Proteomic correlates of cortical thickness in cognitively normal individuals with normal and abnormal cerebrospinal fluid beta-amyloid1-42

Cortical atrophy is an early feature of Alzheimer´s disease (AD). The biological processes associated with variability in cortical thickness remain largely unknown. We studied 220 cerebrospinal fluid (CSF) proteins to evaluate biological pathways associated with cortical thickness in 34 brain regions in 79 cognitively normal older individuals with normal (>192 ng/L, n = 47), and abnormal (≤192 ng/L, n = 32) CSF beta-amyloid1-42 (Aβ42). Interactions for Aβ42 status were tested. Panther GeneOntology and Cytoscape ClueGO analyses were used to evaluate biological processes associated with regional cortical thickness. 170 (77.3 %) proteins related with cortical thickness in at least 1 brain region across the total group, and 171 (77.7 %) proteins showed Aβ42 specific associations. Higher levels of proteins related to axonal and synaptic integrity, amyloid accumulation, and inflammation were associated with thinner cortex in lateral temporal regions, the rostral anterior cingulum, the lateral occipital cortex and the pars opercularis only in the abnormal Aβ42 group. Alterations in CSF proteomics are associated with a regional cortical atrophy in the earliest stages of AD.</p

Competition between reverse water gas shift reaction and methanol synthesis from CO 2 : influence of copper particle size

Converting CO2 into value-added chemicals and fuels, such as methanol, is a promising approach to limit the environmental impact of human activities. Conventional methanol synthesis catalysts have shown limited efficiency and poor stability in a CO2/H2 mixture. To design improved catalysts, crucial for the effective utilization of CO2, an in-depth understanding of the active sites and reaction mechanism is desired. The catalytic performance of a series of carbon-supported Cu catalysts, with Cu particle sizes in the range of 5 to 20 nm, was evaluated under industrially relevant temperature and pressure, i.e. 260 °C and 40 bar(g). The CO2 hydrogenation reaction exhibited clear particle size effects up to 13 nm particles, with small nanoparticles having the lower activity, but higher methanol selectivity. MeOH and CO formation showed a different size-dependence. The TOFCO increased from 1.9 × 10−3 s−1 to 9.4 × 10−3 s−1 with Cu size increasing from 5 nm to 20 nm, while the TOFMeOH was size-independent (8.4 × 10−4 s−1 on average). The apparent activation energies for MeOH and CO formation were size-independent with values of 63 ± 7 kJ mol−1 and 118 ± 6 kJ mol−1, respectively. Hence the size dependence was ascribed to a decrease in the fraction of active sites suitable for CO formation with decreasing particle size. Theoretical models and DFT calculations showed that the origin of the particle size effect is most likely related to the differences in formate coverage for different Cu facets whose abundancy depends on particle size. Hence, the CO2 hydrogenation reaction is intrinsically sensitive to the Cu particle size

Interactions between visual and semantic processing during object recognition revealed by modulatory effects of age of acquisition

The age of acquisition (AoA) of objects and their names is a powerful determinant of processing speed in adulthood, with early-acquired objects being recognized and named faster than late-acquired objects. Previous research using fMRI (Ellis et al., 2006. Traces of vocabulary acquisition in the brain: evidence from covert object naming. NeuroImage 33, 958–968) found that AoA modulated the strength of BOLD responses in both occipital and left anterior temporal cortex during object naming. We used magnetoencephalography (MEG) to explore in more detail the nature of the influence of AoA on activity in those two regions. Covert object naming recruited a network within the left hemisphere that is familiar from previous research, including visual, left occipito-temporal, anterior temporal and inferior frontal regions. Region of interest (ROI) analyses found that occipital cortex generated a rapid evoked response (~ 75–200 ms at 0–40 Hz) that peaked at 95 ms but was not modulated by AoA. That response was followed by a complex of later occipital responses that extended from ~ 300 to 850 ms and were stronger to early- than late-acquired items from ~ 325 to 675 ms at 10–20 Hz in the induced rather than the evoked component. Left anterior temporal cortex showed an evoked response that occurred significantly later than the first occipital response (~ 100–400 ms at 0–10 Hz with a peak at 191 ms) and was stronger to early- than late-acquired items from ~ 100 to 300 ms at 2–12 Hz. A later anterior temporal response from ~ 550 to 1050 ms at 5–20 Hz was not modulated by AoA. The results indicate that the initial analysis of object forms in visual cortex is not influenced by AoA. A fastforward sweep of activation from occipital and left anterior temporal cortex then results in stronger activation of semantic representations for early- than late-acquired objects. Top-down re-activation of occipital cortex by semantic representations is then greater for early than late acquired objects resulting in delayed modulation of the visual response

