Making predictions under interventions: a case study from the PREDICT-CVD cohort in New Zealand primary care.

Background: Most existing clinical prediction models do not allow predictions under interventions. Such predictions allow predicted risk under different proposed strategies to be compared and are therefore useful to support clinical decision making. We aimed to compare methodological approaches for predicting individual level cardiovascular risk under three interventions: smoking cessation, reducing blood pressure, and reducing cholesterol. Methods: We used data from the PREDICT prospective cohort study in New Zealand to calculate cardiovascular risk in a primary care setting. We compared three strategies to estimate absolute risk under intervention: (a) conditioning on hypothetical interventions in non-causal models; (b) combining existing prediction models with causal effects estimated using observational causal inference methods; and (c) combining existing prediction models with causal effects reported in published literature. Results: The median absolute cardiovascular risk among smokers was 3.9%; our approaches predicted that smoking cessation reduced this to a median between a non-causal estimate of 2.5% and a causal estimate of 2.8%, depending on estimation methods. For reducing blood pressure, the proposed approaches estimated a reduction of absolute risk from a median of 4.9% to a median between 3.2% and 4.5% (both derived from causal estimation). Reducing cholesterol was estimated to reduce median absolute risk from 3.1% to between 2.2% (non-causal estimate) and 2.8% (causal estimate). Conclusions: Estimated absolute risk reductions based on non-causal methods were different to those based on causal methods, and there was substantial variation in estimates within the causal methods. Researchers wishing to estimate risk under intervention should be explicit about their causal modelling assumptions and conduct sensitivity analysis by considering a range of possible approaches.

Influence of highly effective modulator therapy on the sputum proteome in cystic fibrosis.

BACKGROUND: There have been dramatic clinical improvements in people with cystic fibrosis (PwCF) commenced on the cystic fibrosis conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI). Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms. Using this technique, we evaluated how ETI changes the sputum proteome in PwCF. METHODS: Sputum samples from 21 CF subjects pre- and post- ETI, 6 CF controls ineligible for ETI, and 15 healthy controls were analysed by liquid chromatography mass spectrometry. RESULTS: Post-ETI, mean FEV1 % increased by 13.7 % (SD 7.9). Principal component and hierarchical clustering analysis revealed that the post-ETI proteome shifted to an intermediate state that was distinct from pre-ETI and healthy controls, even for those achieving normal lung function. Functional analysis showed incomplete resolution of neutrophilic inflammation. The CF control sputum proteome did not alter. At the protein-level many more proteins increased in abundance than decreased following ETI therapy (80 vs 30; adjusted p value <0.05), including many that have anti-inflammatory properties. Of those proteins that reduced in abundance many were pro-inflammatory neutrophil-derived proteins. Several important respiratory proteases were unchanged. CONCLUSIONS: Sputum proteomics can provide insights into CF lung disease mechanisms and how they are modified by therapeutic intervention, in this case ETI. This study identifies imbalances in pro- and anti- inflammatory proteins in sputum that partially resolve with ETI even in those achieving normal spirometry values. This post-ETI intermediate state could contribute to ongoing airway damage and therefore its relevance to clinical outcomes needs to be established.

Integration of Metabolomics and Transcriptomics to Explore Dynamic Alterations in Fruit Color and Quality in 'Comte de Paris' Pineapples during Ripening Processes.

Pineapple color yellowing and quality promotion gradually manifest as pineapple fruit ripening progresses. To understand the molecular mechanism underlying yellowing in pineapples during ripening, coupled with alterations in fruit quality, comprehensive metabolome and transcriptome investigations were carried out. These investigations were conducted using pulp samples collected at three distinct stages of maturity: young fruit (YF), mature fruit (MF), and fully mature fruit (FMF). This study revealed a noteworthy increase in the levels of total phenols and flavones, coupled with a concurrent decline in lignin and total acid contents as the fruit transitioned from YF to FMF. Furthermore, the analysis yielded 167 differentially accumulated metabolites (DAMs) and 2194 differentially expressed genes (DEGs). Integration analysis based on DAMs and DEGs revealed that the biosynthesis of plant secondary metabolites, particularly the flavonol, flavonoid, and phenypropanoid pathways, plays a pivotal role in fruit yellowing. Additionally, RNA-seq analysis showed that structural genes, such as FLS, FNS, F3H, DFR, ANR, and GST, in the flavonoid biosynthetic pathway were upregulated, whereas the COMT, CCR, and CAD genes involved in lignin metabolism were downregulated as fruit ripening progressed. APX as well as PPO, and ACO genes related to the organic acid accumulations were upregulated and downregulated, respectively. Importantly, a comprehensive regulatory network encompassing genes that contribute to the metabolism of flavones, flavonols, lignin, and organic acids was proposed. This network sheds light on the intricate processes that underlie fruit yellowing and quality alterations. These findings enhance our understanding of the regulatory pathways governing pineapple ripening and offer valuable scientific insight into the molecular breeding of pineapples.

Physiological and transcriptomic analysis of IAA-induced antioxidant defense and cell wall metabolism in postharvest mango fruit.

Mango fruit tend to oxidize and senescence rapidly after harvesting, significantly reducing their commercial value. This study investigated the effect of exogenous auxin indole-3-acetic acid (IAA) on fruit quality, antioxidant system, and cell wall metabolism of mango fruit during storage. The results showed that the 1.0 mM IAA treatment delayed weight loss and maintained the firmness, pH and contents of total soluble solids (TSS) and titratable acidity (TA) of the mango fruit. The 1.0 mM IAA treatment increased the peroxidase (POD) and phenylalanine ammonia-lyase (PAL) activities and the ascorbic acid (AsA) and total phenols (TP) contents but decreased the polyphenol oxidase (PPO) activity in postharvest mango fruit. Moreover, beta-galactosidase (ß-Gal) and polygalacturonase (PG) activities were increased, but the pectinesterase (PME) activity was decreased in the IAA-treated fruit. Transcriptome analysis showed that the differentially expressed genes (DEGs) in the IAA vs. control groups were mainly associated with oxidative stress responses, cell wall metabolism, and transcription factors (TFs). The IAA treatment upregulated the antioxidant-related genes (SOD, CAT1, PODs, GSTs, Prxs, and Trxs) and MYB TFs, and downregulated cell wall metabolism-related genes (PG, PME31 and two PME63) and 11 ethylene-responsive transcription factors (ERFs). These results suggested that exogenous IAA could improve the antioxidant system and maintain the storage quality of mango fruit by regulating gene expression and metabolic pathways. The results provide insights into the mechanisms involved in IAA-mediated delayed ripening and senescence of mango fruit.

Exogenous glutathione maintains the postharvest quality of mango fruit by modulating the ascorbate-glutathione cycle.

Background: Mango fruit is prone to decay after harvest and premature senescence, which significantly lowers its quality and commercial value. Methods: The mango fruit (Mangifera indica L.cv. Guixiang) was treated with 0 (control), 2, 5, and 8 mM of reduced glutathione (GSH) after harvest. The fruit was stored at 25 ± 1 °C for 12 days to observe the changes in the antioxidant capacity and postharvest quality. Results: Compared with the control, the 5 mM GSH treatment significantly decreased the weight loss by 44.0% and 24.4%, total soluble solids content by 25.1% and 4.5%, and soluble sugar content by 19.0% and 27.0%. Conversely, the 5 mM GSH treatment increased the firmness by 25.9% and 30.7% on days 4 and 8, respectively, and the titratable acidity content by 115.1% on day 8. Additionally, the 5 mM GSH treatment decreased the malondialdehyde and hydrogen peroxide contents and improved the antioxidant capacity of mango fruit by increasing the superoxide dismutase and peroxidase activities and upregulating the expression of the encoding genes. Meanwhile, the higher levels of monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase enzyme activities and gene expressions accelerated the AsA-GSH cycle, thereby increasing the accumulation of AsA and GSH and maintaining the redox balance. Conclusions: Overall, the experimental results suggest that 5 mM GSH maintains high antioxidant capacity and postharvest quality of mangoes and can use as an effective preservation technique for postharvest mangoes.

Study on the Structure and Bioactivity of Ganoderma lucidum Polysaccharides under Cassava Stalk Stress.

Various carbon sources affect the growth of the G. lucidum fruiting body, and the cassava stalk is considered a promising carbon source for G. lucidum. The composition, functional group characteristics, molecular weight distribution, antioxidant activity in vitro, and growth effect of L. rhamnosus LGG of G. lucidum polysaccharides (GLPs) under cassava stalk stress were investigated by gas chromatography-mass spectrometry, near-infrared spectroscopy, and gel chromatography. The results showed that GLPs consisted of D-glucose, D-galactose, and seven other monosaccharides. The end of the sugar chain had ß-D-Glc and ß-D-Gal configurations. The total sugar content in GLP1 was the highest (4.07%), and GLP1, GLP2, GLP3, and GLP5 had the ß-D-Gal configuration, while GLP4 and GLP6 had the ß-D-Glc configuration. The greater the proportion of cassava stalk, the greater the maximum molecular weight of GLPs. The total antioxidant capacities of GLPs obtained from different cassava stalks significantly varied, as well as their stimulating effects on the L. rhamnosus LGG growth. Higher concentrations of GLPs corresponded to the more intensive growth of L. rhamnosus LGG. This study provided essential data support for cassava stalk as a carbon source in G. lucidum cultivation.

Study of the Metabolite Changes in Ganoderma lucidum under Pineapple Leaf Residue Stress via LC-MS/MS Coupled with a Non-Targeted Metabolomics Approach.

The effects of fermentation metabolites of G. lucidum under different pineapple leaf residue additions were separated and identified using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The mass spectra showed that the metabolites had good response values only in the positive ion mode, and 3019 metabolites with significant differences, mainly distributed in 95 metabolic pathways, were identified. The multivariate analyses, including the principal component analysis (PCA), orthogonal least squares discriminant analysis (OPLS-DA), and volcano plots (VP), revealed that the G. lucidum metabolites exhibited significant differences (p < 0.05) and were well clustered under various pineapple leaf residue additions, featuring 494-545 upregulated and 998-1043 downregulated metabolites. The differential metabolic pathway analysis proved that two metabolic pathways related to the biosynthesis of amino acids and ABC transporters were particularly significant under the addition of pineapple leaf residue, where amino acids such as histidine and lysine were upregulated in contrast to downregulated tyrosine, valine, L-alanine, and L-asparagine. These study results are considered instrumental in substantiating the application of pineapple leaf residue in the cultivation of G. lucidum and improving its utilization rate and added value.

Effects of Three Extraction Methods on Avocado Oil Lipid Compounds Analyzed via UPLC-TOF-MS/MS with OPLS-DA.

Avocado oil is excellent functional oil. Effects of three extraction methods (squeezing extraction, supercritical carbon dioxide extraction, and aqueous extraction) on the species, composition, and contents of lipids in avocado oil were analyzed via ultra-performance liquid chromatography-time-of-flight tandem mass spectrometry (UPLC-TOF-MS/MS), and the differential components of lipids were revealed by OrthogonalPartialLeast Squares-DiscriminantAnalysis (OPLS-DA), S-plot combined with variable importance in the projection (VIP). The results showed that the fatty acid composition of avocado oil mainly consisted of oleic acid (36-42%), palmitic acid (25-26%), linoleic acid (14-18%), and palmitoleic acid (10-12%). A total of 134 lipids were identified first from avocado oil, including 122 glycerides and 12 phospholipids, and the total number of carbon atoms contained in the fatty acid side chains of the lipids was 32-68, and the number of double bonds was 0-9. Forty-eight differential lipid compounds with significant effects of the three extraction methods on the lipid composition of avocado oil were excavated, among which the differences in triglycerides (TG), phosphatidylethanol (PEtOH), and phosphatidylmethanol (PMeOH) contents were highly significant, which provided basic data to support the subsequent guidance of avocado oil processing, quality evaluation, and functional studies.

Analysis of Physicochemical Properties, Lipid Composition, and Oxidative Stability of Cashew Nut Kernel Oil.

Cashew nut kernel oil (CNKO) is an important oil source from tropical crops. The lipid species, composition, and relative content of CNKO were revealed using ultra high performance liquid chromatography time-of-flight tandem mass spectrometry (UPLC-TOF-MS/MS), and the physicochemical properties, functional group structure, and oxidation stability of CNKO at different pressing temperatures were characterized using a near infrared analyzer and other methods. The results showed that CNKO mainly consisted of oleic acid (60.87 ± 0.06%), linoleic acid (17.33 ± 0.28%), stearic acid (10.93 ± 0.31%), and palmitic acid (9.85 ± 0.04%), and a highly unsaturated fatty acid (78.46 ± 0.35%). In addition, 141 lipids, including 102 glycerides and 39 phospholipids, were identified in CNKO. The pressing temperature had a significant effect on the physicochemical properties of cashew kernels, such as acid value, iodine value, and peroxide value, but the change in value was small. The increase in pressing temperature did not lead to changes in the functional group structure of CNKO, but decreased the induction time of CNKO, resulting in a decrease in their oxidative stability. It provided basic data support to guide subsequent cashew kernel processing, quality evaluation, and functional studies.

[Response of Topsoil Fungal Community Structure to Soil Improvement Measures in Degraded Forest of Red Soil Region].

Soil fungal community structure and diversity are highly sensitive to variations in the external environment, as well as soil improvement measures. In order to clarify the effects of soil improvement measures on topsoil fertility or quality, a field experiment was conducted in eroded forest of a red soil region. Organic fertilizer, biochar, and lime+microbial fertilizer were added to the topsoil, respectively. After four years, the chemistry properties and nutrients in the topsoil were measured, and the diversity and composition of fungi were analyzed. The results showed that the additions of organic fertilizer, biochar, and lime+microbial fertilizer reduced fungal richness in topsoil, compared to that with no fertilizer addition (CK). Among them, lime+microbial fertilizer had the most negative effect on fungal richness. The three soil improvement measures also affected the diversity of topsoil fungi, but the impacts were not significant. The dominant fungal phyla in the topsoil were Ascomycota (31.29%-46.55%) and Basidiomycota (30.07%-70.71%), and the dominant fungal genera were Amphinema and Archaeorhizomyces. The effects of soil improvement measures on fungal community structure in the topsoil were different; organic fertilizer increased the relative abundance of Ascomycetes and Archaeopteroides, and biochar enhanced the relative abundance of Basidiomycetes and Archaeopteroides, whereas lime+microbial fertilizer improved the relative abundance of Basidiomycetes and Archaeopteroides. Fungal diversity and community structure in the topsoil was affected by edaphic factors, and fungal richness was regulated by pH value, whereas fungal community structure was influenced by pH, total nitrogen, and organic carbon. This study provides scientific guidance for soil improvement and ecological restoration below the canopy in eroded forests of red soil regions.

Analysis of Lipids in Pitaya Seed Oil by Ultra-Performance Liquid Chromatography-Time-of-Flight Tandem Mass Spectrometry.

Red pitaya (Hylocereus undatus) is an essential tropical fruit in China. To make more rational use of its processing, byproducts and fruit seeds, and the type, composition, and relative content of lipids in pitaya seed oil were analyzed by UPLC-TOF-MS/MS. The results showed that the main fatty acids in pitaya seed oil were linoleic acid 42.78%, oleic acid 27.29%, and palmitic acid 16.66%. The ratio of saturated fatty acids to unsaturated fatty acids to polyunsaturated fatty acids was close to 1:1.32:1.75. The mass spectrum behavior and fracture mechanism of four lipid components, TG 54:5|TG 18:1_18:2_18:2, were analyzed. In addition, lipids are an essential indicator for evaluating the quality of oils and fats, and 152 lipids were isolated and identified from pitaya seed oil for the first time, including 136 glycerides and 16 phospholipids. The main components of glyceride and phospholipids were triglycerides and phosphatidyl ethanol, providing essential data support for pitaya seed processing and functional product development.

Analysis of Lipids in Green Coffee by Ultra-Performance Liquid Chromatography-Time-of-Flight Tandem Mass Spectrometry.

Lipid components in green coffee were clarified to provide essential data support for green coffee processing. The types, components, and relative contents of lipids in green coffee were first analyzed by ultra-performance liquid chromatography-time-of-flight tandem mass spectrometry (UPLC-TOF-MS/MS). The results showed that the main fatty acids in green coffee were linoleic acid (43.39%), palmitic acid (36.57%), oleic acid (8.22%), and stearic acid (7.37%). Proportionally, the ratio of saturated fatty acids/unsaturated fatty acids/polyunsaturated fatty acids was close to 5.5:1:5.2. A total of 214 lipids were identified, including 15 sterols, 39 sphingosines, 12 free fatty acids, 127 glycerides, and 21 phospholipids. The main components of sterols, sphingosines, free fatty acids, glycerides, and phospholipids were acylhexosyl sitosterol, ceramide esterified omega-hydroxy fatty acid sphingosine, linoleic acid, and triglyceride, respectively. UPLC-TOF-MS/MS furnished high-quality and accurate information on TOF MS and TOF MS/MS spectra, providing a reliable analytical technology platform for analyzing lipid components in green coffee.

A systems immunology approach to investigate cytokine responses to viruses and bacteria and their association with disease.

Patterns of human immune responses to viruses and bacteria and how this impacts risk of infections or onset/exacerbation of chronic respiratory diseases are poorly understood. In a population-based birth cohort, we measured peripheral blood mononuclear cell responses (28 cytokines) to respiratory viruses and bacteria, Toll-like receptor ligands and phytohemagglutinin, in 307 children. Cytokine responses were highly variable with > 1000-fold differences between children. Machine learning revealed clear distinction between virus-associated and bacteria-associated stimuli. Cytokines clustered into three functional groups (anti-viral, pro-inflammatory and T-cell derived). To investigate mechanisms potentially explaining such variable responses, we investigated cytokine Quantitative Trait Loci (cQTLs) of IL-6 responses to bacteria and identified nine (eight novel) loci. Our integrative approach describing stimuli, cytokines and children as variables revealed robust immunologically and microbiologically plausible clustering, providing a framework for a greater understanding of host-responses to infection, including novel genetic associations with respiratory disease.

Liraglutide reduces oxidative stress and improves energy metabolism in methylglyoxal-induced SH-SY5Y cells.

Diabetes mellitus can result in severe complications, such as neurodegenerative diseases including cognitive impairment and dementia. The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, is a novel antidiabetic drug with neuroprotective effects against neurodegenerative diseases. In this study, we explored the protective effect of liraglutide on SH-SY5Y cells exposed to methylglyoxal (MG), a byproduct of glucose metabolism that plays a key role in the development of diabetic encephalopathy. We found that liraglutide reduced the MG-induced oxidative stress, increased the activity of superoxide dismutase (SOD) and expression levels of P22phox, Gp91phox, and Xdh genes, and reduced reactive oxygen species (ROS) content. Metabolomics analysis based on 1H nuclear magnetic resonance showed that liraglutide induced alterations in metabolites involved in energy metabolism，including promotion of gluconeogenesis. Moreover, we found that liraglutide promoted oxidative phosphorylation and inhibited glycolysis in SH-SY5Y cells. This study revealed that liraglutide improved diabetes-related neuropathy damage by reducing the level of oxidative stress and maintaining the balance of energy metabolism, thus offering new insights into the potential mechanism of liraglutide in neuronal protection.

In vivo bronchial epithelial interferon responses are augmented in asthma on day 4 following experimental rhinovirus infection.

Despite good evidence of impaired innate antiviral responses in asthma, trials of inhaled interferon-ß given during exacerbations showed only modest benefits in moderate/severe asthma. Using human experimental rhinovirus infection, we observe robust in vivo induction of bronchial epithelial interferon response genes 4 days after virus inoculation in 25 subjects with asthma but not 11 control subjects. This signature correlated with virus loads and lower respiratory symptoms. Our data indicate that the in vivo innate antiviral response is dysregulated in asthma and open up the potential that prophylactic rather than therapeutic interferon therapy may have greater clinical benefit.

Biosynthesis and Metabolism of Garlic Odor Compounds in Cultivated Chinese Chives (Allium tuberosum) and Wild Chinese Chives (Allium hookeri).

Chinese chives is a popular herb vegetable and medicine in Asian countries. Southwest China is one of the centers of origin, and the mountainous areas in this region are rich in wild germplasm. In this study, we collected four samples of germplasm from different altitudes: a land race of cultivated Chinese chives (Allium tuberosum), wide-leaf chives and extra-wide-leaf chives (Allium hookeri), and ovoid-leaf chives (Allium funckiaefolium). Leaf metabolites were detected and compared between A. tuberosum and A. hookeri. A total of 158 differentially accumulated metabolites (DAM) were identified by Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography-Mass Spectrometry (LC-MS), among which there was a wide range of garlic odor compounds, free amino acids, and sugars. A. hookeri contains a higher content of fructose, garlic odor compounds, and amino acids than A. tuberosum, which is supported by the higher expression level of biosynthetic genes revealed by transcriptome analysis. A. hookeri accumulates the same garlic odor compound precursors that A. tuberosum does (mainly methiin and alliin). We isolated full-length gene sequences of phytochelatin synthase (PCS), γ-glutamyltranspeptidases (GGT), flavin-containing monooxygenase (FMO), and alliinase (ALN). These sequences showed closer relations in phylogenetic analysis between A. hookeri and A. tuberosum (with sequence identities ranging from 86% to 90%) than with Allium cepa or Allium sativum (which had a lower sequence identity ranging from 76% to 88%). Among these assayed genes, ALN, the critical gene controlling the conversion of odorless precursors into odor compounds, was undetected in leaves, bulbs, and roots of A. tuberosum, which could account for its weaker garlic smell. Moreover, we identified a distinct FMO1 gene in extra-wide-leaf A. hookeri that is due to a CDS-deletion and frameshift mutation. These results above reveal the molecular and metabolomic basis of impressive strong odor in wild Chinese chives.

