Anxiety-potentiated amygdala-medial frontal coupling and attentional control

Anxiety disorders can be treated both pharmacologically and psychologically, but many individuals either fail to respond to treatment or relapse. Improving outcomes is difficult, in part because we have incomplete understanding of the neurobiological mechanisms underlying current treatments. In a sequence of studies, we have identified 'affective bias-related' amygdala-medial cortical coupling as a candidate substrate underlying adaptive anxiety (that is, anxiety elicited by threat of shock in healthy individuals) and shown that it is also chronically engaged in maladaptive anxiety disorders. We have provided evidence that this circuit can be modulated pharmacologically, but whether this mechanism can be shifted by simple psychological instruction is unknown. In this functional magnetic resonance imaging study, we extend a previously used translational anxiety induction (threat of shock) in healthy subjects (N=43) and cognitive task to include an element of instructed attentional control. Replicating our previous findings, we show that induced anxiety engages 'affective bias-related' amygdala-dorsal medial frontal coupling during the processing of emotional faces. By contrast, instructing subjects to attend to neutral shapes (and ignore faces) disengages this circuitry and increases putative 'attentional control-related' coupling between the amygdala and a more rostral prefrontal region. These neural coupling changes are accompanied by corresponding modulation of behavioural performance. Taken together, these findings serve to further highlight the potential role of amygdala-medial frontal coupling in the pathogenesis of anxiety and highlight a mechanism by which it can be modulated via psychological instructions. This, in turn, generates hypotheses for future work exploring the mechanisms underlying psychological therapeutic interventions for anxiety

Neurobiology of rodent self-grooming and its value for translational neuroscience

Self-grooming is a complex innate behaviour with an evolutionarily conserved sequencing pattern and is one of the most frequently performed behavioural activities in rodents. In this Review, we discuss the neurobiology of rodent self-grooming, and we highlight studies of rodent models of neuropsychiatric disorders-including models of autism spectrum disorder and obsessive compulsive disorder-that have assessed self-grooming phenotypes. We suggest that rodent self-grooming may be a useful measure of repetitive behaviour in such models, and therefore of value to translational psychiatry. Assessment of rodent self-grooming may also be useful for understanding the neural circuits that are involved in complex sequential patterns of action.National Institutes of Health (U.S.) (Grant NS025529)National Institutes of Health (U.S.) (Grant HD028341)National Institutes of Health (U.S.) (Grant MH060379

Serum CD26 is related to histopathological polyp traits and behaves as a marker for colorectal cancer and advanced adenomas

<p>Abstract</p> <p>Background</p> <p>Serum CD26 (sCD26) levels were previously found diminished in colorectal cancer (CRC) patients compared to healthy donors, suggesting its potential utility for early diagnosis. Therefore we aimed to estimate the utility of the sCD26 as a biomarker for CRC and advanced adenomas in a high-risk group of patients. The relationship of this molecule with polyp characteristics was also addressed.</p> <p>Methods</p> <p>sCD26 levels were measured by ELISA in 299 symptomatic and asymptomatic patients who had undergone a colonoscopy. Patients were diagnosed as having no colorectal pathology, non-inflammatory or inflammatory bowel disease, polyps (hyperplastic, non-advanced and advanced adenomas) or CRC.</p> <p>Results</p> <p>At a 460 ng/mL cut-off, the sCD26 has a sensitivity and specificity of 81.8% (95% CI, 64.5-93.0%) and 72.3% (95% CI, 65.0-77.2%) for CRC regarding no or benign colorectal pathology. Clinicopathological analysis of polyps showed a relationship between the sCD26 and the grade of dysplasia and the presence of advanced adenomas. Hence, a 58.0% (95% CI, 46.5-68.9%) sensitivity detecting CRC and advanced adenomas was obtained, with a specificity of 75.5% (95% CI, 68.5-81.0%).</p> <p>Conclusions</p> <p>Our preliminary results show that measurement of the sCD26 is a non-invasive and reasonably sensitive assay, which could be combined with others such as the faecal occult blood test for the early diagnosis and screening of CRC and advanced adenomas. Additional comparative studies in average-risk populations are necessary.</p

Oral Pre-Exposure Prophylaxis by Anti-Retrovirals Raltegravir and Maraviroc Protects against HIV-1 Vaginal Transmission in a Humanized Mouse Model

Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP). Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs

Euphol, a tetracyclic triterpene, from Euphorbia tirucalli induces autophagy and sensitizes temozolomide cytotoxicity on glioblastoma cells

Glioblastoma (GBM) is the most frequent and aggressive type of brain tumor. There are limited therapeutic options for GBM so that new and effective agents are urgently needed. Euphol is a tetracyclic triterpene alcohol, and it is the main constituent of the sap of the medicinal plant Euphorbia tirucalli. We previously identified anti-cancer activity in euphol based on the cytotoxicity screening of 73 human cancer cells. We now expand the toxicological screening of the inhibitory effect and bioactivity of euphol using two additional glioma primary cultures. Euphol exposure showed similar cytotoxicity against primary glioma cultures compared to commercial glioma cells. Euphol has concentration-dependent cytotoxic effects on cancer cell lines, with more than a five-fold difference in the IC50 values in some cell lines. Euphol treatment had a higher selective cytotoxicity index (0.64-3.36) than temozolomide (0.11-1.13) and reduced both proliferation and cell motility. However, no effect was found on cell cycle distribution, invasion and colony formation. Importantly, the expression of the autophagy-associated protein LC3-II and acidic vesicular organelle formation were markedly increased, with Bafilomycin A1 potentiating cytotoxicity. Finally, euphol also exhibited antitumoral and antiangiogenic activity in vivo, using the chicken chorioallantoic membrane assay, with synergistic temozolomide interactions in most cell lines. In conclusion, euphol exerted in vitro and in vivo cytotoxicity against glioma cells, through several cancer pathways, including the activation of autophagy-associated cell death. These findings provide experimental support for further development of euphol as a novel therapeutic agent for GBM, either alone or in combination chemotherapy.The work was supported by the Amazonia Fitomedicamentos (FITO05/2012) Ltda. and Barretos Cancer Hospital, all from Brazil

Age-dependent effects of protein restriction on dopamine release

FUNDING AND DISCLOSURE This work was supported by the Biotechnology and Biological Sciences Research Council [grant # BB/M007391/1 to J.E.M.], the European Commission [grant # GA 631404 to J.E.M.], The Leverhulme Trust [grant # RPG-2017-417 to J.E.M.] and the Tromsø Research Foundation [grant # 19-SG-JMcC to J. E. M.). The authors declare no conflict of interest. ACKNOWLEDGEMENTS The authors would like to acknowledge the help and support from the staff of the Division of Biomedical Services, Preclinical Research Facility, University of Leicester, for technical support and the care of experimental animals.Peer reviewedPublisher PD

Deciphering the sophomore slump: changes to student perceptions during the undergraduate journey

The second year of university is little-researched, despite being a focal point for declining performance, persistence, and satisfaction. It is important to establish appropriate methods for studying this ‘sophomore slump’ and to pinpoint specific antecedents from broad domains noted in literature (e.g. students’ social integration, perceptions of the curriculum). Using a novel methodology, 166 undergraduates were surveyed in successive years of study to derive a gold standard ‘within-subjects’ data sample. Under a replicated design, a ‘between-subjects’ sample of over 1000 students completed the same e-survey just once, in year one, two, or three. Quantitative comparison of the responses across years showed over 85% agreement between samples. This endorses between-subject approaches (i.e. simultaneously surveying students from different years) to facilitate rapid interventions that benefit students before they graduate. In terms of detailed findings, year two saw positive trends in students’ academic engagement (e.g. self-reported independent study time), social integration (e.g. feeling accepted, involvement in extra-curricular activities), and views on teaching staff (e.g. approachability). Although appraisals remained broadly favourable, there was, in contrast, significant deterioration in global perceptions of the learning atmosphere (e.g. course enjoyment), as well as specific elements of the teaching provision (e.g. contact hours, feedback). Notably, there appeared to be little progression in students’ academic self-perceptions (e.g. confidence to make presentations, enter class debates). Year two also saw increased thoughts of drop-out. These results highlight the unique character of the second year at university and indicate potential target areas for enhancing this phase of the undergraduate journey

Supraorbital morphology and social dynamics in human evolution

Uniquely, with respect to Middle Pleistocene hominins, anatomically modern humans do not possess marked browridges, and have a more vertical forehead with mobile eyebrows that play a key role in social signalling and communication. The presence and variability of browridges in archaic Homo and their absence in ourselves have led to debate concerning their morphogenesis and function, with two main hypotheses being put forward; that browridge morphology is the result of the spatial relationship between the orbits and the braincase, and that browridge morphology is significantly impacted by biting mechanics. Here we virtually manipulate browridge morphology of an archaic hominin (Kabwe 1), showing that it is much larger than the minimum required to fulfil spatial demands and that browridge size has little impact on mechanical performance during biting. Since browridge morphology in this fossil is not driven by spatial and mechanical requirements alone, the role of the supraorbital region in social communication is a potentially significant factor. We propose that conversion of the large browridges of our immediate ancestors to a more vertical frontal in modern humans allowed highly mobile eyebrows to display subtle affiliative emotions