The head direction circuit of two insect species

Recent studies of the Central Complex in the brain of the fruit fly have identified neurons with activity that tracks the animal’s heading direction. These neurons are part of a neuronal circuit with dynamics resembling those of a ring attractor. The homologous circuit in other insects has similar topographic structure but with significant structural and connectivity differences. We model the connectivity patterns of two insect species to investigate the effect of these differences on the dynamics of the circuit. We illustrate that the circuit found in locusts can also operate as a ring attractor but differences in the inhibition pattern enable the fruit fly circuit to respond faster to heading changes while additional recurrent connections render the locust circuit more tolerant to noise. Our findings demonstrate that subtle differences in neuronal projection patterns can have a significant effect on circuit performance and illustrate the need for a comparative approach in neuroscience

Protein Shape Sampled by Ion Mobility Mass Spectrometry Consistently Improves Protein Structure Prediction

Ion mobility (IM) mass spectrometry provides structural information about protein shape and size in the form of an orientationally-averaged collision cross-section (CCSIM). While IM data have been used with various computational methods, they have not yet been utilized to predict monomeric protein structure from sequence. Here, we show that IM data can significantly improve protein structure determination using the modelling suite Rosetta. We develop the Rosetta Projection Approximation using Rough Circular Shapes (PARCS) algorithm that allows for fast and accurate prediction of CCSIM from structure. Following successful testing of the PARCS algorithm, we use an integrative modelling approach to utilize IM data for protein structure prediction. Additionally, we propose a confidence metric that identifies near native models in the absence of a known structure. The results of this study demonstrate the ability of IM data to consistently improve protein structure prediction

Progression and mortality in patients with CKD attending outpatient nephrology clinics across Europe: A novel analytic approach

The incidence of renal replacement therapy (RRT) varies across countries. Yet, little is known about the epidemiology of chronic kidney disease (CKD) outcomes. Our aim was to describe progression and mortality risk in CKD patients not on RRT attending outpatient nephrology clinics across Europe. We used individual data from nine CKD cohorts participating in the European CKD Burden Consortium. A joint model was used to estimate mean eGFR change and mortality risk simultaneously, thereby accounting for mortality risk when estimating eGFR decline and vice versa, while also correcting for the measurement error in eGFR. Results were adjusted for important risk factors (baseline eGFR, age, sex, albuminuria, primary renal disease, diabetes, hypertension, obesity and smoking). 27,771 patients from five countries were included. The adjusted mean annual eGFR decline varied from 0.77 (95%CI 0.45,1.08) ml/min/1.73m2 in the Belgium cohort to 2.43 (95%CI 2.11,2.75) ml/min/1.73m2 in the Spanish cohort. As compared to the Italian PIRP cohort, the adjusted mortality hazard ratio varied from 0.22 (95%CI 0.11,0.43) in the London LACKABO cohort to 1.30 (95%CI 1.13,1.49) in the English CRISIS cohort. Outcomes in CKD patients attending outpatient nephrology clinics varied markedly across European regions. Although eGFR decline showed minor variation, the most variation was observed in CKD mortality. Our results suggest that different healthcare organization systems are potentially associated with differences in outcome of CKD patients within Europe. These results can be used by policy makers to plan resources on a regional, national and European level

“UNIFIED”: bridging the researcher–practitioner divide in mind, brain, and education

Mind, Brain, and Education (MBE) science is by definition transdisciplinary. However, the communication and collaboration between constituent disciplines needed for true transdisciplinarity remains relatively rare. Consequently, many of the potential benefits of MBE science remain unrealized for parties on all sides of the discipline. The present commentary first conducts an analysis of the current strengths, weaknesses, opportunities, and threats of transdisciplinary partnerships in MBE. A new, free, and international web platform (“UNIFIED”) is then proposed to broker relationships between researchers and teachers within schools. This website would allow users to form collaborations based on a system of tags indexing their research interests as well as practicalities such as their location. Such a website appears well placed to realize many of the opportunities, and mitigate the threats and weaknesses, of transdisciplinary MBE research. The article concludes with an appeal to interested researchers and schools to contribute to the development of the project

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival