An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome.

Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.

The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans.

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

Assessing trends in the content of maternal and child care following a health system strengthening initiative in rural Madagascar: A longitudinal cohort study.

BACKGROUND: In order to reach the health-related Sustainable Development Goals (SDGs) by 2030, gains attained in access to primary healthcare must be matched by gains in the quality of services delivered. Despite the broad consensus around the need to address quality, studies on the impact of health system strengthening (HSS) have focused predominantly on measures of healthcare access. Here, we examine changes in the content of maternal and child care as a proxy for healthcare quality, to better evaluate the effectiveness of an HSS intervention in a rural district of Madagascar. The intervention aimed at improving system readiness at all levels of care (community health, primary health centers, district hospital) through facility renovations, staffing, equipment, and training, while removing logistical and financial barriers to medical care (e.g., ambulance network and user-fee exemptions). METHODS AND FINDINGS: We carried out a district-representative open longitudinal cohort study, with surveys administered to 1,522 households in the Ifanadiana district of Madagascar at the start of the HSS intervention in 2014, and again to 1,514 households in 2016. We examined changes in healthcare seeking behavior and outputs for sick-child care among children <5 years old, as well as for antenatal care and perinatal care among women aged 15-49. We used a difference-in-differences (DiD) analysis to compare trends between the intervention group (i.e., people living inside the HSS catchment area) and the non-intervention comparison group (i.e., the rest of the district). In addition, we used health facility-based surveys, monitoring service availability and readiness, to assess changes in the operational capacities of facilities supported by the intervention. The cohort study included 657 and 411 children (mean age = 2 years) reported to be ill in the 2014 and 2016 surveys, respectively (27.8% and 23.8% in the intervention group for each survey), as well as 552 and 524 women (mean age = 28 years) reported to have a live birth within the previous two years in the 2014 and 2016 surveys, respectively (31.5% and 29.6% in the intervention group for each survey). Over the two-year study period, the proportion of people who reported seeking care at health facilities experienced a relative change of +51.2% (from 41.4% in 2014 to 62.5% in 2016) and -7.1% (from 30.0% to 27.9%) in the intervention and non-intervention groups, respectively, for sick-child care (DiD p-value = 0.01); +11.4% (from 78.3% to 87.2%), and +10.3% (from 67.3% to 74.2%) for antenatal care (p-value = 0.75); and +66.2% (from 23.1% to 38.3%) and +28.9% (from 13.9% to 17.9%) for perinatal care (p-value = 0.13). Most indicators of care content, including rates of medication prescription and diagnostic test administration, appeared to increase more in the intervention compared to in the non-intervention group for the three areas of care we assessed. The reported prescription rate for oral rehydration therapy among children with diarrhea changed by +68.5% (from 29.6% to 49.9%) and -23.2% (from 17.8% to 13.7%) in the intervention and non-intervention groups, respectively (p-value = 0.05). However, trends observed in the care content varied widely by indicator and did not always match the large apparent increases observed in care seeking behavior, particularly for antenatal care, reflecting important gaps in the provision of essential health services for individuals who sought care. The main limitation of this study is that the intervention catchment was not randomly allocated, and some demographic indicators were better for this group at baseline than for the rest of the district, which could have impacted the trends observed. CONCLUSION: Using a district-representative longitudinal cohort to assess the content of care delivered to the population, we found a substantial increase over the two-year study period in the prescription rate for ill children and in all World Health Organization (WHO)-recommended perinatal care outputs assessed in the intervention group, with more modest changes observed in the non-intervention group. Despite improvements associated with the HSS intervention, this study highlights the need for further quality improvement in certain areas of the district's healthcare system. We show how content of care, measured through standard population-based surveys, can be used as a component of HSS impact evaluations, enabling healthcare leaders to track progress as well as identify and address specific gaps in the provision of services that extend beyond care access.

The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health.

Systematic genetic studies of a handful of diverse organisms over the past 50 years have transformed our understanding of biology. However, many aspects of primate biology, behavior, and disease are absent or poorly modeled in any of the current genetic model organisms including mice. We surveyed the animal kingdom to find other animals with advantages similar to mice that might better exemplify primate biology, and identified mouse lemurs (Microcebus spp.) as the outstanding candidate. Mouse lemurs are prosimian primates, roughly half the genetic distance between mice and humans. They are the smallest, fastest developing, and among the most prolific and abundant primates in the world, distributed throughout the island of Madagascar, many in separate breeding populations due to habitat destruction. Their physiology, behavior, and phylogeny have been studied for decades in laboratory colonies in Europe and in field studies in Malagasy rainforests, and a high quality reference genome sequence has recently been completed. To initiate a classical genetic approach, we developed a deep phenotyping protocol and have screened hundreds of laboratory and wild mouse lemurs for interesting phenotypes and begun mapping the underlying mutations, in collaboration with leading mouse lemur biologists. We also seek to establish a mouse lemur gene "knockout" library by sequencing the genomes of thousands of mouse lemurs to identify null alleles in most genes from the large pool of natural genetic variants. As part of this effort, we have begun a citizen science project in which students across Madagascar explore the remarkable biology around their schools, including longitudinal studies of the local mouse lemurs. We hope this work spawns a new model organism and cultivates a deep genetic understanding of primate biology and health. We also hope it establishes a new and ethical method of genetics that bridges biological, behavioral, medical, and conservation disciplines, while providing an example of how hands-on science education can help transform developing countries.