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Background and aims: Familial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines. Methods: We evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients. Results: Among the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH. Conclusions: FH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high.

IntroductionAssessment of the Comprehensive Feeding Practices Questionnaire in adolescents (CFPQ-Teen) is still limited, with no evaluation of the measurement invariance. The participants comprised 473 Chilean adolescents of both sexes from dual-income nuclear families. The aims of this study were: (1) to adapt to Spanish and validate a model of five-factor version the CFPQ-Teen; (2) to examine the psychometric properties, (3) to evaluate the measurement invariance according to the adolescents’ gender; and (4) to compare the scores of each factor between female and male adolescents.MethodsThe instrument was translated, back-translated, and adapted from the CFPQ-Teen, confirming the equivalence, conceptual, and face validity in a pilot sample of 40 adolescents. An exploratory factor analysis was performed on the five-factor model of the CFPQ-Teen: Monitoring, Adolescent Control, Restriction for weight control, Parental Modeling, and Environment. The Environment factor was eliminated as a result.ResultsThe confirmatory factor analysis presented good reliability, convergent, discriminant, and concurrent validity values. In addition, medium to high goodness-of-fit levels were obtained by eliminating an item from the Adolescent Control factor. These results confirm a final 20-item model representing four factors. The multigroup invariance analysis of the measurement model verified configural, metric, scalar, and partial strict invariance. No significant differences were found between females and males in the scores on the four factors.DiscussionThese results enable comparisons by sex on the perceptions of Food Parenting Practices from the analyzed factors, primarily within the context of the Chilean sample.

Chronic neuroinflammation is characterized by increased blood-brain barrier (BBB) permeability, leading to molecular changes in the central nervous system that can be explored with biomarkers of active neuroinflammatory processes. Magnetic resonance imaging (MRI) has contributed to detecting lesions and permeability of the BBB. Ultra-small superparamagnetic particles of iron oxide (USPIO) are used as contrast agents to improve MRI observations. Therefore, we validate the interaction of peptide-88 with laminin, vectorized on USPIO, to explore BBB molecular alterations occurring during neuroinflammation as a potential tool for use in MRI. The specific labeling of NPS-P88 was verified in endothelial cells (hCMEC/D3) and astrocytes (T98G) under inflammation induced by interleukin 1β (IL-1β) for 3 and 24 hours. IL-1β for 3 hours in hCMEC/D3 cells increased their co-localization with NPS-P88, compared with controls. At 24 hours, no significant differences were observed between groups. In T98G cells, NPS-P88 showed similar nonspecific labeling among treatments. These results indicate that NPS-P88 has a higher affinity towards brain endothelial cells than astrocytes under inflammation. This affinity decreases over time with reduced laminin expression. In vivo results suggest that following a 30-minute post-injection, there is an increased presence of NPS-P88 in the blood and brain, diminishing over time. Lastly, EAE animals displayed a significant accumulation of NPS-P88 in MRI, primarily in the cortex, attributed to inflammation and disruption of the BBB. Altogether, these results revealed NPS-P88 as a biomarker to evaluate changes in the BBB due to neuroinflammation by MRI in biological models targeting laminin.

The consistently low activity level of the old solar analog 51 Peg not only facilitated the discovery of the first hot Jupiter, but also led to the suggestion that the star could be experiencing a magnetic grand minimum. However, the 50 yr time series showing minimal chromospheric variability could also be associated with the onset of weakened magnetic braking (WMB), where sufficiently slow rotation disrupts cycling activity and the production of large-scale magnetic fields by the stellar dynamo, thereby shrinking the Alfvén radius and inhibiting the efficient loss of angular momentum to magnetized stellar winds. In this Letter, we evaluate the magnetic evolutionary state of 51 Peg by estimating its wind braking torque. We use new spectropolarimetric measurements from the Large Binocular Telescope to reconstruct the large-scale magnetic morphology, we reanalyze archival X-ray measurements to estimate the mass-loss rate, and we detect solar-like oscillations in photometry from the Transiting Exoplanet Survey Satellite, yielding precise stellar properties from asteroseismology. Our estimate of the wind braking torque for 51 Peg clearly places it in the WMB regime, driven by changes in the mass-loss rate and the magnetic field strength and morphology that substantially exceed theoretical expectations. Although our revised stellar properties have minimal consequences for the characterization of the exoplanet, they have interesting implications for the current space weather environment of the system.

What are consumers aiming to get when they buy fresh meat? Is it the emotional pleasure, the nutritional quality and functionality, or the status that goes with it? We examine this question for Chinese consumers buying fresh pork. In order to understand the driving forces for pork purchases, we use the concept of perceived value of a product, and distinguish emotional value, quality/performance and social value, together with price/value for money. We look at how perceived value of pork products in China is related to consumers’ attitude to these products and to their repeated purchase of these products. In addition, we look at how value perception and its role in determining attitude and purchase behavior differ between different consumer segments, distinguished based on their shopping behavior. An online survey was carried out in 5 Chinese 1st and 2nd tier cities. Respondents were segmented based on their usage of different ways of shopping for pork using latent class cluster analysis. Relationships between constructs were estimated using PLS. Quality/functional value was the strongest determinant of attitude, but emotional value was both the strongest direct determinant of purchase behavioral and the strongest determinant overall when taking effects mediated by attitude into account. Customer journey segments differed in their pattern of determinants of attitudinal and behavioral loyalty. We conclude that buying fresh meat is, for Chinese consumers, mostly driven by the expected pleasure and to a lesser degree by quality and functional properties like safety and healthiness. The latter do have an impact on consumers’ attitude to the product, but less so on their buying behavior, suggesting that attitude and purchase are driven by different mental processes. We discuss implications for future demand for fresh pork in China.

Background: The COVID-19 pandemic has revealed the fragility of the global food system, sending shockwaves across countries' societies and economy. This has presented formidable challenges to sustaining a healthy and resilient lifestyle. The objective of this study is to examine the food consumption patterns and assess diet diversity indicators, primarily focusing on the food consumption score (FCS), among households in 38 countries both before and during the first wave of the COVID-19 pandemic. Methods: A cross-sectional study with 37 207 participants (mean age: 36.70 ± 14.79, with 77 % women) was conducted in 38 countries through an online survey administered between April and June 2020. The study utilized a pre-tested food frequency questionnaire to explore food consumption patterns both before and during the COVID-19 periods. Additionally, the study computed Food Consumption Score (FCS) as a proxy indicator for assessing the dietary diversity of households. Findings: This quantification of global, regional and national dietary diversity across 38 countries showed an increment in the consumption of all food groups but a drop in the intake of vegetables and in the dietary diversity. The household's food consumption scores indicating dietary diversity varied across regions. It decreased in the Middle East and North Africa (MENA) countries, including Lebanon (p

Histiocytic sarcoma (HS), an infrequent highly aggressive hematopoietic tumor, has been observed in diverse animal species, with isolated occurrences in non-human primates. This study describes the first case of disseminated HS in a 45-year-old female hybrid captive orangutan. The clinical profile mirrored symptoms seen in human HS cases, encompassing anorexia and ascites. Detailed histopathological examination demonstrated characteristic features of this tumor and immunohistochemistry, using markers such as Iba-1 and HLA-DR, confirmed the diagnosis. Significantly, the absence of CD163 and CD204 expression challenges their diagnostic utility in non-human primates. This investigation enhances our understanding of HS diagnosis in non-human primates, underscoring the necessity for standardized markers and diagnostic protocols.

Consumers’ recognition and understanding of food characteristics can have an important role when making purchase decisions. The current study analysed consumer preferences for bread, an important food in the diets of Central European countries. The study included a conjoint experiment on a representative sample of 547 adult consumers in Slovenia. The following bread attributes: functional ingredients (chia seeds, linseed, quinoa, and Tartary buckwheat); nutritional claims (low salt, high fibre, and high protein); and other claims (organic, free from additives, flour from Slovenia, and wholegrain) were studied. The results showed the strongest relative importance for functional ingredients (a mean relative importance of 83.9%). In addition, a deeper insight into consumer preference was investigated by a recently developed modular instrument for food-related lifestyles. Latent class cluster analysis (LCA) enabled the identification of four consumer segments (uninvolved, conservative, health-conscious, and moderate) with different preferences toward selected functional ingredients, nutrition, and other claims. The results provide insights that allow for a better understanding of consumer preferences for functional ingredients and claims, and new perspectives for bread marketing to different consumer segments based on food-related lifestyles. Identifying the drivers that affect bread purchasing and consumption can support reformulation activities and product promotion in the direction of reinforcing healthier food choices.

Abstract We study direct and indirect pseudomagnetoexcitons, formed by an electron and a hole in the layers of gapped graphene under strain-induced gauge pseudomagnetic field. Since the strain-induced pseudomagnetic field acts on electrons and holes the same way, it occurs that the properties of single pseudomagnetoexcitons, their collective effects and phase diagram are cardinally different from those of magnetoexcitons in a real magnetic field. We have derived wave functions and energy spectrum of direct in a monolayer and indirect pseudomagnetoexcitons in a double layer of gapped graphene. The quantum Hall effect for direct and indirect excitons was predicted in the monolayers and double layers of gapped graphene under strain-induced gauge pseudomagnetic field, correspondingly.

The growing burden of non-communicable diseases (NCDs) and an increase in the prevalence of the underlying risk factors are creating a challenge to health systems in low- and middle-income countries (LMICs). In Nepal, deaths attributable to NCDs have been increasing, as has life expectancy. This poses questions with regards to how age and various risk factors interact in affecting NCDs. We analyzed the effects of age on NCD risk factors, using data from the Nepalese STEPs survey 2019, a nationally representative cross-sectional study. Six sociodemographic determinants, four behavioral risk factors, and four biological risk factors were examined. Age effects were analyzed among three age groups: below 35 years (young), 35-59 years (middle aged) and 60 years and above (elderly). The prevalence of selected behavioral risk factors for NCDs, notably smoking, alcohol consumption and insufficient physical activity, and some biological risk factors (hypertension, hyperlipidemia) increases with age. The prevalence of most behavioral risk factors was highest among men and women aged 60 years and above. The prevalence of hypertension and hyperlipidemia was highest among the elderly, but the prevalence of diabetes and overweight/obesity was highest among the middle aged for both sexes. Age interactions in the association between behaviors and biological risk factors were surprisingly weak. However, age interactions were significant in the association between alcohol consumption and -hypertension, -overweight/obesity and -hyperlipidemia among women. While the prevalence of NCD risk factors tends to be higher among elders, the interaction between age and risk factors is complex. Most NCD risk factors are related to behaviors, which originate in young adulthood. It is necessary to diagnose and treat biological risk factors, in younger age groups before they manifest as NCDs. Similarly, behavior change interventions need to target these younger age groups to reduce the risk of NCDs later in life.

During the first half of their main-sequence lifetimes, stars rapidly lose angular momentum to their magnetized winds, a process known as magnetic braking. Recent observations suggest a substantial decrease in the magnetic braking efficiency when stars reach a critical value of the Rossby number, the stellar rotation period normalized by the convective overturn timescale. Cooler stars have deeper convection zones with longer overturn times, reaching this critical Rossby number at slower rotation rates. The nature and timing of the transition to weakened magnetic braking have previously been constrained by several solar analogs and two slightly hotter stars. In this Letter, we derive the first direct constraints from stars cooler than the Sun. We present new spectropolarimetry of the old G8 dwarf τ Cet from the Large Binocular Telescope, and we reanalyze a published Zeeman Doppler image of the younger G8 star 61 UMa, yielding the large-scale magnetic field strengths and morphologies. We estimate mass-loss rates using archival X-ray observations and inferences from Ly α measurements, and we adopt other stellar properties from asteroseismology and spectral energy distribution fitting. The resulting calculations of the wind braking torque demonstrate that the rate of angular momentum loss drops by a factor of 300 between the ages of these two stars (1.4–9 Gyr), well above theoretical expectations. We summarize the available data to help constrain the value of the critical Rossby number, and we identify a new signature of the long-period detection edge in recent measurements from the Kepler mission.

The Comprehensive Feeding Practices Questionnaire (CFPQ) has been evaluated in international studies, but the evaluation of its psychometric properties in Spanish, and in particular for parents of adolescents is still limited, and the invariance of measurement according to gender has not been evaluated. Therefore, the objectives of this study were: (1) To adapt the five-factor model of the CFPQ instrument to Spanish; (2) To examine the psychometric properties of this adaptation; and (3) To evaluate the measurement invariance of the model to verify the equivalence of measurement of the perceptions of food parenting practices between mothers and fathers belonging to nuclear, dual-earner families with adolescent children. Participants were 946 mothers and fathers from Southern Chile. Results showed that the conceptual equivalence for the CFPQ was achieved. An exploratory factor analysis was performed for a five-factor model: Monitoring, Child control, Restriction for weight control, Modeling and Environment. Horn’s parallel analysis identified four factors, while factor loading analysis determined the removal of the environment factor. Confirmatory factor analysis presented good reliability values. Convergent and discriminant validity was confirmed, and medium-to-high levels of goodness of fit were obtained, eliminating two items. Results supported a final model of four factors and 19 items. Multigroup analysis of the measurement model verified the configural and metric invariance between fathers and mothers, while the scalar and strict partial invariance was verified. These findings are a relevant guide to measure factorial scores in the four-factor model of the CFPQ, establishing a characterization of feeding practices of parents and adolescents.

Summary: To investigate long COVID-19 syndrome (LCS) pathophysiology, we performed an exploratory study with blood plasma derived from three groups: 1) healthy vaccinated individuals without SARS-CoV-2 exposure; 2) asymptomatic recovered patients at least three months after SARS-CoV-2 infection and; 3) symptomatic patients at least 3 months after SARS-CoV-2 infection with chronic fatigue syndrome or similar symptoms, here designated as patients with long COVID-19 syndrome (LCS). Multiplex cytokine profiling indicated slightly elevated pro-inflammatory cytokine levels in recovered individuals in contrast to patients with LCS. Plasma proteomics demonstrated low levels of acute phase proteins and macrophage-derived secreted proteins in LCS. High levels of anti-inflammatory oxylipins including omega-3 fatty acids in LCS were detected by eicosadomics, whereas targeted metabolic profiling indicated high levels of anti-inflammatory osmolytes taurine and hypaphorine, but low amino acid and triglyceride levels and deregulated acylcarnitines. A model considering alternatively polarized macrophages as a major contributor to these molecular alterations is presented.

Abstract Birch tar is one of the oldest adhesives known in human history. Its production has been discussed in the framework of early complex behaviours and sophisticated cognitive capacities. The precise production method used in the Palaeolithic remains unknown today. Arguments for or against specific production pathways have been based on efficiency or process complexity. No studies have addressed the question whether birch tar made with different techniques is more or less performant in terms of its properties. We therefore investigate the adhesive performance of birch tar made with three distinct methods: the open-air condensation method and two variations of underground structures that approximate the double-pot method in aceramic conditions. We use lap-shear testing, a standard mechanical test used for testing the strength of industrial adhesives. Tar made in 1 h with the condensation method has a shear strength similar to, although slightly higher than, tar made underground if the underground process lasts for 20 h. However, tars from shorter underground procedures (5 h) are significantly less strong (by a factor of about 3). These findings have important implications for our understanding of the relationship between the investment required for Palaeolithic birch tar production and the benefits that birch tar represented for early technology. In this regard, the simple and low-investment open-air condensation method provides the best ratio.

Current patterns of meat consumption are considered unsustainable. Plant-based products are presented as a solution. However, while some plant-based products thrive, others do not make the cut due to the information “framing” effect issues related to the way information is presented to the consumers. Information on the nutrition and health properties of food products are usually made available at the point of purchase, but their effect on consumer product evaluation and subsequent purchase intent can also occur later, during or after consumption. This research demonstrates that the effect of nutrition information on product evaluation and purchase intention depends on when such information is made available–before first tasting or after first tasting–and that the information interacts with the taste experience in its effect on product evaluation and subsequent purchase intent. Using three plant-based products as an example, we conducted a cross-cultural experimental sensory evaluation with temporal order of information as the main between-subject experimental condition (informed before taste vs. informed after taste vs. control condition), and product experience phase (expectation vs. experience vs. post-experience phase) and information content as within-subject conditions. Information content had two levels: lower vs. higher share of oat protein in the product (i.e., source of protein vs. high in protein). The results indicate that information generally increases consumers’ purchase intentions with information before tasting having a higher weight when compared to the condition when information was presented after tasting. Presenting the information before tasting also mitigates a drop in the evaluation of taste after tasting, observed in the two other conditions. Further, taste acts as a healthiness cue, but the direction of the inference depends on the availability of health-related information: tasting in the informed condition increased the healthiness perception, whereas tasting in the uninformed condition had the opposite effect. Giving the information before the first tasting also increased the weight of healthiness as compared to taste in the formation of purchase intentions. These findings contribute to a better understanding of the effect of temporal order of information and product tasting have on the consumers’ product evaluations of plant-based products from theoretical and managerial perspectives.

In recent years, measurement of quality of life has received increased attention. We use the satisfaction with life and subjective happiness scales in older adults living in urban areas in the Maule Region, Chile; generalized linear models are used (n = 396). We find that (1) gender is linked to satisfaction with life, (2) satisfaction with one’s own economic situation have significant effects on satisfaction with life and happiness, and (3) health, family and satisfaction with food are the most important predictors of both satisfaction with life and happiness.

Reciprocal family influences in the food domain have been little explored, particularly during the COVID-19 pandemic. To fill in this gap, this study explored actor and partner effects between parents’ food modeling and parents’ and their adolescent children’s diet quality and satisfaction with food-related life (SWFoL); and the mediating role of diet quality between modeling and SWFoL. This study used a cross-sectional design. A sample of 430 different-sex dual-earner parents and one adolescent child were recruited in Rancagua, Chile, between March and June 2020. Parents answered the modeling dimension of the Comprehensive Feeding Practices Questionnaire. Parents and adolescents answered the Adapted Healthy Eating Index (AHEI) and the SWFoL Scale. Analyses were conducted using the Actor-Partner Interdependence Model and structural equation modeling. Results showed that one parent’s modeling enhanced diet quality for themselves, their partner, and the adolescents. Parents’ modeling was associated with their own SWFoL, directly and via their own diet quality. There were positive associations between mothers’ modeling and adolescents’ SWFoL; between mothers’ diet quality and fathers’ SWFoL; and between mothers’ modeling and fathers’ SWFoL via the fathers’ diet quality. Parents’ modeling can improve the three family members’ diet quality, while mothers’ modeling and diet quality showed to improve fathers’ and adolescents’ SWFoL.

None of the clinical trials of omega-3 fatty acids using combinations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were able to show any effect on cardiovascular outcomes, despite reductions in triglyceride levels. In contrast, the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT), which employed high-dose (4 g) purified EPA, demonstrated a 25% reduction in atherosclerotic cardiovascular disease–related events compared with placebo (hazard ratio 0.75; 95% confidence interval 0.68–0.83; P

This study examined the relationships between diet quality, satisfaction with food-related life and life satisfaction in mother-adolescent dyads. The sample consisted of 470 mother-adolescent dyads in Temuco, Chile. Mothers and adolescents responded to the Adapted Healthy Eating Index, Satisfaction with Life Scale, and the Satisfaction with Food-related Life scale. Data was analyzed using the Actor-Partner Interdependence Model (APIM) and Structural Equation Modelling (SEM). Diet quality was associated with satisfaction with food-related life, which related to life satisfaction in mothers and adolescents. We did not find direct relationships between diet quality and life satisfaction for either dyad member. Adolescents’ diet quality negatively affected their mothers’ satisfaction with food-related life; adolescents’ food-related life was positively associated with their mothers’ life satisfaction. The mothers’ satisfaction with food-related life played a mediating role between their own diet quality and life satisfaction. Mothers and their adolescent children affect one another in their dietary patterns and life satisfaction. Child-to-mother influences on food-related experiences show that adolescents’ satisfaction with food-related life improves their own and their mothers’ life satisfaction. Interventions to promote healthy eating habits must be addressed to both mothers and their adolescent children.

Acute promyelocytic leukaemia (APL) can be cured by the co-administration of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA). These small molecules relieve the differentiation blockade of the transformed promyelocytes and trigger their maturation into functional neutrophils, which are physiologically primed for apoptosis. This normalization therapy represents a compelling alternative to cytotoxic anticancer chemotherapy, but lacks an in vitro model system for testing the efficiency of novel combination treatments consisting of inducers of differentiation and metallopharmaceuticals. Here, using proteome profiling we present an experimental framework that enables characterising the differentiation– and metal-specific effects of the combination treatment in a panel of acute myeloid leukaemia (AML) cell lines (HL-60 and U937), including APL (NB4). Differentiation had a substantial impact on the proteome on the order of 10% of the identified proteins and featured classical markers and transcription factors of myeloid differentiation. Additionally, ATO provoked specific cytoprotective effects in the AML cell lines HL-60 and U937. In HL-60, these effects included an integrated stress response (ISR) in conjunction with redox defence, while proteasomal responses and a metabolic rewiring were observed in U937 cells. In contrast, the APL cell line NB4 did not display such adaptions indicating a lack of plasticity to cope with the metal-induced stress, which may explain the clinical success of this combination treatment. Based on the induction of these cytoprotective effects, we proposed a novel metal-based compound to be used for the combination treatment instead of ATO. The organoruthenium drug candidate plecstatin-1 was previously shown to induce reactive oxygen species and an ISR. Indeed, the plecstatin-1 combination was found to affect similar pathways compared to the ATO combination in HL-60 cells and did not lead to cytoprotective response signatures in NB4. Moreover, the monocytic cell line U937 showed a low plasticity to cope with the plecstatin-1 combination, which suggests that this combination might achieve therapeutic benefit beyond APL. We propose that the cytoprotective plasticity of cancer cells might serve as a general proxy to discover novel combination treatments in vitro.

ABSTRACT Various commercial anti-Spike SARS-CoV-2 antibody tests are used for studies and in clinical settings after vaccination. An international standard for SARS-CoV-2 antibodies has been established to achieve comparability of such tests, allowing conversions to BAU/mL. This study aimed to investigate the comparability of antibody tests regarding the timing of blood collection after vaccination. For this prospective observational study, antibody levels of 50 participants with homologous AZD1222 vaccination were evaluated at 3 and 11 weeks after the first dose and 3 weeks after the second dose using two commercial anti-Spike binding antibody assays (Roche and Abbott) and a surrogate neutralization assay. The correlation between Roche and Abbott changed significantly depending on the time point studied. Although Abbott provided values three times higher than Roche 3 weeks after the first dose, the values for Roche were twice as high as for Abbott 11 weeks after the first dose and 5 to 6 times higher at 3 weeks after the second dose. The comparability of quantitative anti-Spike SARS-CoV-2 antibody tests was highly dependent on the timing of blood collection after vaccination. Therefore, standardization of the timing of blood collection might be necessary for the comparability of different quantitative SARS-COV-2 antibody assays. IMPORTANCE This work showed that the comparability of apparently standardized SARS-CoV-2 antibody assays (Roche, Abbott; both given in BAU/mL) after vaccination depends on the time of blood withdrawal. Initially (3 weeks after the first dose AZD1222), there were 3 times higher values in the Abbott assay, but this relationship inversed before boosting (11 weeks after the first dose) with Roche 2 times greater than Abbott. After the booster, Roche quantified ca. 5 times higher levels than Abbott. This must be considered by clinicians when interpreting SARS-CoV-2 antibody levels.

We propose a quantitative framework for understanding the knapping force requirements imposed by different raw materials in their unheated and heat-treated states. Our model interprets stone tool knapping as being the result of cracks formed during the first impact with a hammer stone, followed by continued stressing of these cracks that eventually leads to flake detachment. We combine bending strength, indentation fracture resistance and "Griffith" crack lengths of flint and silcrete to obtain functions identifying critical forces for flaking without or after heat treatment. We argue that these forces are a key factor for understanding the "knappability" of different raw materials, because only forces with 100N or less can be used for very precise strike control. Our model explains for the first time why experimental knappers frequently observe that flint (a stronger material, which, in our case, has a strength above 100 MPa) is easier to knap than silcretes (which is relatively weaker with strength values at or below 60 MPa). Our findings allow for understanding the differences between heat-treated and untreated flint and silcrete in terms of knapping quality, and they allow to compare the qualities of different raw materials.

Background and aims Familial dysbetalipoproteinemia (FDBL) is a rare inborn lipid disorder characterized by the formation of abnormal triglyceride- and cholesterol-rich lipoproteins (remnant particles). Patients with FDBL have a high risk for atherosclerotic disease. The effect of PCSK9 inhibition on lipoproteins and its subfractions has not been evaluated in FDBL. Methods Three patients (65±7 years, 23±3 kg/m2, 2 females) with FDBL (diagnosed by isoelectrofocusing) and atherosclerosis (coronary and/or cerebro-vascular and/or peripheral arterial disease) resistant or intolerant to statin and fibrate therapy received evolocumab (140mg every 14 days). In addition to a fasting lipid profile (preparative ultracentrifugation), apoB and cholesterol concentrations were determined in 15 lipoprotein-subfractions (density gradient ultracentrifugation; d 1.006–1.21g/ml) before and after 12 weeks of evolocumab treatment. Patients with LDL-hypercholesterolemia (n = 8, 56±8 years, 31±7 kg/m2) and mixed hyperlipidemia (n = 5, 68±12 years, 30±1 kg/m2) also receiving evolocumab for 12 weeks were used for comparison. Results All patients tolerated PCSK9 inhibition well. PCSK9 inhibitors reduced cholesterol (29–37%), non-HDL-cholesterol (36–50%) and apoB (40–52%) in all patient groups including FDBL. In FDBL, PCSK9 inhibition reduced VLDL-cholesterol and the concentration of apoB containing lipoproteins throughout the whole density spectrum (VLDL, IDL, remnants, LDL). Lipoprotein(a) was decreased in all patient groups to a similar extent. Conclusions This indicates that the dominant fraction of apoB-containing lipoproteins is reduced with PCSK9 inhibition, i.e. LDL in hypercholesterolemia and mixed hyperlipidemia, and cholesterol-rich VLDL, remnants and LDL in FDBL. PCSK9 inhibition may be a treatment option in patients with FDBL resistant or intolerant to statin and/or fibrate therapy.

In Nepal, deaths attributable to NCDs have increased in recent years. Although NCDs constitute a major public health problem, how best to address this has not received much attention. The objective of this study was to assess the readiness of the Nepalese health sector for the prevention and control of NCDs and their risk factors. The study followed a multi-method qualitative approach, using a review of policy documents, focus group discussions (FGDs), and in-depth interviews (IDIs) conducted between August and December 2020. The policy review was performed across four policy categories. FGDs were undertaken with different cadres of health workers and IDIs with policy makers, program managers and service providers. We performed content analysis using the WHO health system building blocks framework as the main categories. Policy documents were concerned with the growing NCD burden, but neglect the control of risk factors. FGDs and IDIs reveal significant perceived weaknesses in each of the six building blocks. According to study participants, existing services were focused on curative rather than preventive interventions. Poor retention of all health workers in rural locations, and of skilled health workers in urban locations led to the health workers across all levels being overburdened. Inadequate quantity and quality of health commodities for NCDs emerged as an important logistics issue. Monitoring and reporting for NCDs and their risk factors was found to be largely absent. Program decisions regarding NCDs did not use the available evidence. The limited budget dedicated to NCDs is being allocated to curative services. The engagement of non-health sectors with the prevention and control of NCDs remained largely neglected. There is a need to redirect health sector priorities towards NCD risk factors, notably to promote healthy diets and physical activity and to limit tobacco and alcohol consumption, at policy as well as community levels.

The study of lithic raw material quality has become one of the major interpretive tools to investigate the raw material selection behaviour and its influence to the knapping technology. In order to make objective assessments of raw material quality, we need to measure their mechanical properties (e.g., fracture resistance, hardness, modulus of elasticity). However, such comprehensive investigations are lacking for the Palaeolithic of Kazakhstan. In this work, we investigate geological and archaeological lithic raw material samples of chert, porphyry, and shale collected from the Inner Asian Mountain Corridor (henceforth IAMC). Selected samples of aforementioned rocks were tested by means of Vickers and Knoop indentation methods to determine the main aspect of their mechanical properties: their indentation fracture resistance (a value closely related to fracture toughness). These tests were complemented by traditional petrographic studies to characterise the mineralogical composition and evaluate the level of impurities that could have potentially affected the mechanical properties. The results show that materials, such as porphyry possess fracture toughness values that can be compared to those of chert. Previously, porphyry was thought to be of lower quality due to the anisotropic composition and coarse feldspar and quartz phenocrysts embedded in a silica rich matrix. However, our analysis suggests that different raw materials are not different in terms of indentation fracture resistance. This work also offers first insight into the quality of archaeological porphyry that was utilised as a primary raw material at various Upper Palaeolithic sites in the Inner Asian Mountain Corridor from 47-21 ka cal BP.

The discovery of hepadnaviruses in cats (domestic cat hepadnavirus, DCH) and of a DCH-like virus in dogs has raised several questions regarding the role of these viruses in pets, with particular emphasis on their potential impact on animal health and epidemiology, as well as possible zoonotic implications. In this study, by screening an age-stratified collection of 600 canine serum samples for DCH with an ELISA assay based on the recombinant core antigen (DCHCAg), specific antibodies were found with an overall prevalence of 10.0% (60/600), with a higher prevalence in younger and older dogs. By retesting the canine DCHCAbs-positive sera with an ELISA test based on the recombinant surface protein of DCH (DCHSAg), a total of 18 sera (30%, 18/60) also contained IgG anti-DCHSAg. All the sera were also assessed molecularly using either a consensus hepadnavirus PCR or a specific real-time PCR for DCH. Hepadnavirus DNA was detected in four seronegative dogs, with a prevalence rate of 0.7% (4/600). On sequence analysis of the polymerase region amplified with pan-hepadnavirus primers, the amplicons displayed the highest nucleotide identity (97.3–99.6%) to DCH sequences detected in cats and to the domestic dog hepadnavirus recently identified in a canine serum sample from Italy.

The bright star λ Ser hosts a hot Neptune with a minimum mass of 13.6 M _⊕ and a 15.5 day orbit. It also appears to be a solar analog, with a mean rotation period of 25.8 days and surface differential rotation very similar to the Sun. We aim to characterize the fundamental properties of this system and constrain the evolutionary pathway that led to its present configuration. We detect solar-like oscillations in time series photometry from the Transiting Exoplanet Survey Satellite, and we derive precise asteroseismic properties from detailed modeling. We obtain new spectropolarimetric data, and we use them to reconstruct the large-scale magnetic field morphology. We reanalyze the complete time series of chromospheric activity measurements from the Mount Wilson Observatory, and we present new X-ray and ultraviolet observations from the Chandra and Hubble space telescopes. Finally, we use the updated observational constraints to assess the rotational history of the star and estimate the wind braking torque. We conclude that the remaining uncertainty on the stellar age currently prevents an unambiguous interpretation of the properties of λ Ser, and that the rate of angular momentum loss appears to be higher than for other stars with a similar Rossby number. Future asteroseismic observations may help to improve the precision of the stellar age.

