Behavioral Phenotyping of Dopamine Transporter Knockout Rats: Compulsive Traits, Motor Stereotypies, and Anhedonia

Alterations in dopamine neurotransmission are generally associated with diseases such as attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Such diseases typically feature poor decision making and lack of control on executive functions and have been studied through the years using many animal models. Dopamine transporter (DAT) knockout (KO) and heterozygous (HET) mice, in particular, have been widely used to study ADHD. Recently, a strain of DAT KO rats has been developed (1). Here, we provide a phenotypic characterization of reward sensitivity and compulsive choice by adult rats born from DAT-HET dams bred with DAT-HET males, in order to further validate DAT KO rats as an animal model for preclinical research. We first tested DAT KO rats' sensitivity to rewarding stimuli, provided by highly appetitive food or sweet water; then, we tested their choice behavior with an Intolerance-to-Delay Task (IDT). During these tests, DAT KO rats appeared less sensitive to rewarding stimuli than wild-type (WT) and HET rats: they also showed a prominent hyperactive behavior with a rigid choice pattern and a wide number of compulsive stereotypies. Moreover, during the IDT, we tested the effects of amphetamine (AMPH) and RO-5203648, a trace amine-associated receptor 1 (TAAR1) partial agonist. AMPH accentuated impulsive behaviors in WT and HET rats, while it had no effect in DAT KO rats. Finally, we measured the levels of tyrosine hydroxylase, dopamine receptor 2 (D2), serotonin transporter, and TAAR1 mRNA transcripts in samples of ventral striatum, finding no significant differences between WT and KO genotypes. Throughout this study, DAT KO rats showed alterations in decision-making processes and in motivational states, as well as prominent motor and oral stereotypies: more studies are warranted to fully characterize and efficiently use them in preclinical research

A meta-analytic review of stand-alone interventions to improve body image

Objective Numerous stand-alone interventions to improve body image have been developed. The present review used meta-analysis to estimate the effectiveness of such interventions, and to identify the specific change techniques that lead to improvement in body image. Methods The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on improving body image), (b) a control group was used, (c) participants were randomly assigned to conditions, and (d) at least one pretest and one posttest measure of body image was taken. Effect sizes were meta-analysed and moderator analyses were conducted. A taxonomy of 48 change techniques used in interventions targeted at body image was developed; all interventions were coded using this taxonomy. Results The literature search identified 62 tests of interventions (N = 3,846). Interventions produced a small-to-medium improvement in body image (d+ = 0.38), a small-to-medium reduction in beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies (d+ = -0.72). However, the effect size for body image was inflated by bias both within and across studies, and was reliable but of small magnitude once corrections for bias were applied. Effect sizes for the other outcomes were no longer reliable once corrections for bias were applied. Several features of the sample, intervention, and methodology moderated intervention effects. Twelve change techniques were associated with improvements in body image, and three techniques were contra-indicated. Conclusions The findings show that interventions engender only small improvements in body image, and underline the need for large-scale, high-quality trials in this area. The review identifies effective techniques that could be deployed in future interventions

Distinct contributions of extrastriate body area and temporoparietal junction in perceiving one's own and others' body.

The right temporoparietal cortex plays a critical role in body representation. Here, we applied repetitive transcranial magnetic stimulation (rTMS) over right extrastriate body area (EBA) and temporoparietal junction (TPJ) to investigate their causative roles in perceptual representations of one's own and others' body. Healthy women adjusted size-distorted pictures of their own body or of the body of another person according to how they perceived the body (subjective task) or how others perceived it (intersubjective task). In keeping with previous reports, at baseline, we found an overall underestimation of body size. Crucially, EBA-rTMS increased the underestimation bias when participants adjusted the images according to how others perceived their own or the other woman's body, suggesting a specific role of EBA in allocentric body representations. Conversely, TPJ-rTMS increased the underestimation bias when participants adjusted the body of another person, either a familiar other or a close friend, in both subjective and intersubjective tasks, suggesting an involvement of TPJ in representing others' bodies. These effects were body-specific, since no TMS-induced modulation was observed when participants judged a familiar object. The results suggest that right EBA and TPJ play active and complementary roles in the complex interaction between the perceptions of one's own and other people's body

Nanotechnology-Based Targeted Drug Delivery: An Emerging Tool to Overcome Tuberculosis

The appearance and rapid spread of drug resistant strains of tuberculosis (TB), one of the deadliest infectious diseases, pose a serious threat to public health and increase the need for shorter, less toxic, and more effective therapies. Developing new drugs is difficult and often associated with side effects, so nanotechnology has emerged as a tool to improve current treatments and to rescue drugs having elevated toxicity or poor solubility. Due to their size and surface chemistry, antimicrobial-loaded nanocarriers are avidly taken up by macrophages, the main cells hostingMycobacterium tuberculosis. Macrophages are continuously recruited to infected areas, they can transport drugs with them, making passive targeting a good strategy for TB treatment. Active targeting (decorating surface of nanocarriers with ligands specific to receptors displayed by macrophages) further increases local drug concentration, and thus treatment efficacy. Although in in vivo studies, nanocarriers are often administered intravenously in order to avoid inaccurate dosage in animals, translation to humans requires more convenient routes like pulmonary or oral administration. This report highlights the importance and progress of pulmonary administration, passive and active targeting strategies toward bacteria reservoirs to overcome the challenges in TB treatment

