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Abstract The Plasmodium falciparum life cycle includes obligate transition between a human and mosquito host. Gametocytes are responsible for transmission from the human to the mosquito vector where gamete fusion followed by meiosis occurs. To elucidate how male and female gametocytes differentiate in the absence of sex chromosomes, we perform FACS-based cell enrichment of a P. falciparum gametocyte reporter line followed by single-cell RNA-seq. In our analyses we define the transcriptional programs and predict candidate driver genes underlying male and female development, including genes from the ApiAP2 family of transcription factors. A motif-driven, gene regulatory network analysis indicates that AP2-G5 specifically modulates male development. Additionally, genes linked to the inner membrane complex, involved in morphological changes, are uniquely expressed in the female lineage. The transcriptional programs of male and female development detailed herein allow for further exploration of the evolution of sex in eukaryotes and provide targets for future development of transmission blocking therapies.

Summary: An adaptive feature of malaria-causing parasites is the digestion of host hemoglobin (HB) to acquire amino acids (AAs). Here, we describe a link between nutrient availability and translation dependent regulation of gene expression as an adaptive strategy. We show that tRNA expression in Plasmodium falciparum does not match the decoding need expected for optimal translation. A subset of tRNAs decoding AAs that are insufficiently provided by HB are lowly expressed, wherein the abundance of a protein-coding transcript is negatively correlated with the decoding requirement of these tRNAs. Proliferation-related genes have evolved a high requirement of these tRNAs, thereby proliferation can be modulated by repressing protein synthesis of these genes during nutrient stress. We conclude that the parasite modulates translation elongation by maintaining a discordant tRNA profile to exploit variations in AA-composition among genes as an adaptation strategy. This study exemplifies metabolic adaptation as an important driving force for protein evolution.

IntroductionMinimizing postprandial glucose response is an important goal for overall diabetes management. Diabetes-specific nutritional shakes (DSNS) have been clinically shown to minimize postprandial glucose response in people with type 2 diabetes (T2DM) compared to high-glycemic foods. However, it is unknown how a high-protein, low-fat DSNS impacts the GLP-1 response.MethodsWe tested the postprandial glucose, insulin, and GLP-1 response to a high-protein, low-fat diabetes-specific nutritional shake (DSNS-HP) compared to isocaloric instant oatmeal (IOM) in a randomized, controlled, crossover study in adults with T2DM (n = 24). Participants were randomly selected to receive IOM or DSNS-HP on two test days. Glucose, insulin, and total GLP-1 concentration were measured at baseline and 15, 30, 45, 60, 90, 120, 180, and 240 min postprandially.ResultsCompared to IOM, the glucose-positive area under the curve (pAUC) was significantly lower (P = .021). DSNS-HP significantly increased GLP-1 pAUC response by 213% (P

Long-term treatment outcomes for patients with high grade ovarian cancers have not changed despite innovations in therapies. There is no recommended assay for predicting patient response to second-line therapy, thus clinicians must make treatment decisions based on each individual patient. Patient-derived xenograft (PDX) tumors have been shown to predict drug sensitivity in ovarian cancer patients, but the time frame for intraperitoneal (IP) tumor generation, expansion, and drug screening is beyond that for tumor recurrence and platinum resistance to occur, thus results do not have clinical utility. We describe a drug sensitivity screening assay using a drug delivery microdevice implanted for 24 h in subcutaneous (SQ) ovarian PDX tumors to predict treatment outcomes in matched IP PDX tumors in a clinically relevant time frame. The SQ tumor response to local microdose drug exposure was found to be predictive of the growth of matched IP tumors after multi-week systemic therapy using significantly fewer animals (10 SQ vs 206 IP). Multiplexed immunofluorescence image analysis of phenotypic tumor response combined with a machine learning classifier could predict IP treatment outcomes against three second-line cytotoxic therapies with an average AUC of 0.91.

Bone fractures are one of the leading causes of emergency room visits worldwide, with approximately 8 million bony fractures occurring annually in the US alone. Although the majority of fractures do not cause significant long-term morbidity and mortality, approximately 10% of these fractures result in impaired fracture healing, drastically affecting quality of life in affected patients. By increasing bone formation, teriparatide, an anabolic agent used in the treatment of postmenopausal osteoporosis, has shown promise in accelerating the rate of fracture healing. We present two patients with impaired healing of metatarsal fractures who were subsequently treated with teriparatide. Both patients experienced successful bony union of the fracture after the use of teriparatide. These findings suggest that teriparatide may be useful in the clinical setting for the acceleration of fracture healing, especially in patients who are at risk for impaired fracture healing.