GLORIA

GEOMAR Library Ocean Research Information Access

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    In: Cardiovascular Diabetology, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2022-12-02)
    Abstract: An “obesity paradox” for mortality has been shown in chronic disorders such as diabetes, and attributed to methodological bias, including the use of body mass index (BMI) for obesity definition. This analysis investigated the independent association of BMI versus surrogate measures of central adiposity with all-cause mortality in individuals with type 2 diabetes. Methods The Renal Insufficiency And Cardiovascular Events Italian Multicentre Study is a prospective cohort study that enrolled 15,773 patients in 19 Italian centres in 2006–2008. Exposures were BMI and the surrogate measures of central adiposity waist circumference (WC), waist-to-height ratio (WHtR), and A Body Shape Index (ABSI). Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%), Results Age- and sex-adjusted hazard ratios and 95% confidence intervals were significantly higher in BMI-based underweight (1.729 [1.193–2.505), P  = 0.004), moderately obese (1.214 [1.058–1.392), P  = 0.006) and severely obese (1.703 [1.402–2.068), P   〈  0.0001), lower in overweight (0.842 [0.775–0.915), P   〈  0.0001) and similar in mildly obese (0.950 [0.864–1.045), P  = 0.292), compared to normal-weight individuals. When further adjusting for smoking, physical activity (PA), and comorbidities, risk was lower also in mildly obese versus normal-weight patients. The BMI-mortality relationship did not change after sequentially excluding ever smokers, individuals with comorbidities, and those died within two years from enrollment and when analyzing separately participants below and above the median age. Conversely, a paradox relationship was observed among inactive/moderately inactive, but not moderately/highly active patients. Mortality risk adjusted for age, gender, smoking, PA and comorbidities was significantly higher in the highest tertile of WC (1.279 [1.089–1.501], P  = 0.003), WHtR (1.372 [1.165–1.615], P   〈  0.0001), and ABSI (1.263 [1.067–1.495], P  = 0.007) versus the lowest tertile. However, risk was lower in the intermediate versus lowest tertile for WC (0.823 [0.693–0.979], P  = 0.028), similar for WHtR, and higher, though not significantly, for ABSI. Conclusions An “overweight paradox” remained after controlling for age, smoking, and comorbidities, arguing against a collider bias or reverse causation. However, it could be partly explained by confounding from PA level, possibly through its impact on lean mass and cardiorespiratory fitness. No obesity paradox was observed with WHtR and especially ABSI, which predicted mortality risk associated with central adiposity better than WC. Trial registration ClinicalTrials.gov, NCT00715481, 15 July, 2008
    Type of Medium: Online Resource
    ISSN: 1475-2840
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2093769-6
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 2
    In: Human Mutation, Hindawi Limited, Vol. 42, No. 1 ( 2021-01), p. 102-116
    Type of Medium: Online Resource
    ISSN: 1059-7794 , 1098-1004
    URL: Issue
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2021
    detail.hit.zdb_id: 1498165-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 3
    In: Brain, Oxford University Press (OUP), Vol. 142, No. 7 ( 2019-07-01), p. 1905-1920
    Abstract: Allele-specific silencing by RNA interference (ASP-siRNA) holds promise as a therapeutic strategy for downregulating a single mutant allele with minimal suppression of the corresponding wild-type allele. This approach has been effectively used to target autosomal dominant mutations and single nucleotide polymorphisms linked with aberrantly expanded trinucleotide repeats. Here, we propose ASP-siRNA as a preferable choice to target duplicated disease genes, avoiding potentially harmful excessive downregulation. As a proof-of-concept, we studied autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) due to lamin B1 (LMNB1) duplication, a hereditary, progressive and fatal disorder affecting myelin in the CNS. Using a reporter system, we screened the most efficient ASP-siRNAs preferentially targeting one of the alleles at rs1051644 (average minor allele frequency: 0.45) located in the 3′ untranslated region of the gene. We identified four siRNAs with a high efficacy and allele-specificity, which were tested in ADLD patient-derived fibroblasts. Three of the small interfering RNAs were highly selective for the target allele and restored both LMNB1 mRNA and protein levels close to control levels. Furthermore, small interfering RNA treatment abrogates the ADLD-specific phenotypes in fibroblasts and in two disease-relevant cellular models: murine oligodendrocytes overexpressing human LMNB1, and neurons directly reprogrammed from patients’ fibroblasts. In conclusion, we demonstrated that ASP-silencing by RNA interference is a suitable and promising therapeutic option for ADLD. Moreover, our results have a broad translational value extending to several pathological conditions linked to gene-gain in copy number variations.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 4
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-03-31)