Competition between reverse water gas shift reaction and methanol synthesis from CO2: influence of copper particle size

Converting CO2 into value-added chemicals and fuels, such as methanol, is a promising approach to limit the environmental impact of human activities. Conventional methanol synthesis catalysts have shown limited efficiency and poor stability in a CO2/H2 mixture. To design improved catalysts, crucial for the effective utilization of CO2, an in-depth understanding of the active sites and reaction mechanism is desired. The catalytic performance of a series of carbon-supported Cu catalysts, with Cu particle sizes in the range of 5 to 20 nm, was evaluated under industrially relevant temperature and pressure, i.e. 260 °C and 40 bar(g). The CO2 hydrogenation reaction exhibited clear particle size effects up to 13 nm particles, with small nanoparticles having the lower activity, but higher methanol selectivity. MeOH and CO formation showed a different size-dependence. The TOFCO increased from 1.9 × 10−3 s−1 to 9.4 × 10−3 s−1 with Cu size increasing from 5 nm to 20 nm, while the TOFMeOH was size-independent (8.4 × 10−4 s−1 on average). The apparent activation energies for MeOH and CO formation were size-independent with values of 63 ± 7 kJ mol−1 and 118 ± 6 kJ mol−1, respectively. Hence the size dependence was ascribed to a decrease in the fraction of active sites suitable for CO formation with decreasing particle size. Theoretical models and DFT calculations showed that the origin of the particle size effect is most likely related to the differences in formate coverage for different Cu facets whose abundancy depends on particle size. Hence, the CO2 hydrogenation reaction is intrinsically sensitive to the Cu particle size

Relationship of Adiposity and Insulin Resistance Mediated by Inflammation in a Group of Overweight and Obese Chilean Adolescents

The mild chronic inflammatory state associated with obesity may be an important link between adiposity and insulin resistance (IR). In a sample of 137 overweight and obese Chilean adolescents, we assessed associations between high-sensitivity C-reactive protein (hs-CRP), IR and adiposity; explored sex differences; and evaluated whether hs-CRP mediated the relationship between adiposity and IR. Positive relationships between hs-CRP, IR and 2 measures of adiposity were found. Hs-CRP was associated with waist circumference (WC) in boys and fat mass index (FMI) in girls. Using path analysis, we found that hs-CRP mediated the relationship between adiposity (WC and FMI) and the homeostatic model assessment of insulin resistance (HOMA-IR) (p < 0.05) in both sexes. Our novel finding is that inflammation statistically mediated the well described link between increased adiposity and IR

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Original COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters

Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.</p

CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis

Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNAdamage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G2-M checkpoint and proliferative signaling.Peer reviewe

Original COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters

Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.</p

Manganese Oxide as a Promoter for Copper Catalysts in CO2 and CO Hydrogenation

In this work, we discuss the role of manganese oxide as a promoter in Cu catalysts supported on graphitic carbon during hydrogenation of CO2 and CO. MnOx is a selectivity modifier in an H2/CO2 feed and is a highly effective activity promoter in an H2/CO feed. Interestingly, the presence of MnOx suppresses the methanol formation from CO2 (TOF of 0.7 ⋅ 10−3 s−1 at 533 K and 40 bar) and enhances the low-temperature reverse water-gas shift reaction (TOF of 5.7 ⋅ 10−3 s−1) with a selectivity to CO of 87 %C. Using time-resolved XAS at high temperatures and pressures, we find significant absorption of CO2 to the MnO, which is reversed if CO2 is removed from the feed. This work reveals fundamental differences in the promoting effect of MnOx and ZnOx and contributes to a better understanding of the role of reducible oxide promoters in Cu-based hydrogenation catalysts