We measure abundances of 12 elements (Na, Mg, Si, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni) in a sample of 86 metal-poor (−2 ≲ [Fe/H] ≲ −1) subgiant stars in the solar neighborhood. Abundances are derived from high-resolution spectra taken with the Potsdam Echelle Polarimetric and Spectroscopic Instrument on the Large Binocular Telescope, modeled using iSpec and MOOG. By carefully quantifying the impact of photon-noise (

Recent observations have shown that the atmospheres of ultrahot Jupiters (UHJs) commonly possess temperature inversions, where the temperature increases with increasing altitude. Nonetheless, which opacity sources are responsible for the presence of these inversions remains largely observationally unconstrained. We used LBT/PEPSI to observe the atmosphere of the UHJ KELT-20 b in both transmission and emission in order to search for molecular agents which could be responsible for the temperature inversion. We validate our methodology by confirming a previous detection of Fe i in emission at 16.9 σ . Our search for the inversion agents TiO, VO, FeH, and CaH results in non-detections. Using injection-recovery testing we set 4 σ upper limits upon the volume mixing ratios for these constituents as low as ∼1 × 10 ^−9 for TiO. For TiO, VO, and CaH, our limits are much lower than expectations from an equilibrium chemical model, while we cannot set constraining limits on FeH with our data. We thus rule out TiO and CaH as the source of the temperature inversion in KELT-20 b, and VO only if the line lists are sufficiently accurate.

In phenylalanine hydroxylase (PAH) deficiency, an easily feasible method to access the progression of neurodegeneration is warranted to contribute to current discussions on treatment indications and targets. The objective of the present study was to investigate whether optical coherence tomography (OCT) measures as markers of neurodegeneration differ between patients with PAH deficiency and healthy controls (HCs) according to phenotype and metabolic control. In this single-center cross-sectional study, 92 patients with different phenotypes of PAH deficiency [PAH deficiency not requiring treatment, early treated phenylketonuria (ETPKU), and late-diagnosed phenylketonuria (PKU)] compared with 76 HCs were examined using spectral-domain OCT. Indices of phenylalanine elevation and variability were correlated with OCT parameters. Late-diagnosed PKU patients showed reduced peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIPL) volume. Adult ETPKU patients were found to have lower GCIPL volume (p = 0.016), which correlated with the indices of phenylalanine control. In pediatric ETPKU patients with poor metabolic control, pRNFL was significantly reduced (p = 0.004). Patients with PAH deficiency not requiring treatment did not exhibit retinal degeneration. Inner nuclear layer (INL) was significantly increased in the pediatric ETPKU patients, driven by those with current poor metabolic control (p = 0.006). Our data provide evidence of retinal neuroaxonal degeneration and INL swelling, depending on the phenotype, current age, and metabolic control. These findings suggest that OCT is suitable to investigate neurodegeneration in PKU and we propose OCT as a sensitive, reliable, safe, low-burden, and low-cost examination for future multicenter studies.

This study aimed to determine the specific cytokine profile in peripheral blood during the early onset of COVID-19 infection. This was a cross-sectional exploratory, single center study. A total of 55 plasma samples were studied. Serum samples of adults showing symptoms of COVID-19 infection who were tested positive for SARS-CoV-2 infection (CoV+, n=18) at the COVID-19 outpatient clinic of the Medical University of Vienna were screened for immune activation markers by Luminex technology. Additionally, age and gender-matched serum samples of patients displaying COVID-19 associated symptoms, but tested negative for SARS-CoV-2 (CoV-, n=16) as well as healthy controls (HC, n=21) were analyzed. COVID-19 positive (CoV+) patients showed a specific upregulation of BLC (141; 74-189 pg/mL), SCD30 (273; 207-576 pg/mL), MCP-2 (18; 12-30 pg/mL) and IP-10 (37; 23-96 pg/mL), compared to patients with COVID19-like symptoms but negative PCR test (CoV-), BLC (61; 22-100 pg/mL), sCD30L (161; 120-210 pg/mL), MCP-2 (8; 5-12 pg/mL) and IP-10 (9; 6-12 pg/mL) and healthy controls (HC) (BLC 22; 11-36 pg/mL, sCD30 74; 39-108 pg/mL, MCP-2 6; 3-9. pg/mL, IP-10 = 8; 5-13). The markers APRIL, sIL-2R, IL7, MIF, MIP-1b, SCF, SDF-1a, sTNF-RII were elevated in both CoV+ and CoV- patient groups compared to healthy controls. HGF, MDC and VEGF-A were elevated in CoV- but not CoV+ compared to healthy controls. BLC, sCD30, MCP-2 and IP-10 are specifically induced during early stages of COVID-19 infection and might constitute attractive targets for early diagnosis and treatment of this disease.

Abstract Background Several lipid guidelines recommend that proprotein convertase subtilisin/kexin type 9 inhibitors should be considered for patients with atherosclerotic cardiovascular disease who are inadequately treated with maximally tolerated lipid-lowering treatment. Objectives The PEARL study assessed the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in patients with hypercholesterolemia in a real-world setting. Methods PEARL was an open, prospective, multicenter, non-interventional study conducted in Germany. Patients (n = 619) for whom treating physicians decided to use alirocumab 75 or 150 mg every 2 weeks according to German guidelines (low-density lipoprotein cholesterol > 1.8/2.6 mmol/L [> 70/100 mg/dL], depending on cardiovascular risk, despite maximally tolerated statin therapy with/without other non-alirocumab lipid-lowering therapy) were enrolled and followed for 24 weeks. Physicians could adjust the alirocumab dose based on their clinical judgment. The primary efficacy endpoint was low-density lipoprotein cholesterol reduction from baseline (prior to alirocumab therapy) to week 24. Results Overall, 72.8% of patients reported complete or partial statin intolerance. Mean low-density lipoprotein cholesterol was 4.7 mmol/L (180.5 mg/dL) and 2.3 mmol/L (89.8 mg/dL) at baseline and week 24, respectively. Least-squares mean percentage change from baseline to week 24 in low-density lipoprotein cholesterol was − 48.6%. Initial alirocumab dose was 75 mg in 72.9% of patients and 150 mg in 24.5% of patients; 19.6% of patients received an alirocumab dose increase (75 to 150 mg) and 1.6% of patients received a dose decrease. Adverse events were reported in 10.3% of patients, with myalgia being the most common. Conclusions In a real-world setting in Germany, alirocumab was used in patients who had high baseline low-density lipoprotein cholesterol levels with/without statin intolerance. Efficacy and safety were consistent with findings observed in the ODYSSEY Phase III program.

