POCUS: mining genomic sequence annotation to predict disease genes

Here we present POCUS (prioritization of candidate genes using statistics), a novel computational approach to prioritize candidate disease genes that is based on over-representation of functional annotation between loci for the same disease. We show that POCUS can provide high (up to 81-fold) enrichment of real disease genes in the candidate-gene shortlists it produces compared with the original large sets of positional candidates. In contrast to existing methods, POCUS can also suggest counterintuitive candidates

Prediction and characterisation of the human B cell response to a heterologous two-dose Ebola vaccine

Ebola virus disease (EVD) outbreaks are increasing, posing significant threats to affected communities. Effective outbreak management depends on protecting frontline health workers, a key focus of EVD vaccination strategies. IgG specific to the viral glycoprotein serves as the correlate of protection for recent vaccine licensures. Using advanced cellular and transcriptomic analyses, we examined B cell responses to the Ad26.ZEBOV, MVA-BN-Filo EVD vaccine. Our findings reveal robust plasma cell and lasting B cell memory responses post-vaccination. Machine-learning models trained on blood gene expression predicted antibody response magnitude. Notably, we identified a unique B cell receptor CDRH3 sequence post-vaccination resembling known Orthoebolavirus zairense (EBOV) glycoprotein-binding antibodies. Single-cell analyses further detailed changes in plasma cell frequency, subclass usage, and CDRH3 properties. These results highlight the predictive power of early immune responses, captured through systems immunology, in shaping vaccine-induced B cell immunity

Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the Clavicipitaceae reveals dynamics of alkaloid Loci

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some—including the infamous ergot alkaloids—have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses

Computational mining of B cell receptor repertoires reveals antigen-specific and convergent responses to Ebola vaccination

Outbreaks of Ebolaviruses, such as Sudanvirus (SUDV) in Uganda in 2022, demonstrate that species other than the Zaire ebolavirus (EBOV), which is currently the sole virus represented in current licensed vaccines, remain a major threat to global health. There is a pressing need to develop effective pan-species vaccines and novel monoclonal antibody-based therapeutics for Ebolavirus disease. In response to recent outbreaks, the two dose, heterologous Ad26.ZEBOV/MVA-BN-Filo vaccine regimen was developed and was tested in a large phase II clinical trial (EBL2001) as part of the EBOVAC2 consortium. Here, we perform bulk sequencing of the variable heavy chain (VH) of B cell receptors (BCR) in forty participants from the EBL2001 trial in order to characterize the BCR repertoire in response to vaccination with Ad26.ZEBOV/MVA-BN-Filo. We develop a comprehensive database, EBOV-AbDab, of publicly available Ebolavirus-specific antibody sequences. We then use our database to predict the antigen-specific component of the vaccinee repertoires. Our results show striking convergence in VH germline gene usage across participants following the MVA-BN-Filo dose, and provide further evidence of the role of IGHV3–15 and IGHV3–13 antibodies in the B cell response to Ebolavirus glycoprotein. Furthermore, we found that previously described Ebola-specific mAb sequences present in EBOV-AbDab were sufficient to describe at least one of the ten most expanded BCR clonotypes in more than two thirds of our cohort of vaccinees following the boost, providing proof of principle for the utility of computational mining of immune repertoires

Exile Vol. LVIII

Autumn Stiles: Biblical Brooklyn 5 Daniel Carlson: A Night Indoors 6 Moriah Ellenborgen: Cradle Drop 8 Nicco Pandolfi: Cardinality 10 Abby Current: Babies in the Snow 11 Maggie Reagan: Chimaera 13 Natalie Olivo: Treading Water 14 Julianne Hyer: Swatch Watch 21 Mimi Mendes de Leon: For Bosnia 23 A. Tangredi: How to Keep from Freezing 24 Autumn Stiles: Bodies and Bread 25 Christie Maillet: The Depth of a Song 26 Sam Heyman: First Kiss 27 Shawn Whites: Five Hundred Miles to Freedom 28 Ammon Hollister: Temptation 31 Caroline Clutterbuck: The Conspiracy in Your Smile 32 Nicco Pandolfi: Sore Subject 33 Meghan Callahan: Why Claire Left 34 Aaron Bennett: Ode to Arden 36 Daniel Carlson: Duty 37 Lindsey Clark: Snapshot 38 Steph Maniaci: Ode to an M&M 39 Abby Current: The Animal Bride 41 Julianne Hyer: Trees Pantoum 42 Ammon Hollister: Life Support 43 Maggie Reagan: Necropolis 44

Promotion of Physical Activity by Health Professionals (PROMOTE-PA) : Protocol for effectiveness outcomes in a hybrid type I effectiveness-implementation cluster randomised controlled trial

Promotion of physical activity by health professionals can increase physical activity participation among patients, however, implementing physical activity promotion within hospital systems is lacking. The Promotion of Physical Activity by Health Professionals (PROMOTE-PA) study is a hybrid type I effectiveness-implementation cluster randomised controlled trial evaluating the effectiveness of support for physical activity promotion by health professionals on physical activity participation of patients. Health professionals delivering outpatient healthcare services within four local health districts and one specialty health network in New South Wales, Australia will be included. The target patient population is children (5–17 years) and adults (18+ years) who are willing to receive additional support to be more physically active. The evidence-based intervention is brief physical activity promotion informed by the ‘5As’ physical activity counselling model and behavioural theory, embedded into routine clinical practice. Our multi-faceted strategy to support implementation of physical activity promotion was developed based on preliminary research and consultation with key stakeholders. The implementation strategy includes education and training as well as a selection of the following (tailored to each clinical team): community referral strategies, experts and clinical mentors, and clinical champions. 30 outpatient clinical teams will be randomised to receive the implementation strategy immediately or after a 3-month delay (waitlist control). Each team will seek to recruit 10–30 patients (n=approx. 720) to report moderate-vigorous physical activity (minutes per week, primary outcome), frequency of balance and strength exercise, mobility, and quality of life at baseline, 3-month and 6-month post patient recruitment. This study aims to address the increasing burden of physical inactivity in a high-risk population using the existing health workforce