Genetic tapestry of Capsicum fruit colors: a comparative analysis of four cultivated species.

KEY MESSAGE: Genome-wide association study of color spaces across the four cultivated Capsicum spp. revealed a shared set of genes influencing fruit color, suggesting mechanisms and pathways across Capsicum species are conserved during the speciation. Notably, Cytochrome P450 of the carotenoid pathway, MYB transcription factor, and pentatricopeptide repeat-containing protein are the major genes responsible for fruit color variation across the Capsicum species. Peppers (Capsicum spp.) rank among the most widely consumed spices globally. Fruit color, serving as a determinant for use in food colorants and cosmeceuticals and an indicator of nutritional contents, significantly influences market quality and price. Cultivated Capsicum species display extensive phenotypic diversity, especially in fruit coloration. Our study leveraged the genetic variance within four Capsicum species (Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum annuum) to elucidate the genetic mechanisms driving color variation in peppers and related Solanaceae species. We analyzed color metrics and chromatic attributes (Red, Green, Blue, L*, a*, b*, Luminosity, Hue, and Chroma) on samples cultivated over six years (2015-2021). We resolved genomic regions associated with fruit color diversity through the sets of SNPs obtained from Genotyping by Sequencing (GBS) and genome-wide association study (GWAS) with a Multi-Locus Mixed Linear Model (MLMM). Significant SNPs with FDR correction were identified, within the Cytochrome P450, MYB-related genes, Pentatricopeptide repeat proteins, and ABC transporter family were the most common among the four species, indicating comparative evolution of fruit colors. We further validated the role of a pentatricopeptide repeat-containing protein (Chr01:31,205,460) and a cytochrome P450 enzyme (Chr08:45,351,919) via competitive allele-specific PCR (KASP) genotyping. Our findings advance the understanding of the genetic underpinnings of Capsicum fruit coloration, with developed KASP assays holding potential for applications in crop breeding and aligning with consumer preferences. This study provides a cornerstone for future research into exploiting Capsicum's diverse fruit color variation.

From genes to ecosystems: Decoding plant tolerance mechanisms to arsenic stress.

Arsenic (As), a metalloid of considerable toxicity, has become increasingly bioavailable through anthropogenic activities, raising As contamination levels in groundwater and agricultural soils worldwide. This bioavailability has profound implications for plant biology and farming systems. As can detrimentally affect crop yield and pose risks of bioaccumulation and subsequent entry into the food chain. Upon exposure to As, plants initiate a multifaceted molecular response involving crucial signaling pathways, such as those mediated by calcium, mitogen-activated protein kinases, and various phytohormones (e.g., auxin, methyl jasmonate, cytokinin). These pathways, in turn, activate enzymes within the antioxidant system, which combat the reactive oxygen/nitrogen species (ROS and RNS) generated by As-induced stress. Plants exhibit a sophisticated genomic response to As, involving the upregulation of genes associated with uptake, chelation, and sequestration. Specific gene families, such as those coding for aquaglyceroporins and ABC transporters, are key in mediating As uptake and translocation within plant tissues. Moreover, we explore the gene regulatory networks that orchestrate the synthesis of phytochelatins and metallothioneins, which are crucial for As chelation and detoxification. Transcription factors, particularly those belonging to the MYB, NAC, and WRKY families, emerge as central regulators in activating As-responsive genes. On a post-translational level, we examine how ubiquitination pathways modulate the stability and function of proteins involved in As metabolism. By integrating omics findings, this review provides a comprehensive overview of the complex genomic landscape that defines plant responses to As. Knowledge gained from these genomic and epigenetic insights is pivotal for developing biotechnological strategies to enhance crop As tolerance.

Perceived Ageism is Associated With Recurrent Falling Among Older Colombian Adults.

