

Predicting progression to Alzheimer's disease with human hippocampal progenitors exposed to serum.

Adult hippocampal neurogenesis is important for learning and memory and is altered early in Alzheimer's disease. As hippocampal neurogenesis is modulated by the circulatory systemic environment, evaluating a proxy of how hippocampal neurogenesis is affected by the systemic milieu could serve as an early biomarker for Alzheimer's disease progression. Here, we used an in vitro assay to model the impact of systemic environment on hippocampal neurogenesis. A human hippocampal progenitor cell line was treated with longitudinal serum samples from individuals with mild cognitive impairment, who either progressed to Alzheimer's disease or remained cognitively stable. Mild cognitive impairment to Alzheimer's disease progression was characterized most prominently with decreased proliferation, increased cell death and increased neurogenesis. A subset of 'baseline' cellular readouts together with education level were able to predict Alzheimer's disease progression. The assay could provide a powerful platform for early prognosis, monitoring disease progression and further mechanistic studies.

In vitro characterization on the role of APOE polymorphism in human hippocampal neurogenesis.

Hippocampal neurogenesis (HN) is considered an important mechanism underlying lifelong brain plasticity, and alterations in this process have been implicated in early Alzheimer's disease progression. APOE polymorphism is the most common genetic risk factor for late-onset Alzheimer's disease where the ε4 genotype is associated with a significantly earlier disease onset compared to the neutral ε3 allele. Recently, APOE has been shown to play an important role in the regulation of HN. However, the time-dependent impact of its polymorphism in humans remains elusive, partially due to the difficulties of studying human HN in vivo. To bridge this gap of knowledge, we used an in vitro cellular model of human HN and performed a time course characterization on isogenic induced pluripotent stem cells with different genotypes of APOE. We found that APOE itself was more highly expressed in ε4 at the stem cell stage, while the divergence of differential gene expression phenotype between ε4 and ε3 became prominent at the neuronal stage of differentiation. This divergence was not associated with the differential capacity to generate dentate gyrus granule cell-like neurons, as its level was comparable between ε4 and ε3. Transcriptomic profiling across different stages of neurogenesis indicated a clear "maturation of functional neurons" phenotype in ε3 neural progenitors and neurons, while genes differentially expressed only in ε4 neurons suggested potential alterations in "metabolism and mitochondrial function." Taken together, our in vitro investigation suggests that APOE ε4 allele can exert a transcriptome-wide effect at the later stages of HN, without altering the overall level of neurogenesis per se.

Industry Competition, Corporate Governance, and Voluntary Disclosure of Greenhouse Gas Emissions Information: Evidence from South Korea.

This study investigates the relationship between industry competition and managers' voluntary disclosure policies and examined how the corporate governance structure affects this relationship in South Korean companies. The fiercer the competition within the industry to which the company belongs, the higher the incentive for managers to perform strategic actions to improve their competition status. This increase in the strategic incentives of managers can be seen through voluntary disclosure policies. The empirical results of this study are as follows. First, it was found that there was a negative relationship between the degree of industry competition and the level of voluntary disclosure of greenhouse gas emissions information. This means that managers perform less disclosure to maximize the value of the company because the more competition within the industry intensifies, the higher the proprietary cost of disclosing information on greenhouse gas emissions information. Second, it was found that the corporate governance structure weakened the relationship between the degree of industry competition and the level of corporate voluntary disclosure. These results can be interpreted as that a good governance structure supports such managers' disclosure decisions because managers are more likely to choose disclosure policies to maximize the value of the company than personal benefits even in the fierce industry competition.

Synthesis of Vacancy-Controlled Copper Iodide Semiconductor for High-Performance p-Type Thin-Film Transistors.

Copper iodide (CuI) has emerged as a promising p-type semiconductor material owing to its excellent carrier mobility, high transparency, and solution processability. Although CuI has potential for numerous applications, including perovskite solar cells, photovoltaic devices, and thin-film transistors (TFTs), the close relationship between the anion vacancy generation and the charge transport mechanism in CuI-based devices is underexplored. In this study, we propose solution-processed p-type CuI TFTs which were subject to the thermal annealing process in air and vacuum atmospheres at temperatures of 100, 200, and 300 °C. The chemical states and surface morphologies of the CuI thin films were systematically investigated, revealing the generation of iodine vacancy states and the reduction of carrier concentration, as well as increased film density and grain size according to the annealing condition. Further, the effective role of the Al2O3 passivation layer on the electrical characteristics of the solution-processed CuI TFTs is demonstrated for the first time, where the Al2O3 precursor greatly enhanced the electrical performance of the CuI TFTs, exhibiting a field-effect mobility of 4.02 cm2/V·s, a subthreshold swing of 0.61 V/decade, and an on/off current ratio of 1.12 × 104, which exceed the values of CuI TFTs reported so far. Based on the synergistic effects of the annealing process and the passivation layer that engineered the iodine vacancy state and morphology of CuI, the proposed CuI TFTs with the Al2O3 passivation layer showed excellent reliability under 100 times repeated operation and long-term stability over 216 h, where the transfer curves slightly shifted in the positive direction of 1.36 and 1.88 V measured at a current level of 10-6 A for the reliability and stability tests, respectively. Thus, this work opens a new window for solution-processed p-type CuI TFTs with excellent stability for developing next-generation complementary logic circuits.

Comparative Analysis of Small-Molecule LIMK1/2 Inhibitors: Chemical Synthesis, Biochemistry, and Cellular Activity.

LIM domain kinases 1 and 2 (LIMK1 and LIMK2) regulate actin dynamics and subsequently key cellular functions such as proliferation and migration. LIMK1 and LIMK2 phosphorylate and inactivate cofilin leading to increased actin polymerization. As a result, LIMK inhibitors are emerging as a promising treatment strategy for certain cancers and neurological disorders. High-quality chemical probes are required if the role of these kinases in health and disease is to be understood. To that end, we report the results of a comparative assessment of 17 reported LIMK1/2 inhibitors in a variety of in vitro enzymatic and cellular assays. Our evaluation has identified three compounds (TH-257, LIJTF500025, and LIMKi3) as potent and selective inhibitors suitable for use as in vitro and in vivo pharmacological tools for the study of LIMK function in cell biology.

Betulinic acid improves TNF-α-induced insulin resistance by inhibiting negative regulator of insulin signalling and inflammation-activated protein kinase in 3T3-L1 adipocytes.

CONTEXT: Obesity is related to insulin resistance, and adipose tissue-secreted TNF-α may play a role in inducing obesity. TNF-α activates inflammatory protein kinase and impairs insulin signalling. OBJECTIVES: We investigated the effect of betulinic acid on insulin resistance caused by TNF-α treatment in 3T3-L1 adipocytes. MATERIAL AND METHODS: 3T3-L1 was exposed to TNF-α in the presence and absence of betulinic acid. Various parameters such as glucose uptake assay, cell viability, expression of proteins involved in insulin resistance were studied. RESULTS: Betulinic acid increased glucose uptake in TNF-α pre-treated cells and inhibited the activation of PTP1B and JNK and reduced IκBα degradation. Tyrosine phosphorylation was increased, and serine phosphorylation was decreased in IRS-1. DISCUSSION: Betulinic acid restored TNF-α impaired insulin signalling and increased PI3K activation and phosphorylation of Akt and increased plasma membrane expression of GLUT 4, which stimulated glucose uptake concentration-dependently. CONCLUSION: These results suggest that betulinic acid is effective at improving TNF-α-induced insulin resistance in adipocytes via inhibiting the activation of negative regulator of insulin signalling and inflammation-activated protein kinase and may potentially improve insulin resistance.

Induced Endothelial Cell-Integrated Liver Assembloids Promote Hepatic Maturation and Therapeutic Effect on Cholestatic Liver Fibrosis.

The transplantation of pluripotent stem cell (PSC)-derived liver organoids has been studied to solve the current donor shortage. However, the differentiation of unintended cell populations, difficulty in generating multi-lineage organoids, and tumorigenicity of PSC-derived organoids are challenges. However, direct conversion technology has allowed for the generation lineage-restricted induced stem cells from somatic cells bypassing the pluripotent state, thereby eliminating tumorigenic risks. Here, liver assembloids (iHEAs) were generated by integrating induced endothelial cells (iECs) into the liver organoids (iHLOs) generated with induced hepatic stem cells (iHepSCs). Liver assembloids showed enhanced functional maturity compared to iHLOs in vitro and improved therapeutic effects on cholestatic liver fibrosis animals in vivo. Mechanistically, FN1 expressed from iECs led to the upregulation of Itgα5/ß1 and Hnf4α in iHEAs and were correlated to the decreased expression of genes related to hepatic stellate cell activation such as Lox and Spp1 in the cholestatic liver fibrosis animals. In conclusion, our study demonstrates the possibility of generating transplantable iHEAs with directly converted cells, and our results evidence that integrating iECs allows iHEAs to have enhanced hepatic maturation compared to iHLOs.

Apolipoprotein E and sex modulate fatty acid metabolism in a prospective observational study of cognitive decline.

BACKGROUND: Fatty acids play prominent roles in brain function as they participate in structural, metabolic and signaling processes. The homeostasis of fatty acids and related pathways is known to be impaired in cognitive decline and dementia, but the relationship between these metabolic disturbances and common risk factors, namely the ɛ4 allele of the apolipoprotein E (ApoE-ɛ4) gene and sex, remains elusive. METHODS: In order to investigate early alterations associated with cognitive decline in the fatty acid-related serum metabolome, we here applied targeted metabolomics analysis on a nested case-control study (N=368), part of a prospective population cohort on dementia. RESULTS: When considering the entire study population, circulating levels of free fatty acids, acyl-carnitines and pantothenic acid were found to be increased among those participants who had greater odds of cognitive decline over a 12-year follow-up. Interestingly, stratified analyses indicated that these metabolomic alterations were specific for ApoE-ɛ4 non-carriers and women. CONCLUSIONS: Altogether, our results highlight that the regulation of fatty acids and related metabolic pathways during ageing and cognitive decline depends on complex inter-relationships between the ApoE-ε4 genotype and sex. A better understanding of the ApoE-ɛ4 and sex dependent modulation of metabolism is essential to elucidate the individual variability in the onset of cognitive decline, which would help develop personalized therapeutic approaches.

The effects of genotype on inflammatory response in hippocampal progenitor cells: A computational approach.

Cell culture models are valuable tools to study biological mechanisms underlying health and disease in a controlled environment. Although their genotype influences their phenotype, subtle genetic variations in cell lines are rarely characterised and taken into account for in vitro studies. To investigate how the genetic makeup of a cell line might affect the cellular response to inflammation, we characterised the single nucleotide variants (SNPs) relevant to inflammation-related genes in an established hippocampal progenitor cell line (HPC0A07/03C) that is frequently used as an in vitro model for hippocampal neurogenesis (HN). SNPs were identified using a genotyping array, and genes associated with chronic inflammatory and neuroinflammatory response gene ontology terms were retrieved using the AmiGO application. SNPs associated with these genes were then extracted from the genotyping dataset, for which a literature search was conducted, yielding relevant research articles for a total of 17 SNPs. Of these variants, 10 were found to potentially affect hippocampal neurogenesis whereby a majority (n=7) is likely to reduce neurogenesis under inflammatory conditions. Taken together, the existing literature seems to suggest that all stages of hippocampal neurogenesis could be negatively affected due to the genetic makeup in HPC0A07/03C cells under inflammation. Additional experiments will be needed to validate these specific findings in a laboratory setting. However, this computational approach already confirms that in vitro studies in general should control for cell lines subtle genetic variations which could mask or exacerbate findings.

Brain Connectivity Affecting Gait Function After Unilateral Supratentorial Stroke.

Gait dysfunction is a leading cause of long-term disability after stroke. The mechanisms underlying recovery of gait function are unknown. We retrospectively evaluated the association between structural connectivity and gait function in 127 patients with unilateral supratentorial stroke (>1 month after stroke). All patients underwent T1-weighted, diffusion tensor imaging and functional ambulation categorization. Voxel-wise linear regression analyses of the images were conducted using fractional anisotropy, mean diffusivity, and mode of anisotropy mapping as dependent variables, while the functional ambulation category was used as an independent variable with age and days after stroke as covariates. The functional ambulation category was positively associated with increased fractional anisotropy in the lesioned cortico-ponto-cerebellar system, corona radiata of the non-lesioned corticospinal tract pathway, bilateral medial lemniscus in the brainstem, and the corpus callosum. The functional ambulation category was also positively associated with increased mode of anisotropy in the lesioned posterior corpus callosum. In conclusion, structural connectivity associated with motor coordination and feedback affects gait function after stroke. Diffusion tensor imaging for evaluating structural connectivity can help to predict gait recovery and target rehabilitation goals after stroke.