ABSTRACT
BACKGROUND: Self-rated health is a subjective yet valuable indicator of overall health status, influenced by various factors including physical, psychological, and socio-economic elements. Self-rated health could be telling and used by primary care physicians to evaluate overall present and predictive health. DESIGN: This study investigates the longitudinal evolution of self-rated health in Switzerland during the COVID-19 pandemic, focusing on the association of persistently favorable self-rated health with various predictors. PARTICIPANTS: This study based on the Specchio cohort, a population-based digital study in Geneva Switzerland, involved participants completing questionnaires from 2021 to 2023. MAIN MEASURES: Self-rated health was assessed alongside factors like physical and mental health, socio-economic status, and lifestyle behaviors. KEY RESULTS: The study included 7006 participants in 2021, and 3888 participants who answered all three follow-ups (2021, 2022, and 2023). At baseline, 34.9% of individuals reported very good, 54.6% reported good, 9.6% reported average, and 1.0% reported poor to very poor self-rated health. Overall, 29.1% had a worsening in their self-rated health between 2021 and 2023. A subset of participants (12.1%) maintained very good self-rated health throughout, demonstrating persistently favorable self-rated health during the COVID-19 pandemic. Positive health behaviors were associated with persistently favorable self-rated health (exercise aOR 1.13 [1.03-1.24]; healthy diet aOR 2.14 [1.70-2.68]; less screen time aOR 1.28 [1.03-1.58]; and better sleep quality aOR 2.48 [2.02-3.04]). Mental health and social support also played significant roles. CONCLUSION: The study underscores the significance of healthy lifestyle choices and social support in maintaining favorable self-rated health, particularly during challenging times like the COVID-19 pandemic. Primary care physicians should focus on promoting these factors, integrating these actions in their routine consultations, and advising patients to undertake in socially engaging activities to improve overall health perceptions and outcomes.
Subject(s)
COVID-19 , Health Behavior , Health Status , Humans , Switzerland/epidemiology , COVID-19/epidemiology , COVID-19/psychology , Male , Female , Middle Aged , Longitudinal Studies , Adult , Aged , Self Report , SARS-CoV-2 , Diagnostic Self EvaluationABSTRACT
BACKGROUND: Sport participation is an important component of a healthy lifestyle and is known to be more common among privileged individuals. However, few studies examined socio-demographic patterns of participation by type of activity. This study aims at quantifying socio-economic inequalities in sport participation by sport type, and to analyse their trend over 15 years. METHODS: We used 2005-2019 data from the Bus Santé study, a yearly population-based cross-sectional survey of Geneva adults. Sport participation was defined as reporting at least one sporting activity over the previous week; educational level, household income and occupational position were used as indicators of socio-economic position. Socio-economic inequalities in sport participation, and their trend over time, were examined using the relative and slope indexes of inequality (RII/SII). RESULTS: Out of 7769 participants (50.8% women, mean age 46 years old), 60% participated in a sporting activity. Results showed that the higher the socioeconomic circumstances, the higher the sport participation (RII = 1.78; 95% Confidence Interval (CI): 1.64-1.92; SII = 0.33; 95%CI: 0.29-0.37 for education). Relative inequalities varied per sport e.g., 0.68 (95%CI: 0.44-1.07) for football and 4.25 (95%CI: 2.68-6.75) for tennis/badminton for education. Yearly absolute inequalities in sport participation tended to increase between 2005 and 2019 for household income, especially among women and older adults. CONCLUSIONS: We observed strong socio-economic inequalities in sport participation in Geneva, with different magnitude depending on the sport type. These inequalities seemed to increase over the 2005-2019 period. Our results call for tailored measures to promote the participation of socially disadvantaged populations in sporting activities.
Subject(s)
Sports , Humans , Female , Aged , Middle Aged , Male , Socioeconomic Factors , Cross-Sectional Studies , Educational Status , Health Status DisparitiesABSTRACT
BackgroundUp-to-date seroprevalence estimates are critical to describe the SARS-CoV-2 immune landscape and to guide public health decisions.AimWe estimate seroprevalence of anti-SARS-CoV-2 antibodies 15 months into the COVID-19 pandemic and 6 months into the vaccination campaign.MethodsWe conducted a population-based cross-sectional serosurvey between 1 June and 7 July 2021, recruiting participants from age- and sex-stratified random samples of the general population. We tested participants for anti-SARS-CoV-2 antibodies targeting the spike (S) or nucleocapsid (N) proteins using the Roche Elecsys immunoassays. We estimated the anti-SARS-CoV-2 antibodies seroprevalence following vaccination and/or infection (anti-S antibodies), or infection only (anti-N antibodies).ResultsAmong 3,355 individuals (54.1% women; 20.8% aged < 18 years and 13.4% aged ≥ 65 years), 2,161 (64.4%) had anti-S antibodies and 906 (27.0%) had anti-N antibodies. The total seroprevalence was 66.1% (95% credible interval (CrI): 64.1-68.0). We estimated that 29.9% (95% Crl: 28.0-31.9) of the population developed antibodies after infection; the rest having developed antibodies via vaccination. Seroprevalence estimates differed markedly across age groups, being lowest among children aged 0-5 years (20.8%; 95% Crl: 15.5-26.7) and highest among older adults aged ≥ 75 years (93.1%; 95% Crl: 89.6-96.0). Seroprevalence of antibodies developed via infection and/or vaccination was higher among participants with higher educational level.ConclusionMost of the population has developed anti-SARS-CoV-2 antibodies, despite most teenagers and children remaining vulnerable to infection. As the SARS-CoV-2 Delta variant spreads and vaccination rates stagnate, efforts are needed to address vaccine hesitancy, particularly among younger individuals and to minimise spread among children.
Subject(s)
COVID-19 , SARS-CoV-2 , Adolescent , Aged , Antibodies, Viral , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Immunization Programs , Infant , Infant, Newborn , Male , Pandemics , Seroepidemiologic Studies , SwitzerlandABSTRACT
BACKGROUND: Transcriptome time series can be used to track the expression of genes during development, allowing the timing, intensity, and dynamics of genetic programmes to be determined. Furthermore, time series analysis can reveal causal relationships between genes, leading to an understanding of how the regulatory networks are rewired during development. Due to its impact on yield, a developmental transition of agricultural interest in crops is the switch from vegetative to floral growth. We previously reported the collection of genome-wide gene expression data during the floral transition in the allopolyploid crop Brassica napus (oilseed rape, OSR). To provide the OSR research community with easy access to this dataset, we have developed the Oilseed Rape Developmental Expression Resource (ORDER; http://order.jic.ac.uk ). RESULTS: ORDER enables users to search for genes of interest and plot expression patterns during the floral transition in both a winter and a spring variety of OSR. We illustrate the utility of ORDER using two case studies: the first investigating the interaction between transcription factors, the second comparing genes that mediate the vernalisation response between OSR and radish (Raphanus sativus L.). All the data is downloadable and the generic website platform underlying ORDER, called AionPlot, is made freely and openly available to facilitate the dissemination of other time series datasets. CONCLUSIONS: ORDER provides the OSR research community with access to a dataset focused on a period of OSR development important for yield. AionPlot, the platform on which ORDER is built, will allow researchers from all fields to share similar time series datasets.
Subject(s)
Brassica napus/genetics , Databases, Genetic , Flowers/genetics , Plant Proteins/genetics , Crops, Agricultural/genetics , Gene Expression Regulation, Plant , Genome, Plant , Internet , Raphanus/genetics , Seeds/geneticsABSTRACT
Polyploidy is a recurrent feature of eukaryotic evolution and has been linked to increases in complexity, adaptive radiation and speciation. Within angiosperms such events have occurred repeatedly in many plant lineages. Here we investigate the retention and spatio-temporal expression dynamics of duplicated genes predicted to regulate the floral transition in Brassica napus (oilseed rape, OSR). We show that flowering time genes are preferentially retained relative to other genes in the OSR genome. Using a transcriptome time series in two tissues (leaf and shoot apex) across development we show that 67% of these retained flowering time genes are expressed. Furthermore, between 64% (leaf) and 74% (shoot apex) of the retained gene homologues show diverged expression patterns relative to each other across development, suggesting neo- or subfunctionalization. A case study of homologues of the shoot meristem identity gene TFL1 reveals differences in cis-regulatory elements that could explain this divergence. Such differences in the expression dynamics of duplicated genes highlight the challenges involved in translating gene regulatory networks from diploid model systems to more complex polyploid crop species.
Subject(s)
Brassica napus/genetics , Flowers/genetics , Genes, Plant/genetics , Polyploidy , Brassica napus/growth & development , Gene Duplication/genetics , Gene Expression Regulation, Developmental , Gene Expression Regulation, Plant , Genes, Plant/physiologyABSTRACT
Macrophage-mediated renal injury promotes the development of diabetic nephropathy. Blockade of chemokine (C-C motif) receptor 2 (CCR2) inhibits kidney macrophage accumulation and early glomerular damage in diabetic animals. This study tested early and late interventions with a CCR2 antagonist (CCR2A) in a model of progressive diabetic glomerulosclerosis and determined whether CCR2A provides added benefit over conventional treatment with an angiotensin-converting enzyme inhibitor (ACEi). Diabetes was induced in hypertensive endothelial nitric oxide synthase (Nos3)-deficient mice by administration of five low-dose streptozotocin (STZ) injections daily. Groups of diabetic Nos3-/- mice received a CCR2A (30 mg·kg-1·day-1 PF-04634817 in chow) as an early intervention (weeks 2-15 after STZ). The late intervention (weeks 8-15 after STZ) involved PF-04634817 alone, ACEi (captopril in water 10 mg·kg-1·day-1) alone, or combined ACEi + CCR2A. Control diabetic and nondiabetic Nos3-/- mice received normal chow and water. Early intervention with a CCR2A inhibited kidney inflammation and glomerulosclerosis, albuminuria, podocyte loss, and renal function impairment but not hypertension in diabetic Nos3-/- mice. Late intervention with a CCR2A also inhibited kidney inflammation, glomerulosclerosis, and renal dysfunction but did not affect albuminuria. ACEi alone suppressed hypertension and albuminuria and partially reduced podocyte loss and glomerulosclerosis but did not affect renal dysfunction. Compared with ACEi alone, the combined late intervention with ACEi + CCR2A provided better protection against kidney damage (inflammation, glomerulosclerosis, and renal function impairment) but not albuminuria. In conclusion, this study demonstrates that combining CCR2A and ACEi provides broader and superior renal protection than ACEi alone in a model of established diabetic glomerulosclerosis with hypertension.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Diabetic Nephropathies/prevention & control , Nitric Oxide Synthase Type III/genetics , Receptors, CCR2/antagonists & inhibitors , Albuminuria/prevention & control , Animals , Azabicyclo Compounds/therapeutic use , Captopril/therapeutic use , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/pathology , Disease Progression , Hypertension, Renal/etiology , Hypertension, Renal/prevention & control , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide Synthase Type III/deficiency , Podocytes/pathology , Pyrimidines/therapeutic useABSTRACT
To identify determinants of early progressive renal decline in type 2 diabetes a range of markers was studied in 1032 patients enrolled into the 2nd Joslin Kidney Study. eGFR slopes estimated from serial measurements of serum creatinine during 5-12 years of follow-up were used to define early renal decline. At enrollment, all patients had normal eGFR, 58% had normoalbuminuria and 42% had albuminuria. Early renal decline developed in 6% and in 18% patients, respectively. As determinants, we examined baseline values of clinical characteristics, circulating markers: TNFR1, KIM-1, and FGF23, and urinary markers: albumin, KIM-1, NGAL, MCP-1, EGF (all normalized to urinary creatinine) and the ratio of EGF to MCP-1. In univariate analysis, all plasma and urinary markers were significantly associated with risk of early renal decline. When analyzed together, systolic blood pressure, TNFR1, KIM-1, the albumin to creatinine ratio, and the EGF/MCP-1 ratio remained significant with the latter having the strongest effect. Integration of these markers into a multi-marker prognostic test resulted in a significant improvement of discriminatory performance of risk prediction of early renal decline, compared with the albumin to creatinine ratio and systolic blood pressure alone. However, the positive predictive value was only 50% in albuminuric patients. Thus, markers in plasma and urine indicate that the early progressive renal decline in Type 2 diabetes has multiple determinants with strong evidence for involvement of tubular damage. However, new, more informative markers are needed to develop a better prognostic test for such decline that can be used in a clinical setting.
Subject(s)
Biomarkers , Diabetes Mellitus, Type 2/diagnosis , Diabetic Nephropathies/etiology , Adult , Albuminuria/diagnosis , Albuminuria/etiology , Albuminuria/physiopathology , Biomarkers/blood , Biomarkers/urine , Blood Pressure , Chemokine CCL2/urine , Creatinine/urine , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/urine , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/physiopathology , Disease Progression , Early Diagnosis , Epidermal Growth Factor/urine , Female , Fibroblast Growth Factor-23 , Glomerular Filtration Rate , Hepatitis A Virus Cellular Receptor 1/blood , Humans , Kidney/physiopathology , Male , Middle Aged , Predictive Value of Tests , Prognosis , Receptors, Tumor Necrosis Factor, Type I/blood , Risk Assessment , Risk Factors , Time FactorsABSTRACT
The nucleolus is the most prominent nuclear substructure assigned to produce ribosomes; molecular machines that are responsible for carrying out protein synthesis. To meet the increased demand for proteins during cell growth and proliferation the cell must increase protein synthetic capacity by upregulating ribosome biogenesis. While larger nucleolar size and number have been recognized as hallmark features of many tumor types, recent evidence has suggested that, in addition to overproduction of ribosomes, decreased ribosome biogenesis as well as qualitative changes in this process could also contribute to tumor initiation and cancer progression. Furthermore, the nucleolus has become the focus of intense attention for its involvement in processes that are clearly unrelated to ribosome biogenesis such as sensing and responding to endogenous and exogenous stressors, maintenance of genome stability, regulation of cell-cycle progression, cellular senescence, telomere function, chromatin structure, establishment of nuclear architecture, global regulation of gene expression and biogenesis of multiple ribonucleoprotein particles. The fact that dysregulation of many of these fundamental cellular processes may contribute to the malignant phenotype suggests that normal functioning of the nucleolus safeguards against the development of cancer and indicates its potential as a therapeutic approach. Here we review the recent advances made toward understanding these newly-recognized nucleolar functions and their roles in normal and cancer cells, and discuss possible future research directions.
Subject(s)
Cell Nucleolus/genetics , Cell Nucleolus/metabolism , Neoplasms/pathology , Cell Nucleolus/pathology , Chromosome Segregation , DNA Damage , DNA, Ribosomal , Epigenesis, Genetic , Genomic Instability , Humans , Mitosis , RNA, Ribosomal/metabolism , Ribosomes/metabolism , TelomereABSTRACT
Design of Phase III trials for diabetic nephropathy currently requires patients at a high risk of progression defined as within three years of a hard end point (end-stage renal disease, 40% loss of estimated glomerular filtration rate, or death). To improve the design of these trials, we used natural history data from the Joslin Kidney Studies of chronic kidney disease in patients with diabetes to develop an improved criterion to identify such patients. This included a training cohort of 279 patients with type 1 diabetes and 134 end points within three years, and a validation cohort of 221 patients with type 2 diabetes and 88 end points. Previous trials selected patients using clinical criteria for baseline urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. Application of these criteria to our cohort data yielded sensitivities (detection of patients at risk) of 70-80% and prognostic values of only 52-63%. We applied classification and regression trees analysis to select from among all clinical characteristics and markers the optimal prognostic criterion that divided patients with type 1 diabetes according to risk. The optimal criterion was a serum tumor necrosis factor receptor 1 level over 4.3 ng/ml alone or 2.9-4.3 ng/ml with an albumin-to-creatinine ratio over 1900 mg/g. Remarkably, this criterion produced similar results in both type 1 and type 2 diabetic patients. Overall, sensitivity and prognostic value were high (72% and 81%, respectively). Thus, application of this criterion to enrollment in future clinical trials could reduce the sample size required to achieve adequate statistical power for detection of treatment benefits.
Subject(s)
Clinical Trials, Phase III as Topic/methods , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/etiology , Endpoint Determination , Glomerular Filtration Rate , Kidney Failure, Chronic/etiology , Kidney/physiopathology , Patient Selection , Adult , Albuminuria/etiology , Albuminuria/physiopathology , Biomarkers/blood , Biomarkers/urine , Creatinine/urine , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 2/diagnosis , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/physiopathology , Diabetic Nephropathies/therapy , Disease Progression , Female , Humans , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/physiopathology , Kidney Failure, Chronic/therapy , Male , Middle Aged , Predictive Value of Tests , Receptors, Tumor Necrosis Factor, Type I/blood , Reproducibility of Results , Risk Assessment , Risk Factors , Time FactorsABSTRACT
Despite the high medical burden experienced by patients with focal segmental glomerulosclerosis, the etiology of the condition remains largely unknown. Focal segmental glomerulosclerosis is highly heterogeneous in clinical and morphologic manifestations. While this presents challenges for the development of new treatments, research investments over the last 2 decades have yielded a surfeit of potential avenues for therapeutic intervention. The development of many of those ideas and concepts into new therapies, however, has been very disappointing. Here, we describe some of the factors that have potentially contributed to the poor translational performance from this research investment, including the confidence we ascribe to a target, the conduct of experimental studies, and the availability of selective reagents to test hypotheses. We will discuss the significance of genetic and systems traits as well as other methods for reducing bias. We will analyze the limitations of a successful drug development. We will use specific examples hoping that these will guide a consensus for investment and drive greater translational quality. We hope that this substrate will serve to exemplify the tremendous opportunity for intervention as well as facilitate greater collaborative effort between industry, academia, and private foundations in promoting appropriate validation of these targets. Only then will we have achieved our goal for curative therapies for this devastating disease.