Literature on the association between ageism and falling among older adults is limited. Using data from the nationwide cross-sectional SABE (Salud, Bienestar y Envejecimiento) Colombia Survey in 2015 with 18,875 participants aged ≥60 years living in the communities, the study aims to evaluate the association between perceived ageism within the family, neighborhood, health services, and public services, and recurrent falling. Participants had a mean age of 69.2 ± 7.1; 56.1% were female. Recurrent falling prevalence was 15%, and experiencing any ageism was 10%. Multivariable logistic regression analyses showed higher odds of recurrent falling for any ageism (OR = 1.81, 95% CI 1.61-2.02, p < .0001). High depressive symptoms mediated 10.1% of the association between any ageism and recurrent falling, followed by low instrumental activities of daily living (9.7%) and multimorbidity (9.3%). Current findings open new areas of gerontological research by expanding the risk factors for falling among older adults to include ageism perceptions.

Woolly mutation with Get02 locus overcomes the polygenic nature of trichome-based pest resistance in tomato.

Type-IV glandular trichomes, which only occur in the juvenile developmental phase of the cultivated tomato (Solanum lycopersicum), produce acylsugars that broadly protect against arthropod herbivory. Previously, we introgressed the capacity to retain type-IV trichomes in the adult phase from the wild tomato, Solanum galapagense, into the cultivated species cv. Micro-Tom (MT). The resulting MT-Get (MicroTom-Galapagos enhanced trichome) introgression line contained five loci associated with enhancing the density of type-IV trichomes in adult plants. We genetically dissected MT-Get and obtained a sub-line containing only the locus on chromosome 2 (MT-Get02). This genotype displayed about half the density of type-IV trichomes compared to the wild progenitor. However, when we stacked the gain-of-function allele of WOOLLY, which encodes an HD-ZIP IV transcription factor, Get02/Wo exhibited double the number of type-IV trichomes compared to S. galapagense. This discovery corroborates previous reports positioning WOOLLY as a master regulator of trichome development. Acylsugar levels in Get02/Wo were comparable to the wild progenitor, although the composition of acylsugar types differed, especially regarding fewer types with medium-length acyl chains. Agronomical parameters of Get02/Wo, including yield, were comparable to MT. Pest resistance assays showed enhanced protection against silverleaf whitefly (Bemisia tabaci), tobacco hornworm (Manduca sexta), and the fungus Septoria lycopersici. However, resistance levels did not reach that of the wild progenitor, suggesting the specificity of acylsugar types in the pest resistance mechanism. Our findings in trichome-mediated resistance advance the development of robust, naturally resistant tomato varieties, harnessing the potential of natural genetic variation. Moreover, by manipulating only two loci, we achieved exceptional results for a highly complex, polygenic trait, such as herbivory resistance in tomato.

Social determinants of health and metabolic syndrome in Colombian older adults.

BACKGROUND AND AIMS: Social determinants of health (SDH) are critical in health outcomes. More insight is needed on the correlation between SDH and metabolic syndrome (MetS) in the aging population. This study assessed the association between SDH and MetS scores among older adults in Colombia. METHODS AND RESULTS: This cross-sectional country-wide study includes a sample of 4085 adults aged ≥60 from the SABE Colombia Survey. MetS measurements were central obesity, hyperglycemia or diabetes, hypertriglyceridemia, arterial hypertension, and low HDL cholesterol (MetS score 0-5). SDH includes four levels: 1- general socioeconomic and environmental conditions; 2-social and community networks; 3- individual lifestyle; and 4-constitutional factors. In multivariate linear regression analysis, the SDH factors with greater effect sizes, calculated by Eta Squared, predicting higher MetS mean scores were women followed by low education, no alcohol intake, urban origin, and residing in unsafe neighborhoods. Two interactions: men, but not women, have lower MetS in safe neighborhoods compared to unsafe, and men, but not women, have lower MetS when having low education (0-5 years) compared to high (≥6). CONCLUSION: Gender, education, alcohol intake, and origin have the greatest effect sizes on MetS. Education level and neighborhood safety modified the relationship between gender and MetS. Low-educated men or those residing in safe neighborhoods have lower MetS. Neighborhood environments and educational differences influencing MetS should be considered in future studies.

Evaluation of the Catheter Clamp over Hydrophilic Guide Wire Central Venous Catheter Exchange Technique for Air Embolism Prophylaxis in an In Vitro Model.

PURPOSE: To develop a reproducible in vitro model simulating central venous catheter (CVC) exchange with high potential for air embolization and test the hypothesis that a closed catheter clamp over hydrophilic guide wire exchange technique will significantly reduce the volume of air introduced during CVC exchange. MATERIALS AND METHODS: The model consisted of a 16-F valved sheath, 240-mL container, and pressure transducer submerged in water in a 1,200-mL suction canister system. Continuous wall suction was applied to the canister to maintain negative pressure at -7 mm Hg or -11 mm Hg. Each trial consisted of 0.035-inch hydrophilic guide wire introduction, over-the-wire catheter exchange, and wire removal following clinical protocol. A total of 256 trials were performed, 128 trials at each pressure with the catheter clamp open (n = 64) or closed (n = 64) around the hydrophilic guide wire. RESULTS: There was a statistically significant lower volume of air introduced with closed clamp over-the-wire exchanges than with open clamp exchanges at both pressures (2-tailed t-test, P < .001). At -7 mm Hg, a mean of 48.0 mL (SD ± 9.3) of air was introduced with open clamp and 20.6 mL (SD ± 4.7) of air was introduced with closed clamp. At -11 mm Hg, 97.8 mL (SD ± 11.9) of air was introduced with open clamp and 37.8 mL (SD ± 6.3) of air was introduced with closed clamp. CONCLUSIONS: This study demonstrated the use of a reproducible in vitro model mimicking conditions causing air embolism during CVC exchange. Results showed that CVC exchange using closed catheter clamp over hydrophilic guide wire exchange technique significantly reduced the volume of air introduced per exchange.

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer's disease mouse model.

BACKGROUND: Cognitive decline in Alzheimer's disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity. METHODS: To determine the therapeutic benefit of inhibiting this elevation, we evaluated PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model. Additionally, we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus (AAV) encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus. The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored. We examined ceramide levels, histopathological changes, and pTau content within EVs isolated from the mouse plasma. RESULTS: Similar to human AD, the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity; both were completely normalized by PDDC treatment. The PS19 mice also exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all of which were pathologic features of human AD. PDDC treatment reduced these changes. The plasma of PDDC-treated PS19 mice had reduced levels of neuronal- and microglial-derived EVs, the former carrying lower pTau levels, compared to untreated mice. In the tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side. CONCLUSIONS: PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity, leading to the slowing of tau spread in AD mice.

Specific neuropsychiatric symptoms are associated with functional decline trajectories in Alzheimer's disease and Lewy body dementia: a five-year follow-up study.

Background: Neuropsychiatric symptoms (NPS) are often overlooked and under-identified symptoms associated with dementia, despite their significant impact on the prognosis of individuals living with the disease. The specific role of certain NPS in functional prognosis remains unclear. Aims: To determine the association of different NPS with functional decline in people living with Alzheimer's disease (AD) or Lewy body dementia (LBD). Methods: This is an analysis of data from the Dementia Study of Western Norway (DemVest) with 196 patients included of which 111 had AD and 85 LBD. The Neuropsychiatric Inventory (NPI) and the Rapid Disability Rating Scale (RDRS-2) for activities of daily living were administered annually for 5 years. NPI total score and individual items with RDRS-2 trajectories were analyzed with linear mixed models. Results: The LBD group exhibited higher levels of functional impairment and a greater burden of NPS at baseline. Over the 5-year follow-up, hallucinations, aggression, depression, anxiety, apathy, disinhibition, aberrant motor behavior, nighttime behavior disturbances, and abnormal eating patterns were significantly associated with the decline in functional abilities in individuals with AD, as well as irritability and aberrant motor behavior in those with LBD. Discussion: These results highlight the relevance of early detection and intervention of these particularly relevant NPS, due to its potential of also impacting physical function. Better detection and management of these NPS could improve functional prognosis in people living with dementia. Conclusion: Specific NPS demonstrate relevant distinct associations with Longitudinal trajectories of functional decline in AD and LBD.

Influence of Long-Term CaO Storage Conditions on the Calcium Looping Thermochemical Reactivity.

Long-term storage capability is often claimed as one of the distinct advantages of the calcium looping process as a potential thermochemical energy storage system for integration into solar power plants. However, the influence of storage conditions on the looping performance has seldom been evaluated experimentally. The storage conditions must be carefully considered as any potential carbonation at the CaO storage tank would reduce the energy released during the subsequent carbonation, thereby penalizing the round-trip efficiency. From lab-scale to conceptual process engineering, this work considers the effects of storing solids at low temperatures (50-200 °C) in a CO2 atmosphere or at high temperatures (800 °C) in N2. Experimental results show that carbonation at temperatures below 200 °C is limited; thus, the solids could be stored during long times even in CO2. It is also demonstrated at the lab scale that the multicycle performance is not substantially altered by storing the solids at low temperatures (under CO2) or high temperatures (N2 atmosphere). From an overall process perspective, keeping solids at high temperatures leads to easier heat integration, a better plant efficiency (+2-4%), and a significantly higher energy density (+40-62%) than considering low-temperature storage. The smooth difference in the overall plant efficiency with the temperature suggests a proper long-term energy storage performance if adequate energy integration is carried out.

A Genome-Wide Identification and Comparative Analysis of the Heavy-Metal-Associated Gene Family in Cucurbitaceae Species and Their Role in Cucurbita pepo under Arsenic Stress.

The heavy-metal-associated (HMA) proteins are a class of PB1-type ATPases related to the intracellular transport and detoxification of metals. However, due to a lack of information regarding the HMA gene family in the Cucurbitaceae family, a comprehensive genome-wide analysis of the HMA family was performed in ten Cucurbitaceae species: Citrullus amarus, Citrullus colocynthis, Citrullus lanatus, Citrullus mucosospermus, Cucumis melo, Cucumis sativus, Cucurbita maxima, Cucurbita moschata, Cucurbita pepo, and Legenaria siceraria. We identified 103 Cucurbit HMA proteins with various members, ranging from 8 (Legenaria siceraria) to 14 (Cucurbita pepo) across species. The phylogenetic and structural analysis confirmed that the Cucurbitaceae HMA protein family could be further classified into two major clades: Zn/Co/Cd/Pb and Cu/Ag. The GO-annotation-based subcellular localization analysis predicted that all HMA gene family members were localized on membranes. Moreover, the analysis of conserved motifs and gene structure (intron/exon) revealed the functional divergence between clades. The interspecies microsynteny analysis demonstrated that maximum orthologous genes were found between species of the Citrullus genera. Finally, nine candidate HMA genes were selected, and their expression analysis was carried out via qRT-PCR in root, leaf, flower, and fruit tissues of C. pepo under arsenic stress. The expression pattern of the CpeHMA genes showed a distinct pattern of expression in root and shoot tissues, with a remarkable expression of CpeHMA6 and CpeHMA3 genes from the Cu/Ag clade. Overall, this study provides insights into the functional analysis of the HMA gene family in Cucurbitaceae species and lays down the basic knowledge to explore the role and mechanism of the HMA gene family to cope with arsenic stress conditions.

Agronomic performance and remote sensing assessment of organic and mineral fertilization in rice fields.

