Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

Antigenic variation enables pathogens to avoid the host immune response by continual switching of surface proteins. The protozoan blood parasite Trypanosoma brucei causes human African trypanosomiasis ("sleeping sickness") across sub-Saharan Africa and is a model system for antigenic variation, surviving by periodically replacing a monolayer of variant surface glycoproteins (VSG) that covers its cell surface. We compared the genome of Trypanosoma brucei with two closely related parasites Trypanosoma congolense and Trypanosoma vivax, to reveal how the variant antigen repertoire has evolved and how it might affect contemporary antigenic diversity. We reconstruct VSG diversification showing that Trypanosoma congolense uses variant antigens derived from multiple ancestral VSG lineages, whereas in Trypanosoma brucei VSG have recent origins, and ancestral gene lineages have been repeatedly co-opted to novel functions. These historical differences are reflected in fundamental differences between species in the scale and mechanism of recombination. Using phylogenetic incompatibility as a metric for genetic exchange, we show that the frequency of recombination is comparable between Trypanosoma congolense and Trypanosoma brucei but is much lower in Trypanosoma vivax. Furthermore, in showing that the C-terminal domain of Trypanosoma brucei VSG plays a crucial role in facilitating exchange, we reveal substantial species differences in the mechanism of VSG diversification. Our results demonstrate how past VSG evolution indirectly determines the ability of contemporary parasites to generate novel variant antigens through recombination and suggest that the current model for antigenic variation in Trypanosoma brucei is only one means by which these parasites maintain chronic infections

A trial protocol for the effectiveness of digital interventions for preventing depression in adolescents : The Future Proofing Study

Background: Depression frequently first emerges during adolescence, and one in five young people will experience an episode of depression by the age of 18 years. Despite advances in treatment, there has been limited progress in addressing the burden at a population level. Accordingly, there has been growing interest in prevention approaches as an additional pathway to address depression. Depression can be prevented using evidence-based psychological programmes. However, barriers to implementing and accessing these programmes remain, typically reflecting a requirement for delivery by clinical experts and high associated delivery costs. Digital technologies, specifically smartphones, are now considered a key strategy to overcome the barriers inhibiting access to mental health programmes. The Future Proofing Study is a large-scale school-based trial investigating whether cognitive behaviour therapies (CBT) delivered by smartphone application can prevent depression. Methods: A randomised controlled trial targeting up to 10,000 Year 8 Australian secondary school students will be conducted. In Stage I, schools will be randomised at the cluster level either to receive the CBT intervention app (SPARX) or to a non-active control group comparator. The primary outcome will be symptoms of depression, and secondary outcomes include psychological distress, anxiety and insomnia. At the 12-month follow-up, participants in the intervention arm with elevated depressive symptoms will participate in an individual-level randomised controlled trial (Stage II) and be randomised to receive a second CBT app which targets sleep difficulties (Sleep Ninja) or a control condition. Assessments will occur post intervention (both trial stages) and at 6, 12, 24, 36, 48 and 60 months post baseline. Primary analyses will use an intention-to-treat approach and compare changes in symptoms from baseline to follow-up relative to the control group using mixed-effect models. Discussion: This is the first trial testing the effectiveness of smartphone apps delivered to school students to prevent depression at scale. Results from this trial will provide much-needed insight into the feasibility of this approach. They stand to inform policy and commission decisions concerning if and how such programmes should be deployed in school-based settings in Australia and beyond

Canagliflozin extends life span in genetically heterogeneous male but not female mice.

Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases

Factors Associated With Referring Close Contacts to an App With Individually-Tailored Vaccine Information

Background: Infants too young to be fully vaccinated are vulnerable to potentially deadly influenza and pertussis infections. The cocooning strategy limits this risk by vaccinating those likely to interact with the infant and mother during this vulnerable time, such as close friends and family members. Distribution of accurate and accessible vaccine information through existing social networks could be an important tool in increasing vaccine confidence and coverage. Methods: We surveyed 1095 pregnant women from diverse prenatal care practices in Georgia and Colorado. These women were surveyed through a mobile app to assess vaccine intentions, attitudes, beliefs, norms, and levels of trust, and then presented brief individually-tailored educational videos about maternal and infant vaccines and the cocooning strategy. They were then given the opportunity to refer up to six contacts to enroll in the app and receive similar vaccine education. Results: Twenty-eight percent of these women referred at least one contact, with an average of 2.67 contacts per referring woman. Most referrals (93%) were partners, parents, siblings, relatives, or close friends. Attitudinal constructs significantly associated with increased likelihood of referring contacts included: intention to receive maternal influenza vaccine, perceived safety of maternal Tdap vaccine, perceived efficacy of maternal influenza vaccine, perceived susceptibility to and severity of influenza during pregnancy, and trust in vaccine information from the Centers for Disease Control and Prevention (CDC) and academic institutions. Uncertainty about infant vaccine intentions was associated with decreased likelihood of referring contacts. Conclusions: Pregnant women who valued vaccination and trusted vaccine information from academic institutions were more likely to refer an educational app about vaccines than those who did not. Further research is needed to determine the potential impact of this strategy on vaccine coverage when implemented on a large scale. Trial Registration: The survey informing this article was part of a randomized controlled trial funded by the National Institutes of Health [clinicaltrials.gov registration number NCT02898688]

Decoding Face Information in Time, Frequency and Space from Direct Intracranial Recordings of the Human Brain

Faces are processed by a neural system with distributed anatomical components, but the roles of these components remain unclear. A dominant theory of face perception postulates independent representations of invariant aspects of faces (e.g., identity) in ventral temporal cortex including the fusiform gyrus, and changeable aspects of faces (e.g., emotion) in lateral temporal cortex including the superior temporal sulcus. Here we recorded neuronal activity directly from the cortical surface in 9 neurosurgical subjects undergoing epilepsy monitoring while they viewed static and dynamic facial expressions. Applying novel decoding analyses to the power spectrogram of electrocorticograms (ECoG) from over 100 contacts in ventral and lateral temporal cortex, we found better representation of both invariant and changeable aspects of faces in ventral than lateral temporal cortex. Critical information for discriminating faces from geometric patterns was carried by power modulations between 50 to 150 Hz. For both static and dynamic face stimuli, we obtained a higher decoding performance in ventral than lateral temporal cortex. For discriminating fearful from happy expressions, critical information was carried by power modulation between 60–150 Hz and below 30 Hz, and again better decoded in ventral than lateral temporal cortex. Task-relevant attention improved decoding accuracy more than10% across a wide frequency range in ventral but not at all in lateral temporal cortex. Spatial searchlight decoding showed that decoding performance was highest around the middle fusiform gyrus. Finally, we found that the right hemisphere, in general, showed superior decoding to the left hemisphere. Taken together, our results challenge the dominant model for independent face representation of invariant and changeable aspects: information about both face attributes was better decoded from a single region in the middle fusiform gyrus

Modulation of the surface proteome through multiple ubiquitylation pathways in African Trypanosomes

Recently we identified multiple suramin-sensitivity genes with a genome wide screen in Trypanosoma brucei that includes the invariant surface glycoprotein ISG75, the adaptin-1 (AP-1) complex and two deubiquitylating enzymes (DUBs) orthologous to ScUbp15/HsHAUSP1 and pVHL-interacting DUB1 (type I), designated TbUsp7 and TbVdu1, respectively. Here we have examined the roles of these genes in trafficking of ISG75, which appears key to suramin uptake. We found that, while AP-1 does not influence ISG75 abundance, knockdown of TbUsp7 or TbVdu1 leads to reduced ISG75 abundance. Silencing TbVdu1 also reduced ISG65 abundance. TbVdu1 is a component of an evolutionarily conserved ubiquitylation switch and responsible for rapid receptor modulation, suggesting similar regulation of ISGs in T. brucei. Unexpectedly, TbUsp7 knockdown also blocked endocytosis. To integrate these observations we analysed the impact of TbUsp7 and TbVdu1 knockdown on the global proteome using SILAC. For TbVdu1, ISG65 and ISG75 are the only significantly modulated proteins, but for TbUsp7 a cohort of integral membrane proteins, including the acid phosphatase MBAP1, that is required for endocytosis, and additional ISG-related proteins are down-regulated. Furthermore, we find increased expression of the ESAG6/7 transferrin receptor and ESAG5, likely resulting from decreased endocytic activity. Therefore, multiple ubiquitylation pathways, with a complex interplay with trafficking pathways, control surface proteome expression in trypanosomes

Understanding the circumgalactic medium is critical for understanding galaxy evolution

Galaxies evolve under the influence of gas flows between their interstellar medium and their surrounding gaseous halos known as the circumgalactic medium (CGM). The CGM is a major reservoir of galactic baryons and metals, and plays a key role in the long cycles of accretion, feedback, and recycling of gas that drive star formation. In order to fully understand the physical processes at work within galaxies, it is therefore essential to have a firm understanding of the composition, structure, kinematics, thermodynamics, and evolution of the CGM. In this white paper we outline connections between the CGM and galactic star formation histories, internal kinematics, chemical evolution, quenching, satellite evolution, dark matter halo occupation, and the reionization of the larger-scale intergalactic medium in light of the advances that will be made on these topics in the 2020s. We argue that, in the next decade, fundamental progress on all of these major issues depends critically on improved empirical characterization and theoretical understanding of the CGM. In particular, we discuss how future advances in spatially-resolved CGM observations at high spectral resolution, broader characterization of the CGM across galaxy mass and redshift, and expected breakthroughs in cosmological hydrodynamic simulations will help resolve these major problems in galaxy evolution.Comment: Astro2020 Decadal Science White Pape

Understanding biomolecular motion, recognition, and allostery by use of conformational ensembles

We review the role conformational ensembles can play in the analysis of biomolecular dynamics, molecular recognition, and allostery. We introduce currently available methods for generating ensembles of biomolecules and illustrate their application with relevant examples from the literature. We show how, for binding, conformational ensembles provide a way of distinguishing the competing models of induced fit and conformational selection. For allostery we review the classic models and show how conformational ensembles can play a role in unravelling the intricate pathways of communication that enable allostery to occur. Finally, we discuss the limitations of conformational ensembles and highlight some potential applications for the future