Associations of CAIDE Dementia Risk Score with MRI, PIB-PET measures, and cognition

Background: CAIDE Dementia Risk Score is the first validated tool for estimating dementia risk based on a midlife risk profile. Objectives: This observational study investigated longitudinal associations of CAIDE Dementia Risk Score with brain MRI, amyloid burden evaluated with PIB-PET, and detailed cognition measures. Methods: FINGER participants were at-risk elderly without dementia. CAIDE Risk Score was calculated using data from previous national surveys (mean age 52.4 years). In connection to baseline FINGER visit (on average 17.6 years later, mean age 70.1 years), 132 participants underwent MRI scans, and 48 underwent PIB-PET scans. All 1,260 participants were cognitively assessed (Neuropsychological Test Battery, NTB). Neuroimaging assessments included brain cortical thickness and volumes (Freesurfer 5.0.3), visually rated medial temporal atrophy (MTA), white matter lesions (WML), and amyloid accumulation. Results: Higher CAIDE Dementia Risk Score was related to more pronounced deep WML (OR 1.22, 95% CI 1.05-1.43), lower total gray matter (beta- coefficient -0.29, p = 0.001) and hippocampal volume (beta- coefficient -0.28, p = 0.003), lower cortical thickness (beta-coefficient -0.19, p = 0.042), and poorer cognition (beta-coefficients -0.31 for total NTB score, -0.25 for executive functioning, -0.33 for processing speed, and -0.20 for memory, all p <0.001). Higher CAIDE Dementia Risk Score including APOE genotype was additionally related to more pronounced MTA (OR 1.15,95% CI 1.00-1.30). No associations were found with periventricular WML or amyloid accumulation. Conclusions: The CAIDE Dementia Risk Score was related to indicators of cerebrovascular changes and neurodegeneration on MRI, and cognition. The lack of association with brain amyloid accumulation needs to be verified in studies with larger sample sizes.Peer reviewe

Pretargeted PET Imaging of trans-Cyclooctene-Modified Porous Silicon Nanoparticles

Pretargeted positron emission tomography (PET) imaging based on bioorthogonal chemical reactions has proven its potential in immunoimaging. It may also have great potential in nanotheranostic applications. Here, we report the first successful pretargeted PET imaging of trans-cyclooctene-modified mesoporous silicon nanoparticles, using F-18-labeled tetrazine as a tracer. The inverse electron-demand Diels-Alder cycloaddition (IEDDA) reaction was fast, resulting in high radioactivity accumulation in the expected organs within 10 min after the administration of the tracer. The highest target-to-background ratio was achieved 120 min after the tracer injection. A clear correlation between the efficiency of the in vivo IEDDA labeling reaction and the injected amount of the tracer was observed. The radioactivity accumulation decreased with the increased amount of the co-injected carrier, indicating saturation in the reaction sites. This finding was supported by the in vitro results. Our study suggests that pretargeted imaging has excellent potential in nanotheranostic PET imaging when using high-specific-activity tracers

Methyl jasmonate-elicited herbivore resistance: does MeJA function as a signal without being hydrolyzed to JA?

Treatment with methyl jasmonate (MeJA) elicits herbivore resistance in many plant species and over-expression of JA carboxyl methyltransferase (JMT) constitutively increases JA-induced responses in Arabidopsis. When wild-type (WT) Nicotiana attenuata plants are treated with MeJA, a rapid transient endogenous JA burst is elicited, which in turn increases levels of nicotine and trypsin proteinase inhibitors (TPIs) and resistance to larvae of the specialist herbivore, Manduca sexta. All of these responses are impaired in plants silenced in lipoxygenase 3 expression (asLOX3) but are restored to WT levels by MeJA treatment. Whether these MeJA-induced responses are directly elicited by MeJA or by its cleavage product, JA, is unknown. Using virus-induced gene silencing (VIGS), we silenced MeJA-esterase (NaMJE) expression and found this gene responsible for most of the MeJA-cleaving activity in N. attenuata protein extracts. Silencing NaMJE in asLOX3, but not in WT plants, significantly reduced MeJA-induced nicotine levels and resistance to M. sexta, but not TPI levels. MeJA-induced transcript levels of threonine deaminase (NaTD) and phenylalanine ammonia lyase (NaPAL1) were also decreased in VIGS MJE (asLOX3) plants. Finally the performance of M. sexta larvae that fed on plants treated with JA or MeJA demonstrated that silencing NaMJE inhibited MeJA-induced but not JA-induced resistance in asLOX3 plants. From these results, we conclude that the resistance elicited by MeJA treatment is directly elicited not by MeJA but by its de-methylated product, JA

Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts

Aims/hypothesis Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case−control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24–45 years). Associations between baseline metabolites and risk of developing diabetes during 8–15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59–1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31–1.33) and triacylglycerol within VLDL particles (OR 1.33–1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). Conclusions/interpretation Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk

Coordinated Multiwavelength Observations of BL Lacertae in 2000

BL Lacertae was the target of an extensive multiwavelength monitoring campaign in the second half of 2000. Simultaneous or quasi-simultaneous observations were taken at radio (UMRAO and Metsaehovi) and optical(WEBT collaboration) frequencies, in X-rays (BeppoSAX and RXTE), and at VHE gamma-rays (HEGRA). The WEBT optical campaign achieved an unprecedented time coverage, virtually continuous over several 10 - 20 hour segments. It revealed intraday variability on time scales of ~ 1.5 hours and evidence for spectral hardening associated with increasing optical flux. During the campaign, BL Lacertae underwent a major transition from a rather quiescent state prior to September 2000, to a flaring state for the rest of the year. This was also evident in the X-ray activity of the source. BeppoSAX observations on July 26/27 revealed a rather low X-ray flux and a hard spectrum, while a BeppoSAX pointing on Oct. 31 - Nov. 2, 2000, indicated significant variability on time scales of < a few hours, and provided evidence for the synchrotron spectrum extending out to ~ 10 keV during that time. During the July 26/27 observation, there is a tantalizing, though not statistically significant, indication of a time delay of ~ 4 - 5 hr between the BeppoSAX and the R-band light curve. Also, a low-significance detection of a time delay of 15 d between the 14.5 GHz and the 22 GHz radio light curves is reported. Several independent methods to estimate the co-moving magnetic field in the source are presented, suggesting a value of ~ 2 e_B^{2/7} G, where e_B is the magnetic-field equipartition factor w.r.t. the electron energy density in the jet.Comment: Accepted for publication in Ap

Young, healthy males and females present cardiometabolic protection against the detrimental effects of a 7-day high-fat high-calorie diet

Purpose: High-fat, high-calorie (HFHC) diets have been used as a model to investigate lipid-induced insulin resistance. Short-term HFHC diets reduce insulin sensitivity in young healthy males, but to date, no study has directly compared males and females to elucidate sex-specific differences in the effects of a HFHC diet on functional metabolic and cardiovascular outcomes. Methods: Eleven males (24 ± 4 years; BMI 23 ± 2 kg.m−2; V̇O2 peak 62.3 ± 8.7 ml.min−1.kg−1FFM) were matched to 10 females (25 ± 4 years; BMI 23 ± 2 kg.m−2; V̇O2 peak 58.2 ± 8.2 ml.min−1.kg−1FFM). Insulin sensitivity, measured via oral glucose tolerance test, metabolic flexibility, arterial stiffness, body composition and blood lipids and liver enzymes were measured before and after 7 days of a high-fat (65% energy) high-calorie (+ 50% kcal) diet. Results: The HFHC diet did not change measures of insulin sensitivity, metabolic flexibility or arterial stiffness in either sex. There was a trend towards increased total body fat mass (kg) after the HFHC diet (+ 1.8% and + 2.3% for males and females, respectively; P = 0.056). In contrast to females, males had a significant increase in trunk to leg fat mass ratio (+ 5.1%; P = 0.005). Conclusion: Lean, healthy young males and females appear to be protected from the negative cardio-metabolic effects of a 7-day HFHC diet. Future research should use a prolonged positive energy balance achieved via increased energy intake and reduced energy expenditure to exacerbate negative metabolic and cardiovascular functional outcomes to determine whether sex-specific differences exist under more metabolically challenging conditions

Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Correction to: Nature Communications https://doi.org/10.1038/s41467-020-19366-9, published online 5 January 2021. The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article

Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Correction to: Nature Communications https://doi.org/10.1038/s41467-020-19366-9, published online 5 January 2021. The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article

Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis

Background: Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis.Methods: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer).Results: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses.Conclusions: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.</p