Subject(s)
Drug Discovery , Glomerulosclerosis, Focal Segmental/drug therapy , Kidney Glomerulus/pathology , Molecular Targeted Therapy , Podocytes/metabolism , Proteinuria/drug therapy , Translational Research, Biomedical/trends , Clinical Trials as Topic , Glomerular Filtration Rate , Glomerulosclerosis, Focal Segmental/genetics , Humans , Kidney Glomerulus/metabolism , Mutation , Phenotype , Podocytes/pathology , Protein Kinases/genetics , Proteinuria/geneticsABSTRACT
During flowering, primordia on the flanks of the shoot apical meristem are specified to form flowers instead of leaves. Like many plants, Arabidopsis thaliana integrates environmental and endogenous signals to control the timing of reproduction. To study the underlying regulatory logic of the floral transition, we used a combination of modeling and experiments to define a core gene regulatory network. We show that FLOWERING LOCUS T (FT) and TERMINAL FLOWER1 (TFL1) act through FD and FD PARALOG to regulate the transition. The major floral meristem identity gene LEAFY (LFY) directly activates FD, creating a positive feedback loop. This network predicts flowering behavior for different genotypes and displays key properties of the floral transition, such as signal integration and irreversibility. Furthermore, modeling suggests that the control of TFL1 is important to flexibly counterbalance incoming FT signals, allowing a pool of undifferentiated cells to be maintained despite strong differentiation signals in nearby cells. This regulatory system requires TFL1 expression to rise in proportion to the strength of the floral inductive signal. In this network, low initial levels of LFY or TFL1 expression are sufficient to tip the system into either a stable flowering or vegetative state upon floral induction.
Subject(s)
Arabidopsis Proteins/metabolism , Arabidopsis/metabolism , Flowers/physiology , Arabidopsis/genetics , Arabidopsis/physiology , Arabidopsis Proteins/genetics , Cell Differentiation , Feedback, Physiological , Flowers/genetics , Flowers/metabolism , Gene Expression Regulation, Plant , Gene Regulatory Networks , Genes, Plant , Genotype , Meristem/genetics , Meristem/metabolism , Models, Molecular , Plant Cells/metabolism , Plant Leaves/genetics , Plant Leaves/metabolism , Promoter Regions, Genetic , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Uncontrolled diabetes, inflammation, and hypertension are key contributors to progressive renal fibrosis and subsequent loss of renal function. Reduced fibrinolysis appears to be a feature of ESRD, but its contribution to the fibrotic program has not been extensively studied. Here, we show that in patients with CKD, the activity levels of serum thrombin-activated fibrinolysis inhibitor and plasmin strongly correlated with the degree of renal function impairment. We made similar observations in rats after subtotal nephrectomy and tested whether pharmacologic inhibition of thrombin-activated fibrinolysis inhibitor with UK-396082 could reduce renal fibrosis and improve renal function. Compared with untreated animals, UK-396082-treated animals had reduced glomerular and tubulointerstitial fibrosis after subtotal nephrectomy. Renal function, as measured by an increase in creatinine clearance, was maintained and the rate of increase in proteinuria was reduced in UK-396082-treated animals. Furthermore, cumulative survival improved from 16% to 80% with inhibition of thrombin-activated fibrinolysis inhibitor. Taken together, these data support the importance of the fibrinolytic axis in regulating renal fibrosis and point to a potentially important therapeutic role for suppression of thrombin-activated fibrinolysis inhibitor activity.
Subject(s)
Amino Acids/therapeutic use , Carboxypeptidase B2/blood , Fibrinolysin/metabolism , Imidazoles/therapeutic use , Renal Insufficiency, Chronic/blood , Adult , Aged , Amino Acids/pharmacology , Animals , Biomarkers/urine , Carboxypeptidase B2/antagonists & inhibitors , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Fibrosis , Humans , Imidazoles/pharmacology , Kidney/drug effects , Kidney/pathology , Kidney Function Tests , Male , Middle Aged , Nephrectomy , Random Allocation , Rats, Wistar , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/mortality , Renal Insufficiency, Chronic/urineABSTRACT
Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.