Introduction: Rice heavily relies on nitrogen fertilizers, posing environmental, resource, and geopolitical challenges. This study explores sustainable alternatives like animal manure and remote sensing for resource-efficient rice cultivation. It aims to assess the long-term impact of organic fertilization and remote sensing monitoring on agronomic traits, yield, and nutrition. Methods: A six-year experiment in rice fields evaluated fertilization strategies, including pig slurry (PS) and chicken manure (CM) with mineral fertilizers (MIN), MIN-only, and zero-fertilization. Traits, yield, spectral responses, and nutrient content were measured. Sentinel-2 remote sensing tracked crop development. Results: Cost-effective organic fertilizers (PS and CM) caused a 13% and 15% yield reduction but still doubled zero-fertilization yield. PS reduced nitrogen leaching. Heavy metals in rice grains were present at safe amounts. Organic-fertilized crops showed nitrogen deficiency at the late vegetative stages, affecting yield. Sentinel-2 detected nutrient deficiencies through NDVI. Discussion: Organic fertilizers, especially PS, reduce nitrogen loss, benefiting the environment. However, they come with yield trade-offs and nutrient management challenges that can be managed and balanced with reduced additional mineral applications. Sentinel-2 remote sensing helps manage nutrient deficiencies. In summary, this research favors cost-effective organic fertilizers with improved nutrient management for sustainable rice production.

Soil Fertility and Phosphorus Leaching in Irrigated Calcareous Soils of the Mediterranean Region.

To ensure soil quality and soil health, it is necessary to improve fertilization practices while minimizing environmental impacts. The aim of this study was to record the state of the art on soil fertility related to fertilization management (organic and/or mineral) and to detect environmental challenges in highly productive fields. A soil survey was set up in a new irrigated area (c. 20 years old), in the north-eastern part of Spain, which is mainly devoted to double annual crop rotations of cereals and maize. The area also supports an important animal rearing activity. The survey covered 733 ha of calcareous soils, owned by 35 farmers. At each farm, fertilization management was recorded, and soil was analyzed for nutrients and heavy metals. Multivariate analyses were performed. Total N, P, Cu and Zn, and available P, Cu, Zn and Mn soil concentrations were associated to the use of organic amendments. Heavy metals concentrations were below established thresholds. Available P (Olsen-P) was identified as an indicator of the previously adopted fertilization management and of the potential of P leaching towards deeper soil layers. Regression analyses were performed. A displacement of available P from the uppermost layer (0-0.3 m) occurs in the breakpoint of 86 mg P kg-1 soil. Preventative actions might be established from 53 mg P kg-1 soil due to the slowdown in P immobilization. Our results reinforce the importance of setting up P threshold soil levels for best practices of fertilization, as a basis for sustainable agriculture intensification.

Comparative assessment of Alzheimer's disease-related biomarkers in plasma and neuron-derived extracellular vesicles: a nested case-control study.

Introduction: Alzheimer's disease (AD) is currently defined according to biomarkers reflecting the core underlying neuropathological processes: Aß deposition, Tau, and neurodegeneration (ATN). The soluble phase of plasma and plasma neuron-derived extracellular vesicles (NDEVs) are increasingly being investigated as sources of biomarkers. The aim of this study was to examine the comparative biomarker potential of these two biofluids, as well as the association between respective biomarkers. Methods: We retrospectively identified three distinct diagnostic groups of 44 individuals who provided samples at baseline and at a mean of 3.1 years later; 14 were cognitively unimpaired at baseline and remained so (NRM-NRM), 13 had amnestic MCI that progressed to AD dementia (MCI-DEM) and 17 had AD dementia at both timepoints (DEM-DEM). Plasma NDEVs were isolated by immunoaffinity capture targeting the neuronal markers L1CAM, GAP43, and NLGN3. In both plasma and NDEVs, we assessed ATN biomarkers (Aß42, Aß40, total Tau, P181-Tau) alongside several other exploratory markers. Results: The Aß42/Aß40 ratio in plasma and NDEVs was lower in MCI-DEM than NRM-NRM at baseline and its levels in NDEVs decreased over time in all three groups. Similarly, plasma and NDEV-associated Aß42 was lower in MCI-DEM compared to NRM-NRM at baseline and its levels in plasma decreased over time in DEM-DEM. For NDEV-associated proBDNF, compared to NRM-NRM, its levels were lower in MCI-DEM and DEM-DEM at baseline, and they decreased over time in the latter group. No group differences were found for other exploratory markers. NDEV-associated Aß42/Aß40 ratio and proBDNF achieved the highest areas under the curve (AUCs) for discriminating between diagnostic groups, while proBDNF was positively associated with Mini-Mental State Examination (MMSE) score. No associations were found between the two biofluids for any assessed marker. Discussion: The soluble phase of plasma and plasma NDEVs demonstrate distinct biomarker profiles both at a single time point and longitudinally. The lack of association between plasma and NDEV measures indicates that the two types of biofluids demonstrate distinct biomarker signatures that may be attributable to being derived through different biological processes. NDEV-associated proBDNF may be a useful biomarker for AD diagnosis and monitoring.