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer's disease.

Perivascular spaces (PVS) drain brain waste metabolites, but their specific flow paths are debated. Meningeal pia mater reportedly forms the outermost boundary that confines flow around blood vessels. Yet, we show that pia is perforated and permissive to PVS fluid flow. Furthermore, we demonstrate that pia is comprised of vascular and cerebral layers that coalesce in variable patterns along leptomeningeal arteries, often merging around penetrating arterioles. Heterogeneous pial architectures form variable sieve-like structures that differentially influence cerebrospinal fluid (CSF) transport along PVS. The degree of pial coverage correlates with macrophage density and phagocytosis of CSF tracer. In vivo imaging confirms transpial influx of CSF tracer, suggesting a role of pia in CSF filtration, but not flow restriction. Additionally, pial layers atrophy with age. Old mice also exhibit areas of pial denudation that are not observed in young animals, but pia is unexpectedly hypertrophied in a mouse model of Alzheimer's disease. Moreover, pial thickness correlates with improved CSF flow and reduced ß-amyloid deposits in PVS of old mice. We show that PVS morphology in mice is variable and that the structure and function of pia suggests a previously unrecognized role in regulating CSF transport and amyloid clearance in aging and disease.

Molecular characterization of fast-growing melanomas.

BACKGROUND: The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM) and the potential to stratify patients at high risk of death has not been comprehensively studied. OBJECTIVE: To investigate the epidemiologic, clinical, and mutational profile of primary cutaneous melanomas with a thickness ≥ 1 mm, stratified by rate of growth. METHODS: Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin-embedded primary melanoma samples. Comparison of FGMM (rate of growth > 0.5 mm/month) and nonFGMM (rate of growth ≤ 0.5 mm/month). RESULTS: Two hundred patients were enrolled, among wom 70 had FGMM. The relapse-free survival was lower in the FGMM group (P = .014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than nonFGMM (P = .033). Ulceration (P = .032), thickness (P = .006), lower sun exposure (P = .049), and fibroblast growth factor receptor 2 (FGFR2) mutations (P = .037) were significantly associated with fast growth. LIMITATIONS: Single-center study, cohort size, potential memory bias, number of investigated genes. CONCLUSION: Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness, and FGFR2 mutations are associated with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM, which are probably good candidates for adjuvant therapies.

Structural and Functional Abnormalities of Olfactory-Related Regions in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease.

BACKGROUND: Odor identification (OI) dysfunction is an early marker of Alzheimer's disease (AD), but it remains unclear how olfactory-related regions change from stages of subjective cognitive decline (SCD) and mild cognitive impairment (MCI) to AD dementia. METHODS: Two hundred and sixty-nine individuals were recruited in the present study. The olfactory-related regions were defined as the regions of interest, and the grey matter volume (GMV), low-frequency fluctuation, regional homogeneity (ReHo), and functional connectivity (FC) were compared for exploring the changing pattern of structural and functional abnormalities across AD, MCI, SCD, and normal controls. RESULTS: From the SCD, MCI to AD groups, the reduced GMV, increased low-frequency fluctuation, increased ReHo, and reduced FC of olfactory-related regions became increasingly severe, and only the degree of reduced GMV of hippocampus and caudate nucleus clearly distinguished the 3 groups. SCD participants exhibited reduced GMV (hippocampus, etc.), increased ReHo (caudate nucleus), and reduced FC (hippocampus-hippocampus and hippocampus-parahippocampus) in olfactory-related regions compared with normal controls. Additionally, reduced GMV of the bilateral hippocampus and increased ReHo of the right caudate nucleus were associated with OI dysfunction and global cognitive impairment, and they exhibited partially mediated effects on the relationships between OI and global cognition across all participants. CONCLUSION: Structural and functional abnormalities of olfactory-related regions present early with SCD and deepen with disease severity in the AD spectrum. The hippocampus and caudate nucleus may be the hub joining OI and cognitive function in the AD spectrum.

Sex differences in innate anti-viral immune responses to respiratory viruses and in their clinical outcomes in a birth cohort study.

The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34-2.06-fold lower in males than females (P = 0.018 - < 0.001). IFN-ß, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy (P = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.