    Abstract: During Central Nervous System ontogenesis, myelinating oligodendrocytes (OLs) arise from highly ramified and proliferative precursors called oligodendrocyte progenitor cells (OPCs). OPC architecture, proliferation and oligodendro-/myelino-genesis are finely regulated by the interplay of cell-intrinsic and extrinsic factors. A variety of extrinsic cues converge on the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK) pathway. Here we found that the germinal ablation of the MAPK c-Jun N-Terminal Kinase isoform 1 (JNK1) results in a significant reduction of myelin in the cerebral cortex and corpus callosum at both postnatal and adult stages. Myelin alterations are accompanied by higher OPC density and proliferation during the first weeks of life, consistent with a transient alteration of mechanisms regulating OPC self-renewal and differentiation. JNK1 KO OPCs also show smaller occupancy territories and a less complex branching architecture in vivo. Notably, these latter phenotypes are recapitulated in pure cultures of JNK1 KO OPCs and of WT OPCs treated with the JNK inhibitor D-JNKI-1. Moreover, JNK1 KO and WT D-JNKI-1 treated OLs, while not showing overt alterations of differentiation in vitro, display a reduced surface compared to controls. Our results unveil a novel player in the complex regulation of OPC biology, on the one hand showing that JNK1 ablation cell-autonomously determines alterations of OPC proliferation and branching architecture and, on the other hand, suggesting that JNK1 signaling in OLs participates in myelination in vivo.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2615211-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 5
    In: Applied Sciences, MDPI AG, Vol. 13, No. 7 ( 2023-03-28), p. 4289-
    Abstract: Machine learning is usually associated with big data; however, experimental or clinical data are usually limited in size. The aim of this study was to describe how supervised machine learning can be used to classify astrocytes from a small sample into different morphological classes. Our dataset was composed of only 193 cells, with unbalanced morphological classes and missing observations. We combined classification trees and ensemble algorithms (boosting and bagging) with under sampling to classify the nuclear morphology (homogeneous, dotted, wrinkled, forming crumples, and forming micronuclei) of astrocytes stained with anti-LMNB1 antibody. Accuracy, sensitivity (recall), specificity, and F1 score were assessed with bootstrapping, leave one-out (LOOCV) and stratified cross-validation. We found that our algorithm performed at rates above chance in predicting the morphological classes of astrocytes based on the nuclear expression of LMNB1. Boosting algorithms (tree ensemble) yielded better classifications over bagging ones (tree bagger). Moreover leave-one-out and bootstrapping yielded better predictions than the more commonly used k-fold cross-validation. Finally, we could identify four important predictors: the intensity of LMNB1 expression, nuclear area, cellular area, and soma area. Our results show that a tree ensemble can be optimized, in order to classify morphological data from a small sample, even in the presence of highly unbalanced classes and numerous missing data.
    Type of Medium: Online Resource
    ISSN: 2076-3417
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2704225-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 6
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-04-28)
    Abstract: In the developing mouse forebrain, temporally distinct waves of oligodendrocyte progenitor cells (OPCs) arise from different germinal zones and eventually populate either dorsal or ventral regions, where they present as transcriptionally and functionally equivalent cells. Despite that, developmental heterogeneity influences adult OPC responses upon demyelination. Here we show that accumulation of DNA damage due to ablation of citron-kinase or cisplatin treatment cell-autonomously disrupts OPC fate, resulting in cell death and senescence in the dorsal and ventral subsets, respectively. Such alternative fates are associated with distinct developmental origins of OPCs, and with a different activation of NRF2-mediated anti-oxidant responses. These data indicate that, upon injury, dorsal and ventral OPC subsets show functional and molecular diversity that can make them differentially vulnerable to pathological conditions associated with DNA damage.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2553671-0
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 7
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 13 ( 2021-06-29), p. 7032-
    Abstract: Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM). Enhanced platelet reactivity is considered a main determinant of the increased atherothrombotic risk of diabetic patients. Thrombopoietin (THPO), a humoral growth factor able to stimulate megakaryocyte proliferation and differentiation, also modulates the response of mature platelets by enhancing both activation and binding to leukocytes in response to different agonists. Increased THPO levels have been reported in different clinical conditions characterized by a generalized pro-thrombotic state, from acute coronary syndromes to sepsis/septic shock, and associated with elevated indices of platelet activation. To investigate the potential contribution of elevated THPO levels in platelet activation in T1DM patients, we studied 28 T1DM patients and 28 healthy subjects. We measured plasma levels of THPO, as well as platelet-leukocyte binding, P-selectin, and THPO receptor (THPOR) platelet expression. The priming activity of plasma from diabetic patients or healthy subjects on platelet–leukocyte binding and the role of THPO on this effect was also studied in vitro. T1DM patients had higher circulating THPO levels and increased platelet–monocyte and platelet–granulocyte binding, as well as platelet P-selectin expression, compared to healthy subjects, whereas platelet expression of THPOR did not differ between the two groups. THPO concentrations correlated with platelet–leukocyte binding, as well as with fasting glucose and Hb1Ac. In vitro, plasma from diabetic patients, but not from healthy subjects, primed platelet–leukocyte binding and platelet P-selectin expression. Blocking THPO biological activity using a specific inhibitor prevented the priming effect induced by plasma from diabetic patients. In conclusion, augmented THPO may enhance platelet activation in patients with T1DM, potentially participating in increasing atherosclerotic risk.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...