Survey of organ-derived small extracellular vesicles and particles (sEVPs) to identify selective protein markers in mouse serum.

Extracellular vesicles and particles (EVPs) are secreted by organs across the body into different circulatory systems, including the bloodstream, and reflect pathophysiologic conditions of the organ. However, the heterogeneity of EVPs in the blood makes it challenging to determine their organ of origin. We hypothesized that small (s)EVPs (<100 nm in diameter) in the bloodstream carry distinctive protein signatures associated with each originating organ, and we investigated this possibility by studying the proteomes of sEVPs produced by six major organs (brain, liver, lung, heart, kidney, fat). We found that each organ contained distinctive sEVP proteins: 68 proteins were preferentially found in brain sEVPs, 194 in liver, 39 in lung, 15 in heart, 29 in kidney, and 33 in fat. Furthermore, we isolated sEVPs from blood and validated the presence of sEVP proteins associated with the brain (DPP6, SYT1, DNM1L), liver (FABPL, ARG1, ASGR1/2), lung (SFPTA1), heart (CPT1B), kidney (SLC31), and fat (GDN). We further discovered altered levels of these proteins in serum sEVPs prepared from old mice compared to young mice. In sum, we have cataloged sEVP proteins that can serve as potential biomarkers for organ identification in serum and show differential expression with age.

Drosophila melanogaster as a Translational Model System to Explore the Impact of Phytochemicals on Human Health.

Fruits, vegetables, and spices are natural sources of bioactive phytochemicals, such as polyphenols, carotenoids, flavonoids, curcuminoids, terpenoids, and capsaicinoids, possessing multiple health benefits and relatively low toxicity. These compounds found in the diet play a central role in organism development and fitness. Given the complexity of the whole-body response to dietary changes, invertebrate model organisms can be valuable tools to examine the interplay between genes, signaling pathways, and metabolism. Drosophila melanogaster, an invertebrate model with its extensively studied genome, has more than 70% gene homology to humans and has been used as a model system in biological studies for a long time. The notable advantages of Drosophila as a model system, such as their low maintenance cost, high reproductive rate, short generation time and lifespan, and the high similarity of metabolic pathways between Drosophila and mammals, have encouraged the use of Drosophila in the context of screening and evaluating the impact of phytochemicals present in the diet. Here, we review the benefits of Drosophila as a model system for use in the study of phytochemical ingestion and describe the previously reported effects of phytochemical consumption in Drosophila.

Neuron-derived extracellular vesicles in blood reveal effects of exercise in Alzheimer's disease.

BACKGROUND: Neuron-derived extracellular vesicles (NDEVs) in blood may be used to derive biomarkers for the effects of exercise in Alzheimer's disease (AD). For this purpose, we studied changes in neuroprotective proteins proBDNF, BDNF, and humanin in plasma NDEVs from patients with mild to moderate AD participating in the randomized controlled trial (RCT) of exercise ADEX. METHODS: proBDNF, BDNF, and humanin were quantified in NDEVs immunocaptured from the plasma of 95 ADEX participants, randomized into exercise and control groups, and collected at baseline and 16 weeks. Exploratorily, we also quantified NDEV levels of putative exerkines known to respond to exercise in peripheral tissues. RESULTS: NDEV levels of proBDNF, BDNF, and humanin increased in the exercise group, especially in APOE ε4 carriers, but remained unchanged in the control group. Inter-correlations between NDEV biomarkers observed at baseline were maintained after exercise. NDEV levels of putative exerkines remained unchanged. CONCLUSIONS: Findings suggest that the cognitive benefits of exercise could be mediated by the upregulation of neuroprotective factors in NDEVs. Additionally, our results indicate that AD subjects carrying APOE ε4 are more responsive to the neuroprotective effects of physical activity. Unchanged NDEV levels of putative exerkines after physical activity imply that exercise engages different pathways in neurons and peripheral tissues. Future studies should aim to expand upon the effects of exercise duration, intensity, and type in NDEVs from patients with early AD and additional neurodegenerative disorders. TRIAL REGISTRATION: The Effect of Physical Exercise in Alzheimer Patients (ADEX) was registered in ClinicalTrials.gov on April 30, 2012 with the identifier NCT01681602.

QTL and PACE analyses identify candidate genes for anthracnose resistance in tomato.

Anthracnose, caused by the fungal pathogen Colletotrichum spp., is one of the most significant tomato diseases in the United States and worldwide. No commercial cultivars with anthracnose resistance are available, limiting resistant breeding. Cultivars with genetic resistance would significantly reduce crop losses, reduce the use of fungicides, and lessen the risks associated with chemical application. A recombinant inbred line (RIL) mapping population (N=243) has been made from a cross between the susceptible US28 cultivar and the resistant but semiwild and small-fruited 95L368 to identify quantitative trait loci (QTLs) associated with anthracnose resistance. The RIL population was phenotyped for resistance by inoculating ripe field-harvested tomato fruits with Colletotrichum coccodes for two seasons. In this study, we identified twenty QTLs underlying resistance, with a range of phenotypic variance of 4.5 to 17.2% using a skeletal linkage map and a GWAS. In addition, a QTLseq analysis was performed using deep sequencing of extreme bulks that validated QTL positions identified using traditional mapping and resolved candidate genes underlying various QTLs. We further validated AP2-like ethylene-responsive transcription factor, N-alpha-acetyltransferase (NatA), cytochrome P450, amidase family protein, tetratricopeptide repeat, bHLH transcription factor, and disease resistance protein RGA2-like using PCR allelic competitive extension (PACE) genotyping. PACE assays developed in this study will enable high-throughput screening for use in anthracnose resistance breeding in tomato.

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in murine Alzheimer's disease.

Background: Cognitive decline in Alzheimer's disease (AD) is associated with prion-like tau propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EV). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that tau expression triggers an elevation in brain ceramides and nSMase2 activity. Methods: To determine the therapeutic benefit of inhibiting this elevation, we evaluated the efficacy of PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor, in the PS19 tau transgenic AD murine model. Changes in brain ceramide and sphingomyelin levels, Tau content, histopathology, and nSMase2 target engagement were monitored, as well as changes in the number of brain-derived EVs in plasma and their Tau content. Additionally, we evaluated the ability of PDDC to impede tau propagation in a murine model where an adeno-associated virus(AAV) encoding for P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus and the contralateral transfer to the dentate gyrus was monitored. Results: Similar to human AD, PS19 mice exhibited increased brain ceramides and nSMase2 activity; both were completely normalized by PDDC treatment. PS19 mice exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all pathologic features of human AD. PDDC treatment significantly attenuated these aberrant changes. Mouse plasma isolated from PDDC-treated PS19 mice exhibited reduced levels of neuron- and microglia-derived EVs, the former carrying lower phosphorylated Tau(pTau) levels, compared to untreated mice. In the AAV tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly decreased tau spreading to the contralateral side. Conclusions: PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity leading to the slowing of tau spread in AD mice.