Background: Onychomycosis numbers among the most common fungal infections in humans affecting finger- or toenails. Histology remains a frequently applied screening technique to diagnose onychomycosis. Screening slides for fungal elements can be time-consuming for pathologists, and sensitivity in cases with low amounts of fungi remains a concern. Convolutional neural networks (CNNs) have revolutionized image classification in recent years. The goal of our project was to evaluate if a U-NET-based segmentation approach as a subcategory of CNNs can be applied to detect fungal elements on digitized histologic sections of human nail specimens and to compare it with the performance of 11 board-certified dermatopathologists. Methods: In total, 664 corresponding H&E- and PAS-stained histologic whole-slide images (WSIs) of human nail plates from four different laboratories were digitized. Histologic structures were manually annotated. A U-NET image segmentation model was trained for binary segmentation on the dataset generated by annotated slides. Results: The U-NET algorithm detected 90.5% of WSIs with fungi, demonstrating a comparable sensitivity with that of the 11 board-certified dermatopathologists (sensitivity of 89.2%). Conclusions: Our results demonstrate that machine-learning-based algorithms applied to real-world clinical cases can produce comparable sensitivities to human pathologists. Our established U-NET may be used as a supportive diagnostic tool to preselect possible slides with fungal elements. Slides where fungal elements are indicated by our U-NET should be reevaluated by the pathologist to confirm or refute the diagnosis of onychomycosis.

This paper reported a case of a metastrongyloid nematode Angiostrongylus vasorum infection in a fennec (Vulpes zerda) kept in a zoo in central Italy. The fennec had shown paralysis of the hind limbs, anorexia, weakness and respiratory signs before death. Cardiomegaly and granulomatous pneumonia were the major anatomopathological findings. Inflammatory lesions associated with parasitic larvae were observed in the lungs, brain, liver, heart, spinal cord and kidney of the fennec at histology. A. vasorum diagnosis was confirmed by both morphological and molecular identification of adult worms recovered at necropsy. Fennecs are active predators and maintain their hunting behaviour in captivity. Hence, it is likely that the animal was exposed to infection by preying on parasitised gastropods, intermediate hosts of A. vasorum, entering zoo enclosures from the surrounding environment. This is the first report of A. vasorum systemic infection in a captive fennec (V. zerda) in a zoo in Italy.

Cutaneous vascular tumors consist of a heterogeneous group of benign proliferations, including a range of hemangiomas and vascular malformations, as well as heterogeneous groups of both borderline and malignant neoplasms such as Kaposi’s sarcoma and angiosarcomas. The genetics of these tumors have been assessed independently in smaller individual cohorts making comparisons difficult. In our study, we analyzed a representative cohort of benign vascular proliferations observed in a clinical routine setting as well as a selection of malignant vascular proliferations. Our cohort of 104 vascular proliferations including hemangiomas, malformations, angiosarcomas and Kaposi’s sarcoma were screened by targeted next-generation sequencing for activating genetic mutations known or assumed to be potentially relevant in vascular proliferations. An association analysis was performed for mutation status and clinico-pathological parameters. Frequent activating hotspot mutations in GNA genes, including GNA14 Q205, GNA11 and GNAQ Q209 were identified in 16 of 64 benign vascular tumors (25%). GNA gene mutations were particularly frequent (52%) in cherry (senile) hemangiomas (13 of 25). In angiosarcomas, activating RAS mutations (HRAS and NRAS) were identified in three samples (16%). No activating GNA or RAS gene mutations were identified in Kaposi’s sarcomas. Our study identifies GNA14 Q205, GNA11 and GNAQ Q209 mutations as being the most common and mutually exclusive mutations in benign hemangiomas. These mutations were not identified in malignant vascular tumors, which could be of potential diagnostic value in distinguishing these entities.

Organizations increasingly use technology-mediated interviews. However, only limited research is available concerning the comparability of different interview media and most of the available studies stem from a time when technology-mediated interviews were less common than in the present time. In an experiment using simulated selection interviews, we compared traditional face-to-face (FTF) interviews with telephone and videoconference interviews to determine whether ratings of interviewees’ performance, their perceptions of the interview, or their strain and anxiety are affected by the type of interview. Before participating in the actual interview, participants had a more positive view of FTF interviews compared to technology-mediated interviews. However, fairness perceptions did not differ anymore after the interview. Furthermore, there were no differences between the three interview media concerning psychological and physiological indicators of strain or interview anxiety. Nevertheless, ratings of interviewees’ performance were lower in the technology-mediated interviews than in FTF interviews. Thus, differences between different interview media can still be found nowadays even though most applicants are much more familiar with technology-mediated communication than in the past. The results show that organizations should take this into account and therefore avoid using different interview media when they interview different applicants for the same job opening.

Applicants use faking in selection interviews to create a favorable impression and to increase their chances for a job offer. Theoretical models assume that such a behavior is influenced by situational and dispositional variables. However, previous research has mainly focused on dispositional variables whereas research about situational variables is sparse. To address this gap, we conducted three studies in which we examined how competition for a job and warning interviewees that information from their answers will be verified can influence faking intentions. Furthermore, we wanted to know whether these situational variables are able to explain additional variance in faking intentions beyond dispositional variables and whether there are interactions between situational and dispositional variables. In Study 1, we only found that high competition led to slightly higher faking intentions than low competition in a student sample. In Study 2, only a warning about the verification of applicants’ answers led to slightly lower faking intentions compared to no warning concerning verification in a working sample. Furthermore, faking intentions were lower in Study 2 than in the student sample in Study 1. In Study 3, we found no impact of our situational variables in a combined sample of students and non-students. We only found slightly higher honest impression management intentions in the high competition and the verification warning condition. We also found hardly any support for interaction effects between the situational and dispositional variables. Furthermore, the situational variables did not explain additional variance beyond the dispositional variables in any of the three studies. Possible reasons for the non-significant or small effect sizes for the situational variables can be found in a qualitative analysis of answers to an open-ended question in Study 3. However, we found that Honesty-humility und all facets of the Dark Triad were related to faking intentions. These results indicate that dispositional variables in particular have an impact on faking intentions.

Deep penetrating nevi (DPN) are rare melanocytic nevi, which can exhibit atypical histological features hampering the differentiation from malignant melanoma. DPN are considered benign melanocytic lesions, but rare spread to lymph nodes and unfavorable clinical outcomes associated with borderline/atypical DPN (B-DPN) has been reported. Since no guidelines are available for DPN and B-DPN, we aimed to review the literature on DPN and B-DPN to assess the management and prognosis. We screened 3,513 references from EMBASE, Scopus and Medline databases, and included 15 studies with a total of 355 DPN patients and 48 B-DPN patients. Therapeutic interventions ranged from simple excision to wide excisions and sentinel lymph node biopsy (SLNB), with block lymph node dissection in some positive SLNB cases. Follow-up periods ranged from 3 months to 23 years during which a total of five recurrences, two in DPN and three in B-DPN group, and three metastases, in B-DPN group, were reported. While some of the included studies comprised clinical and histopathological correlation, few included genetic assessment. The present review highlights the need for prospective cohort studies applying composite measures to identify effective regimens of diagnostic workup and treatment in DPN and B-DPN.

This study explored the spillover and crossover associations between satisfaction with food-related life and life satisfaction in mothers, fathers and adolescent children in dual-earned families. This is a cross-sectional design study with mothers, fathers and children surveyed in Temuco, Chile. The participants were 303 dual-earner parents and their adolescent children (mean age 13.3 years, 51.5% female). Actor-partner Interdependence Model (APIM) and structural equation modeling were used to explore spillover (actor effect) and crossover (partner effect) associations among family members. As a result, fathers’ satisfaction with food-related life was positively associated with their own life satisfaction (p ≤ 0.01), as well as with their partner’s (mother’s) satisfaction with life (p ≤ 0.05), but not with their adolescent child’s life satisfaction (p > 0.1). Mothers and children presented positive spillovers between their own levels of satisfaction with food-related life and life satisfaction (p ≤ 0.01). No crossover effects were found between mothers and children (p > 0.1). This study results underscore the positive association between satisfaction with food-related life and life satisfaction among members of dual-earner families with adolescent children. Special efforts should be made by dual-earner parents to improve the variables related to their satisfaction with food-related life as well as their children’s satisfaction.

Previous research on the construct validity of assessment center (AC) ratings has usually struggled to find support for dimension factors as an underlying source of variance of these ratings. Confirmatory factor analysis (CFA) remains the most widely used method to specify and validate the internal structure of AC ratings. However, the research support for dimension effects in AC ratings remains mixed. In addition, competing CFA models (e.g., correlated dimensions-correlated exercises models) are often plagued by non-convergence and estimation problems. Recently, it has been proposed that increasing the number of indicators per dimension and exercise combination might help to find support for dimension factors, in addition to exercise factors, in CFAs of AC ratings. Furthermore, it was also suggested that the increased ratio of indicators to dimensions may also solve some of the methodological problems associated with CFA models used to model AC ratings. However, in this research it remained unclear whether the support for dimension factors was solely due to the use of a larger indicator-dimension ratio or due to parceling that combines several behavioral indicators per dimension and exercise combination into more reliable measures of the targeted dimension. These are important empirical questions that have been left unanswered in the literature but can be potentially meaningful in seeking more balanced support for dimension effects in AC research. Using data from N = 213 participants from a 1-day AC, we aimed to investigate the impact of using different indicator-dimension ratios when specifying CFA models of AC ratings. Therefore, we investigated the impact of using different indicator-dimension ratios in the form of item parcels with data from an operational AC. On average, using three parcels eventually led to support for dimension factors in CFAs. However, exercise-based CFA models still performed better than dimension-based models. Thus, the present results point out potential limits concerning the generalizability of recent results that provided support for dimension factors in ACs.

Background: Immunoglobulin(Ig)E-associated allergies result from misguided immune responses against innocuous antigens. CD4+ T lymphocytes are critical for initiating and perpetuating that process, yet the crucial factors determining whether an individual becomes sensitized towards a given allergen remain largely unknown. Objective: To determine the key factors for sensitization and allergy towards a given allergen. Methods: We here created a novel human T cell receptor(TCR) and human leucocyte antigen (HLA)-DR1 (TCR-DR1) transgenic mouse model of asthma, based on the human-relevant major mugwort (Artemisia vulgaris) pollen allergen Art v 1 to examine the critical factors for sensitization and allergy upon natural allergen exposure via the airways in the absence of systemic priming and adjuvants. Results: Acute allergen exposure led to IgE-independent airway hyperreactivity (AHR) and T helper(Th)2-prone lung inflammation in TCR-DR1, but not DR1, TCR or wildtype (WT) control mice, that was alleviated by prophylactic interleukin(IL)-2-αIL-2 mAb complex-induced expansion of Tregs. Chronic allergen exposure sensitized one third of single DR1 transgenic mice, however, without impacting on lung function. Similar treatment led to AHR and Th2-driven lung pathology in >90% of TCR-DR1 mice. Prophylactic and therapeutic expansion of Tregs with IL-2-αIL-2 mAb complexes blocked the generation and boosting of allergen-specific IgE associated with chronic allergen exposure. Conclusions: We identify genetic restriction of allergen presentation as primary factor dictating allergic sensitization and disease against the major pollen allergen from the weed mugwort, which frequently causes sensitization and disease in humans. Furthermore, we demonstrate the importance of the balance between allergen-specific T effector and Treg cells for modulating allergic immune responses. Keywords: Sensitization, Airway hyperreactivity, T regulatory cells, IL-2-αIL-2 complexes, Allergen-specific TCR, Tolerance, Aeroallergen, Mugwort allergy

Objective: Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function. Methods: We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization. Results: GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies. Conclusions: Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity. Keywords: Neuropeptide, Hypothalamus, Sympathetic nerve, Adipose tissue, Obesity