Subject(s)
Acute Kidney Injury/prevention & control , Research Design/standards , Translational Research, Biomedical/standards , Acetylcysteine/therapeutic use , Acute Kidney Injury/chemically induced , Animals , Contrast Media/adverse effects , Disease Models, Animal , Erythropoietin/therapeutic use , Free Radical Scavengers/therapeutic use , Humans , Sodium Bicarbonate/therapeutic useABSTRACT
Platelet derived growth factor-BB (PDGF-BB) is an important mitogen and cell survival factor during development. PDGF-BB binds PDGF receptor-ß (PDGFRß) to trigger receptor dimerization and tyrosine kinase activation. We present the pharmacological and biophysical characterization of a blocking PDGF-BB monoclonal antibody, MOR8457, and contrast this to PDGFRß. MOR8457 binds to PDGF-BB with high affinity and selectivity, and prevents PDGF-BB induced cell proliferation competitively and with high potency. The structural characterization of the MOR8457-PDGF-BB complex indicates that MOR8457 binds with a 2:1 stoichiometry, but that binding of a single MOR8457 moiety is sufficient to prevent binding to PDGFRß. Comparison of the MOR8457-PDGF-BB structure with that of the PDGFRß-PDGF-BB complex suggested the potential reason for this was a substantial bending and twisting of PDGF-BB in the MOR8457 structure, relative to the structures of PDGF-BB alone, bound to a PDGF-BB aptamer or PDGFRß, which makes it nonpermissive for PDGFRß binding. These biochemical and structural data offer insights into the permissive structure of PDGF-BB needed for agonism as well as strategies for developing specific PDGF ligand antagonists.
Subject(s)
Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/chemistry , Proto-Oncogene Proteins c-sis/antagonists & inhibitors , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/pharmacology , Aptamers, Peptide/chemistry , Aptamers, Peptide/genetics , Aptamers, Peptide/metabolism , Aptamers, Peptide/pharmacology , Becaplermin , Binding Sites, Antibody , Cell Proliferation/drug effects , Cells, Cultured , Humans , Proto-Oncogene Proteins c-sis/chemistry , Proto-Oncogene Proteins c-sis/metabolism , Receptor, Platelet-Derived Growth Factor betaABSTRACT
Mucosal addressin cell adhesion molecule (MAdCAM) binds integrin α4ß7. Their interaction directs lymphocyte homing to mucosa-associated lymphoid tissues. The interaction between the two immunoglobulin superfamily (IgSF) domains of MAdCAM and integrin α4ß7 is unusual in its ability to mediate either rolling adhesion or firm adhesion of lymphocytes on vascular surfaces. We determined four crystal structures of the IgSF domains of MAdCAM to test for unusual structural features that might correlate with this functional diversity. Higher resolution 1.7- and 1.4-Å structures of the IgSF domains of MAdCAM in a previously described crystal lattice revealed two alternative conformations of the integrin-binding loop, which were deformed by large lattice contacts. New crystal forms in the presence of two different Fabs to MAdCAM demonstrate a shift in IgSF domain topology from the I2- to I1-set, with a switch of integrin-binding loop from CC' to CD. The I1-set fold and CD loop appear biologically relevant. The different conformations seen in crystal structures suggest that the integrin-binding loop of MAdCAM is inherently flexible. This contrasts with rigidity of the corresponding loops in vascular cell adhesion molecule, intercellular adhesion molecule (ICAM)-1, ICAM-2, ICAM-3, and ICAM-5 and may reflect a specialization of MAdCAM to mediate both rolling and firm adhesion by binding to different α4ß7 integrin conformations.
