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Psychiatric trials have some of the lowest success rates across therapeutic areas, resulting in decreased investment in psychopharmacological drug development even as the need for more effective treatments grows. Digital measures and digital biomarkers (DBMs) provide one potential avenue for ameliorating three of the largest problems impeding clinical trial success in psychiatry: diagnostic heterogeneity, endpoint subjectivity, and high placebo response rates. First, DBMs may address heterogeneity and comorbidity in psychiatric nosology by identifying predictive DBMs of treatment response via the targeting of drugs to psychiatric subtypes. Second, DBMs can provide objective measures of physiology and behavior that when grounded in meaningful aspects of health (MAH) could support use for regulatory decision-making. By objectively and continuously measuring aspects of a patient’s disease that the patient wants to improve or prevent from getting worse, DBMs might provide clinical trial endpoints that are more sensitive to treatment effects as compared to traditional clinician-reported outcomes. Lastly, DBMs could help address challenges surrounding high placebo response rates. Development of predictive DBMs of placebo response may allow for improved enrichment study designs to reduce placebo response. Objective digital measures may also be more robust against the placebo effect and offer an improved study endpoint alternative. Successful deployment of DBMs to address the historical challenges facing psychiatric drug trials will require close collaboration between industry, academic, and regulatory partners.

High-throughput peptide synthesis and mass spectrometry are used to generate a near-complete reference map of the Saccharomyces cerevisiae proteome; two versions of the map (supporting discovery- and hypothesis-driven proteomics) are then applied to a protein-based quantitative trait locus analysis. A global map of yeast proteins Complete 'gold standard' reference maps of the components within a system are valuable resources for a research community. This paper presents one such resource, a complete mass-spectrometric reference map of the budding yeast Saccharomyces cerevisiae . The map comes in two versions — one for discovery-driven (shotgun) and the other for hypothesis-driven (targeted) proteomic measurements — and will support most studies performed with contemporary proteomic technologies. The maps provide essentially a set of highly specific assays for the detection and quantification of every yeast protein in any sample, and their value is demonstrated here in a protein quantitative trait locus analysis. Experience from different fields of life sciences suggests that accessible, complete reference maps of the components of the system under study are highly beneficial research tools. Examples of such maps include libraries of the spectroscopic properties of molecules, or databases of drug structures in analytical or forensic chemistry. Such maps, and methods to navigate them, constitute reliable assays to probe any sample for the presence and amount of molecules contained in the map. So far, attempts to generate such maps for any proteome have failed to reach complete proteome coverage 1 , 2 , 3 . Here we use a strategy based on high-throughput peptide synthesis and mass spectrometry to generate an almost complete reference map (97% of the genome-predicted proteins) of the Saccharomyces cerevisiae proteome. We generated two versions of this mass-spectrometric map, one supporting discovery-driven (shotgun) 3 , 4 and the other supporting hypothesis-driven (targeted) 5 , 6 proteomic measurements. Together, the two versions of the map constitute a complete set of proteomic assays to support most studies performed with contemporary proteomic technologies. To show the utility of the maps, we applied them to a protein quantitative trait locus (QTL) analysis 7 , which requires precise measurement of the same set of peptides over a large number of samples. Protein measurements over 78 S. cerevisiae strains revealed a complex relationship between independent genetic loci, influencing the levels of related proteins. Our results suggest that selective pressure favours the acquisition of sets of polymorphisms that adapt protein levels but also maintain the stoichiometry of functionally related pathway members.

Malaria elimination requires tools that interrupt parasite transmission. Here, we characterize B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230 kDa gamete surface protein Pfs230, a key protein in sexual stage development of P. falciparum parasites. Among nine Pfs230 human monoclonal antibodies (mAbs) that we generated, one potently blocks transmission to mosquitoes in a complement-dependent manner and reacts to the gamete surface; the other eight show only low or no blocking activity. The structure of the transmission-blocking mAb in complex with vaccine antigen reveals a large discontinuous conformational epitope, specific to domain 1 of Pfs230 and comprising six structural elements in the protein. The epitope is conserved, suggesting the transmission-blocking mAb is broadly functional. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination. Vaccines that interrupt malaria transmission will be important tools for malaria elimination. Here the authors identify a human monoclonal antibody from Pfs230 vaccinated individuals that blocks transmission of Plasmodium falciparum to mosquitoes in a complement-dependent manner and reacts with gamete surface.

Testosterone has been theorized to influence the development of post-traumatic stress disorder (PTSD). However, the relationship between testosterone level and PTSD is still not well understood. We evaluated the potential association between testosterone and subsequent development of PTSD symptoms using a large sample size, in a civilian context, inclusive of both males and females. Out of around 500,000 total UK Biobank participants, our sample had 130,471 participants who: had testosterone measures, completed the mental health questionnaire, and passed outlier exclusion. After adjusting for relevant covariates, we used linear regression to assess the relationship between testosterone level and future development of symptoms, in males and females separately (N males  = 61,758, N females  = 67,053). In both males and females, small but significant nonlinear (and oftentimes U-shaped) relationships were observed between testosterone levels and PTSD symptoms. When grouping participants into deciles of testosterone for both sexes, the strongest associations between testosterone levels and PTSD symptoms were observed in the central deciles. For example, for total testosterone, compared to decile 1: individuals in decile 7 had the lowest PTSD symptom scores in both males ( beta  = −0.16, p  = 1.58 × 10 −3 ) and females ( beta  = −0.23, p  = 3.04 × 10 −5 ). We also found that body mass index (BMI) moderated the relationship between testosterone and PTSD symptoms, such that the relationship was considerably stronger among individuals with higher BMI. Results were similar for depression and anxiety measures. Analyses using calculated free testosterone (cFT) and the free androgen index (FAI) were generally consistent with total testosterone (TT) results. These findings suggest that mid-range testosterone levels are associated with the lowest risk of PTSD symptoms in both sexes, and future work should seek to examine if this relationship is causal.

ABSTRACT Malaria elimination requires tools that interrupt parasite transmission. Here, we characterized B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230kDa gamete surface protein Pfs2301–3 to neutralize sexual stage P. falciparum parasites and halt their further spread. We generated nine Pfs230 human monoclonal antibodies (mAbs). One mAb potently blocked transmission to mosquitoes in a complement-dependent manner and reacted strongly to gamete surface while eight mAbs showed only low or no blocking activity. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination. Competing Interest Statement M.B.S, W.P., X.H., B.B., and M.E. declare competing financial interests as all are employees of iRepertoire Inc., and J.H. is co-founder and CEO. J.D.G. is an employee of Alchemab Therapeutics Limited. Footnotes * ↵12 These authors jointly directed this work Niraj H. Tolia1, Patrick E. Duffy * Malaria elimination requires tools that interrupt parasite transmission. Here, we characterized B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230kDa gamete surface protein Pfs2301-3 to neutralize sexual stage P. falciparum parasites and halt their further spread. We generated nine Pfs230 human monoclonal antibodies (mAbs). One mAb potently blocked transmission to mosquitoes in a complement-dependent manner and reacted strongly to gamete surface while eight mAbs showed only low or no blocking activity. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination.