Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.

Smoking-related cues elicit craving and mesocorticolimbic brain activation in smokers. Severity of nicotine dependence seems to moderate cue reactivity, but the direction and mechanisms of its influence remains unclear. Although tobacco control policies demand a ban on tobacco advertising, cue reactivity studies in smokers so far have not employed tobacco advertisement as experimental stimuli. We investigated whether tobacco advertisement elicits cue reactivity at a behavioral (subjective craving) and a neural level (using functional magnetic resonance imaging) in 22 smokers and 21 never-smokers. Moreover, we studied the influence of severity of dependence on cue reactivity. In smokers, tobacco advertisement elicited substantially more craving than control advertisement whereas never-smokers reported no cue induced craving. Surprisingly, neuronal cue reactivity did not differ between smokers and never-smokers. Moderately dependent smokers' craving increased over the course of the experiment, whereas highly dependent smokers' craving was unaffected. Moderately dependent smokers' brain activity elicited by tobacco advertisement was higher in the amygdala, hippocampus, putamen and thalamus compared with highly dependent smokers. Furthermore, limbic brain activation predicted picture recognition rates after the scanning session, even in never-smokers. Our findings show that tobacco advertisement elicits cigarette craving and neuronal cue reactivity primarily in moderately dependent smokers, indicating that they might be particularly responsive towards external smoking-related cues. On the other hand, neuronal cue reactivity and cigarette craving in highly dependent smokers is more likely triggered by internal cues such as withdrawal symptoms. Tobacco advertisement seems to likewise appeal to smokers and non-smokers, clarifying the potential danger especially for young non-smokers.

Objectives:The aim of this cross-sectional study was to investigate whether sex hormones (testosterone, oestradiol, sex-hormone-binding globulin = SHBG) are associated with general joint laxity (GJL) and hypermobility or derangements of the temporomandibular joint (TMJ) in adolescents. Methods:Within the LIFE Child study, 970 adolescents (10-18 years) were included.GJL was assessed using the Beighton test. Maximum mouth opening (MMO) and clinical clicking sounds as signs of disc displacement (DD) in the TMJ were assessed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD).Serum levels of sex hormones were assessed using standardised laboratory analyses.Results: Hypermobile joints were found in 54.9% (N = 532) of the sample; females were more affected than males (61.4% vs. 51.8%, P < 0.001). Using logistic regression analyses, the odds ratio (OR) for having >1 hypermobile joints increased to 1.15 (95% confidence interval [CI]: 1.04-1.27) in males and 1.09 (95% CI: 1.02-1.17) in females per 10 units of the SHBG serum level, compared to those without hypermobile joints-after controlling for the effect of age, adjusted BMI, pubertal development (Tanner scale), testosterone as well as oestradiol levels. Female subjects with >1 hypermobile joints showed a higher OR (1.89; 95% CI: 1.05-3.43) for having clinical clicking sounds in the TMJ and a 3.28 times higher OR (95% CI: 1.44-7.44) for MMO ≥ 55 mm. Conclusions:We observed age-and gender-independent associations of higher SHBG serum levels with GJL in adolescents. Moreover, hypermobile female adolescents show a more frequent hypermobility of the TMJ and clinical signs of DD. K E Y W O R D Sadolescents, general joint laxity, hypermobility, sex hormones, temporomandibular disorders

Dopamine (DA) modulates the response of the amygdala. However, the relation between dopaminergic neurotransmission in striatal and extrastriatal brain regions and amygdala reactivity to affective stimuli has not yet been established. To address this issue, we measured DA D2/D3 receptor (DRD2/3) availability in twenty-eight healthy men (nicotine-dependent smokers and never-smokers) using positron emission tomography with [ 18 F]fallypride. In the same group of participants, amygdala response to unpleasant visual stimuli was determined using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. The effects of DRD2/3 availability in emotion-related brain regions and nicotine dependence on amygdala response to unpleasant stimuli were examined by multiple regression analysis. We observed enhanced prefrontal DRD2/3 availability in those individuals with higher amygdala response to unpleasant stimuli. As compared to never-smokers, smokers showed an attenuated amygdala BOLD response to unpleasant stimuli. Thus, individuals with high prefrontal DRD2/3 availability may be more responsive toward aversive and stressful information. Through this mechanism, dopaminergic neurotransmission might influence vulnerability for affective and anxiety disorders. Neuronal reactivity to unpleasant stimuli seems to be reduced by smoking. This observation could explain increased smoking rates in individuals with mental disorders. Hum Brain Mapp 31:716-726,

Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.

Incentives have surprisingly inconsistent effects when it comes to encouraging people to behave prosocially. Classical economic theory, according to which a specific behavior becomes more prevalent when it is rewarded, struggles to explain why incentives sometimes backfire. More recent theories therefore posit a reputational cost offsetting the benefits of receiving an incentive -yet unexplained effects of incentives remain, for instance across incentive types and countries. We propose that social norms can offer an explanation for these inconsistencies. Ultimately, social norms determine the reputational costs or benefits resulting from a given behavior, and thus variation in the effect of incentives may reflect variation in norms. We implemented a formal model of prosocial behavior integrating social norms, which we empirically tested on the real-world prosocial behavior of blood donation. Blood donation is essential for many life-saving medical procedures, but also presents an ideal testing ground for our theory: Various incentive policies for blood donors exist across countries, enabling a comparative approach. Our preregistered analyses reveal that social norms can indeed account for the varying effects of financial and time incentives on individual-level blood donation behavior across 28 European countries. Incentives are associated with higher levels of prosociality when norms regarding the incentive are more positive. The results indicate that social norms play an important role in explaining the relationship between incentives and prosocial behavior. More generally, our approach highlights the potential of integrating theory from across the economic and behavioral sciences to generate novel insights, with tangible consequences for policy-making.

Blood donors are indispensable for enabling a myriad of medical procedures and treatments. Although blood donation takes place in a medical setting within the larger healthcare system, little is known about how (perceptions of) these healthcare systems shape an individual’s decision to donate. In this study, we examined how public trust in the healthcare system and indicators of healthcare quality relate to individuals' likelihood of donating blood across Europe. We employed large-scale survey data on blood donation behavior from representative samples of 28 European countries (N = 27,868). This dataset was combined with country-level data on public trust in the healthcare system and healthcare quality. We used multilevel models to examine the effects of individual- and country-level factors on individual-level blood donation behavior. Our preregistered analyses revealed that public trust was positively associated with donating blood. That is, individuals living in countries where trust in the healthcare system is higher were more likely to have donated blood. However, we found no clear evidence that healthcare quality predicted blood donation. Notably, most countries exhibited a decrease in public trust in the healthcare system while healthcare quality increased over time. Our results suggest that subjective perceptions of the healthcare system (i.e., public trust), rather than the objective state of healthcare, play a role for blood donation behavior. We highlight the implications of our findings for vital blood collection efforts in light of the observed erosion of public trust over time.

Impersonal cooperation among strangers enables societies to create valuable public goods, such as infrastructure, public services, and democracy. Several factors have been proposed to explain variation in impersonal cooperation across societies, referring to institutions (e.g., rule of law), religion (e.g., belief in God as a third-party punisher), cultural beliefs (e.g., trust) and values (e.g., collectivism), and ecology (e.g., relational mobility). We tested 17 pre-registered hypotheses in a meta-analysis of 1,506 studies of impersonal cooperation in social dilemmas (e.g., the Public Goods Game) conducted across 70 societies (k = 2,271), where people make costly decisions to cooperate among strangers. After controlling for 10 study characteristics that can affect the outcome of studies, we found very little cross-societal variation in impersonal cooperation. Categorizing societies into cultural groups explained no variance in cooperation. Similarly, cultural, ancestral, and linguistic distance between societies explained little variance in cooperation. None of the cross-societal factors hypothesized to relate to impersonal cooperation explained variance in cooperation across societies. We replicated these conclusions when meta-analyzing 514 studies across 41 states and nine regions in the United States (k = 783). Thus, we observed that impersonal cooperation occurred in all societies – and to a similar degree across societies – suggesting that prior research may have overemphasized the magnitude of differences between modern societies in impersonal cooperation. We discuss the discrepancy between theory, past empirical research and the meta-analysis, address a limitation of experimental research on cooperation to study culture, and raise possible directions for future research.