Subject(s)
Immunoglobulins/chemistry , Mucoproteins/chemistry , Animals , CHO Cells , Cell Adhesion/physiology , Cell Adhesion Molecules/chemistry , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Cricetinae , Cricetulus , Crystallography, X-Ray , Humans , Immunoglobulins/genetics , Immunoglobulins/metabolism , Integrin alpha4/chemistry , Integrin alpha4/genetics , Integrin alpha4/metabolism , Integrin beta Chains/chemistry , Integrin beta Chains/genetics , Integrin beta Chains/metabolism , Mice , Mucoproteins/genetics , Mucoproteins/metabolism , Protein Structure, Secondary , Protein Structure, TertiaryABSTRACT
Oilseed rape (Brassica napus) is an important global oil crop, with spring and winter varieties grown commercially. To understand the transcriptomic differences between these varieties, we collected transcriptomes from apex and leaf tissue from a spring variety, Westar, and a winter variety, Tapidor, before, during, and after vernalisation treatment, until the plants flowered. Large transcriptomic differences were noted in both varieties during the vernalisation treatment because of temperature and day length changes. Transcriptomic alignment revealed that the apex transcriptome reflects developmental state, whereas the leaf transcriptome is more closely aligned to the age of the plant. Similar numbers of copies of genes were expressed in both varieties during the time series, although key flowering time genes exhibited expression pattern differences. BnaFLC copies on A2 and A10 are the best candidates for the increased vernalisation requirement of Tapidor. Other BnaFLC copies show tissue-dependent reactivation of expression post-cold, with these dynamics suggesting some copies have retained or acquired a perennial nature. BnaSOC1 genes, also related to the vernalisation pathway, have expression profiles which suggest tissue subfunctionalisation. This understanding may help to breed varieties with more consistent or robust vernalisation responses, of special importance due to the milder winters resulting from climate change.
Subject(s)
Brassica napus , Transcriptome , Time Factors , Plant Breeding , Plant Leaves/genetics , Gene Expression Profiling , Gene Expression Regulation, PlantABSTRACT
BACKGROUND: Mental health deteriorated in the early stages of the COVID-19 pandemic, but improved relatively quickly as restrictions were eased, suggesting overall resilience. However, longer-term follow-up of mental health in the general population is scarce. METHODS: We examined mental health trajectories in 5624 adults (58 % women; aged 18-97 years) from the Specchio-COVID19 cohort, using the Generalized Anxiety Disorder scale-2 and the Patient Health Questionnaire-2, administered each month from February to June 2021, and in Spring 2022 and 2023. RESULTS: Depressive and anxiety symptoms declined during a pandemic wave from February to May 2021 (ß = -0.06 [-0.07, -0.06]; -0.06 [-0.07, -0.05]), and remained lower at longer-term follow-up than at the start of the wave. Loneliness also declined over time, with the greatest decline during the pandemic wave (ß = -0.25 [-0.26, -0.24]). Many higher-risk groups, including socioeconomically disadvantaged individuals, those with a chronic condition, and those living alone had poorer mental health levels throughout the study period. Women and younger individuals had a faster improvement in mental health during the pandemic wave. Loneliness trajectories were associated with mental health trajectories throughout the study period. LIMITATIONS: We cannot definitively conclude that the observed changes in mental health were due to experiences of the pandemic. CONCLUSIONS: While there was a need for additional mental health support during stricter policy responses to COVID-19, overall, mental health improved relatively soon after measures were eased. Nevertheless, the persistence of mental health disparities highlights the need for further efforts from the government and healthcare practitioners to support vulnerable groups beyond the pandemic.
Subject(s)
Anxiety , COVID-19 , Depression , Loneliness , Mental Health , Humans , COVID-19/psychology , COVID-19/epidemiology , Female , Adult , Middle Aged , Male , Aged , Switzerland/epidemiology , Aged, 80 and over , Adolescent , Young Adult , Mental Health/statistics & numerical data , Anxiety/epidemiology , Anxiety/psychology , Loneliness/psychology , Depression/epidemiology , Depression/psychology , SARS-CoV-2 , Risk FactorsABSTRACT
There are concerns about acute and long-term mental health effects of the COVID-19 pandemic. This study examined the prevalence and predictors of psychological distress before, during, and after a pandemic wave in Switzerland, 2021. Prevalence of psychological distress was estimated in adults aged 35-96 years using the General Health Questionnaire-12 administered in June 2021 (Specchio-COVID19 cohort, N = 3965), and compared to values from 2003 to 2006 (CoLaus|PsyCoLaus cohort, N = 5667). Anxiety and depression were assessed from February to June 2021 using the Generalised Anxiety Disorder scale-2 and the Patient Health Questionnaire-2, respectively. Prevalence of psychological distress in June 2021, after the pandemic wave (16.0% [95% CI, 14.6%-17.4%]) was comparable to pre-pandemic levels (15.1% [14.0%-16.2%]). Anxiety and depression were highest at the start of the pandemic wave in February 2021, and declined from February to June with the relaxation of measures. Predictors of psychological distress included being younger, female, a single parent, unemployed, a change in working hours or job loss in the past 6 months, greater perceived severity and contagiousness of COVID-19, and self-reported post COVID-19. By June 2021, following a pandemic wave, prevalence of psychological distress in Switzerland was closer to pre-pandemic levels. These findings highlight the need for additional mental health support during times of stricter government policies relating to COVID-19; yet they also suggest that individuals can adapt relatively quickly to the changing context.
Subject(s)
COVID-19 , Psychological Distress , Adult , Female , Humans , COVID-19/epidemiology , Pandemics , SARS-CoV-2 , Prevalence , Switzerland/epidemiology , Depression/epidemiology , Anxiety/epidemiologyABSTRACT
OBJECTIVE: We aimed to examine factors associated with parental willingness to vaccinate their children against COVID-19. METHODS: We surveyed adults included in a digital longitudinal cohort study composed of participants in previous SARS-CoV-2 serosurveys conducted in Geneva, Switzerland. In February 2022, an online questionnaire collected information on COVID-19 vaccination acceptance, parental willingness to vaccinate their children aged ≥5 years and reasons for vaccination preference. We used multivariable logistic regression to assess the demographic, socioeconomic and health-related factors associated with being vaccinated and with parental intention to vaccinate their children. RESULTS: We included 1,383 participants (56.8% women; 69.3% aged 35-49 years). Parental willingness to vaccinate their children increased markedly with the child's age: 84.0%, 60.9% and 21.2%, respectively, for parents of adolescents aged 16-17 years, 12-15 years and 5-12 years. For all child age groups, unvaccinated parents more frequently indicated not intending to vaccinate their children than vaccinated parents. Refusal to vaccine children was associated with having a secondary education (1.73; 1.18-2.47) relative to a tertiary education and with middle (1.75; 1.18-2.60) and low (1.96; 1.20-3.22) household income relative to high income. Refusal to vaccine their children was also associated with only having children aged 12-15 years (3.08; 1.61-5.91), aged 5-11 years (19.77; 10.27-38.05), or in multiple age groups (6.05; 3.22-11.37), relative to only having children aged 16-17 years. CONCLUSION: Willingness to vaccinate children was high for parents of adolescents aged 16-17 years but decreased significantly with decreasing child age. Unvaccinated, socioeconomically disadvantaged parents and those with younger children were less likely to be willing to vaccinate their children. These results are important for vaccination programs and developing communication strategies to reach vaccine-hesitant groups, both in the context of COVID-19 and in the prevention of other diseases and future pandemics.
Subject(s)
COVID-19 , Adolescent , Adult , Humans , Child , Female , Aged, 80 and over , Male , COVID-19/prevention & control , Switzerland , SARS-CoV-2 , COVID-19 Vaccines , Cross-Sectional Studies , Longitudinal Studies , Parents , VaccinationABSTRACT
Background: Children and adolescents are highly vulnerable to the impact of sustained stressors during developmentally sensitive times. We investigated how demographic characteristics intersect with socioeconomic dimensions to shape the social patterning of quality of life and mental health in children and adolescents, two years into the COVID-19 pandemic. Methods: We used data from the prospective SEROCoV-KIDS cohort study of children and adolescents living in Geneva (Switzerland, 2022). We conducted an intersectional Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy by nesting participants within 48 social strata defined by intersecting sex, age, immigrant background, parental education and financial hardship in Bayesian multilevel logistic models for poor health-related quality of life (HRQoL, measured with PedsQL) and mental health difficulties (measured with the Strengths and Difficulties Questionnaire). Results: Among participants aged 2-17 years, 240/2096 (11.5%, 95%CI 10.1-12.9) had poor HRQoL and 105/2135 (4.9%, 95%CI 4.0-5.9) had mental health difficulties. The predicted proportion of poor HRQoL ranged from 3.4% for 6-11 years old Swiss girls with highly educated parents and no financial hardship to 34.6% for 12-17 years old non-Swiss girls with highly educated parents and financial hardship. Intersectional strata involving adolescents and financial hardship showed substantially worse HRQoL than their counterparts. Between-stratum variations in the predicted frequency of mental health difficulties were limited (range 4.4%-6.5%). Conclusions: We found considerable differences in adverse outcomes across social strata. Our results suggest that, post-pandemic, interventions to address social inequities in HRQoL should focus on specific intersectional strata involving adolescents and families experiencing financial hardship, while those aiming to improve mental health should target all children and adolescents.