A Trouble Shared Is a Trouble Halved: Social Context and Status Affect Pain in Mouse Dyads

In mice behavioral response to pain is modulated by social status. Recently, social context also has been shown to affect pain sensitivity. In our study, we aimed to investigate the effects of interaction between status and social context in dyads of outbred CD-1 male mice in which the dominance/submission relationship was stable. Mice were assessed for pain response in a formalin (1% concentration) test either alone (individually tested-IT), or in pairs of dominant and subordinate mice. In the latter condition, they could be either both injected (BI) or only one injected (OI) with formalin. We observed a remarkable influence of social context on behavioral response to painful stimuli regardless of the social status of the mice. In the absence of differences between OI and IT conditions, BI mice exhibited half as much Paw-licking behavior than OI group. As expected, subordinates were hypoalgesic in response to the early phase of the formalin effects compared to dominants. Clear cut-differences in coping strategies of dominants and subordinates appeared. The former were more active, whereas the latter were more passive. Finally, analysis of behavior of the non-injected subjects (the observers) in the OI dyads revealed that dominant observers were more often involved in Self-grooming behavior upon observation of their subordinate partner in pain. This was not the case for subordinate mice observing the pain response of their dominant partner. In contrast, subordinate observers Stared at the dominant significantly more frequently compared to observer dominants in other dyads. The observation of a cagemate in pain significantly affected the observer's behavior. Additionally, the quality of observer's response was also modulated by the dominance/submission relationship

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Malignant mesothelioma (MM) is a fatal type of neoplasia with poor therapeutic prognosis, largely due to resistance to apoptosis. We investigated the apoptotic effect of alpha-tocopheryl succinate (alpha-TOS), a strong proapoptotic agent, in combination with the immunological apoptogen TNF-related apoptosis-inducing ligand (TRAIL) on both MM and nonmalignant mesothelial cells, since MM cells show low susceptibility to the clinically intriguing TRAIL. All MM cell lines tested were sensitive to alpha-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or alpha-TOS alone or in combination caused apoptosis in nonmalignant mesothelial cells. Isobologram analysis of the cytotoxicity assays revealed a synergistic interaction between the two agents in MM cells and their antagonistic effect in nonmalignant mesothelial cells. TRAIL-induced apoptosis and its augmentation by alpha-TOS were inhibited by the caspase-8 inhibitor Z-IETD-FMK and the pan-caspase inhibitor Z-VAD-FMK. Activation of caspase-8 was required to induce apoptosis, which was amplified by alpha-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by alpha-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that alpha-TOS and TRAIL act in synergism to kill MM cells via mitochondrial pathway, and are nontoxic to nonmalignant mesothelial cells. These findings are indicative of a novel strategy for treatment of thus far fatal MM

PPARγ1 and LXRα face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1

Peroxisome proliferator-activated receptor γ1 (PPARγ1) and liver X receptor α (LXRα) are nuclear receptors that play pivotal roles in macrophage cholesterol homeostasis and inflammation; key biological processes in atherogenesis. The activation of PPARγ1 and LXRα by natural or synthetic ligands results in the transactivation of ABCA1, ABCG1, and ApoE; integral players in cholesterol efflux and reverse cholesterol transport. In this review, we describe the structure, isoforms, expression pattern, and functional specificity of PPARs and LXRs. Control of PPARs and LXRs transcriptional activity by coactivators and corepressors is also highlighted. The specific roles that PPARγ1 and LXRα play in inducing macrophage cholesterol efflux mediators and antagonizing macrophage inflammatory responsiveness are summarized. Finally, this review focuses on the recently reported regulatory functions that adipocyte enhancer-binding protein 1 (AEBP1) exerts on PPARγ1 and LXRα transcriptional activity in the context of macrophage cholesterol homeostasis and inflammation

Phase I interim results of a phase I/II study of the IgG-Fc fusion COVID-19 subunit vaccine, AKS-452

To address the coronavirus disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recombinant subunit vaccine, AKS-452, is being developed comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain (SP/RBD) antigen and human IgG1 Fc emulsified in the water-in-oil adjuvant, Montanide™ ISA 720. A single-center, open-label, phase I dose-finding and safety study was conducted with 60 healthy adults (18–65 years) receiving one or two doses 28 days apart of 22.5 µg, 45 µg, or 90 µg of AKS-452 (i.e., six cohorts, N = 10 subjects per cohort). Primary endpoints were safety and reactogenicity and secondary endpoints were immunogenicity assessments. No AEs ≥ 3, no SAEs attributable to AKS-452, and no SARS-CoV-2 viral infections occurred during the study. Seroconversion rates of anti-SARS-CoV-2 SP/RBD IgG titers in the 22.5, 45, and 90 µg cohorts at day 28 were 70%, 90%, and 100%, respectively, which all increased to 100% at day 56 (except 89% for the single-dose 22.5 µg cohort). All IgG titers were Th1-isotype skewed and efficiently bound mutant SP/RBD from several SARS-CoV-2 variants with strong neutralization potencies of live virus infection of cells (including alpha and delta variants). The favorable safety and immunogenicity profiles of this phase I study (ClinicalTrials.gov: NCT04681092) support phase II initiation of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain