Hydatidiform mole (HM) is an abnormal human pregnancy with no embryo and cystic degeneration of placental villi. We report five mutations in the maternal gene NALP7 in individuals with familial and recurrent HMs. NALP7 is a member of the CATERPILLER protein family involved in inflammation and apoptosis. NALP7 is the first maternal effect gene identified in humans and is also responsible for recurrent spontaneous abortions, stillbirths and intrauterine growth retardation.

In this contribution, we describe a multi-omics systems biology study of the metabolic changes that occur during aging in Caenorhabditis elegans. Sampling several time points from young adulthood until early old age, our study covers the full duration of aging and include transcriptomics, and targeted MS-based metabolomics. In order to focus on the metabolic changes due to age we used two strains that are metabolically close to wild-type, yet are conditionally non-reproductive. Using these data in combination with a whole-genome model of the metabolism of C. elegans and mathematical modeling, we predicted metabolic fluxes during early aging. We find that standard Flux Balance Analysis does not accurately predict in vivo measured fluxes nor age-related changes associated with the Citric Acid cycle. We present a novel Flux Balance Analysis method where we combined biomass production and targeted metabolomics information to generate an objective function that is more suitable for aging studies. We validated this approach with a detailed case study of the age-associated changes in the Citric Acid cycle. Our approach provides a comprehensive time-resolved multi-omics and modeling resource for studying the metabolic changes during normal aging in C. elegans.

Hydatidiform mole (HM) is a human pregnancy with abnormal embryonic development. NLRP7 is a major autosomal recessive gene responsible for recurrent molar pregnancies and associated reproductive wastage in patients from several populations. Here, we report NLRP7 mutation analysis in 35 unrelated Chinese patients with recurrent reproductive wastage, including at least one HM. We describe three new protein-truncating mutations in NLRP7 and show the presence of three founder mutations in China and Asian populations. We determined the parental contribution to six molar tissues and show the occurrence of three diploid androgenetic moles in patients with one defective allele, while three diploid biparental moles occurred in patients with two defective alleles. We document the failure of pregnancies after assisted reproductive technologies (ARTs) in three patients with two defective alleles each and a successful pregnancy in one of two patients with one defective allele. Our data suggest that patients with a single defective allele have better reproductive outcomes than patients with two defective alleles, and some of them may benefit from ART.

To survive elevated temperatures, ectotherms adjust the fluidity of membranes by fine-tuning lipid desaturation levels in a process previously described to be cell autonomous. We have discovered that, in Caenorhabditis elegans, neuronal heat shock factor 1 (HSF-1), the conserved master regulator of the heat shock response (HSR), causes extensive fat remodeling in peripheral tissues. These changes include a decrease in fat desaturase and acid lipase expression in the intestine and a global shift in the saturation levels of plasma membrane’s phospholipids. The observed remodeling of plasma membrane is in line with ectothermic adaptive responses and gives worms a cumulative advantage to warm temperatures. We have determined that at least 6 TAX-2/TAX-4 cyclic guanosine monophosphate (cGMP) gated channel expressing sensory neurons, and transforming growth factor ß (TGF-β)/bone morphogenetic protein (BMP) are required for signaling across tissues to modulate fat desaturation. We also find neuronal hsf-1 is not only sufficient but also partially necessary to control the fat remodeling response and for survival at warm temperatures. This is the first study to show that a thermostat-based mechanism can cell nonautonomously coordinate membrane saturation and composition across tissues in a multicellular animal.

The Killer Immunoglobulin-like Receptors are a highly polymorphic family of receptors encoded by fifteen genes clustered on 19q13.4. Due to the complexity of the genetic analysis of the KIR cluster much of the data regarding KIR sequences and alleles has been generated by cDNA typing and partial sequencing. Here we report the genomic sequencing of the KIR genes in individuals with three different haplotypes homozygous by descent. We provide a detailed analysis of their haplotypes and identify new alleles for KIR3DL3 and KIR2DL1. The primers we describe will be a valuable tool for studying the involvement of the KIR genes in various human diseases.

Highlights Gene-regulatory inference provides global network of long-lived animalsThe large-scale topology of the network has an hourglass structure Membership to the core of the hourglass is a good predictor of functionality Discovered 50 novel aging genes, including sup-37, a DAF-16 dependent gene

An organisms' ability to adapt to heat can be key to its survival. Cells adapt to temperature shifts by adjusting lipid desaturation levels and the fluidity of membranes in a process that is thought to be controlled cell autonomously. We have discovered that subtle, step-wise increments in ambient temperature can lead to the conserved heat shock response being activated in head neurons of C. elegans. This response is exactly opposite to the expression of the lipid desaturase FAT-7 in the worm's gut. We find that the over-expression of the master regulator of this response, Hsf-1, in head neurons, causes extensive fat remodeling to occur across tissues. These changes include a decrease in FAT-7 expression and a shift in the levels of unsaturated fatty acids in the plasma membrane. These shifts are in line with membrane fluidity requirements to survive in warmer temperatures. We have identified that the cGMP receptor, TAX-2/TAX-4, as well as TGF-β/BMP signaling, as key players in the transmission of neuronal stress to peripheral tissues. This is the first study to suggest that a thermostat-based mechanism can centrally coordinate membrane fluidity in response to warm temperatures across tissues in multicellular animals. 2004; Hedgecock and Russell, 1975)Although thermostat-based behaviours help ectotherms to escape noxious stimuli like heat, the longer-term survival of ectotherms when environmental temperatures change depends on their ability to remodel lipids within the plasma membrane, which is highly sensitive to external temperatures. Homeoviscous adaptation (HVA) is a mechanism that regulates the viscosity and permeability of membranes to ensure the robustness of biochemical reactions (Sinensky 1974;Cossins and Prosser 1978). In homeoviscous cold adaptation, membrane bilayers undergo a reversible change of state from a non-fluid (ordered) to a fluid (disordered) structure whereby the membrane's phospholipids (PLs) fatty acyl (FA) chains become increasingly unsaturated (Mendoza 2014; Ernst, Ejsing, and Antonny 2016). In C. elegans, three Δ9-acyl desaturase both the regulators of SCD enzymes -such as MDT-15-and SCD enzymes themselves are known to negatively regulate HSP expression at 15°C 19 (Savory et al 2011a) . However, it is not known whether Hsf-1 dependent cellular responses can modulate SCD expression and MUFA levels.Here, we show that hsp transcripts are expressed primarily in the head neurons of C. elegans at 20°C and show a clear temperature-sensitive expression pattern. We used the neuronal overexpression of HSF-1 (nhsf-1) as a tool to study the consequences of ectopically activating HSR in neurons at 20°C. We find that HSF-1 overexpression, via nhsf-1, in addition to its previously described role in controlling peripheral stress responses and longevity (Douglas et al. 2015), remodels lipid metabolism. This function is performed by decreasing the expression of fat-7 in the intestine, whilst activating the expression of catabolic lysosomal lipases. We identified the cGMP receptors TAX-2/TAX-4 and TGF-β...

Despite being isogenic and grown under controlled conditions, C. elegans populations exhibit widespread inter-individual variability in many traits, making it an ideal model organism to investigate non-genetic influences on phenotypic diversity. Our particular interest is to study the consequences of inter-individual variability in genes encoding heat shock proteins, which are expressed at low levels under non-stimulated conditions. To robustly quantify inter-individual gene expression, we developed a novel pipeline that combines a highly efficient cDNA extraction method with a high-throughput qPCR nanofluidics technology with a bespoke computational analysis. We validated our approach by benchmarking against in vivo reporters. We also screened among hundreds of stress inducible genes, and identified a regulon formed by transcripts belonging to the inducible heat shock protein family. We demonstrate, using a bipartite in vivo fluorescent reporter, that the inter-individual variability in the stress regulon stems mostly from anterior neurons. Our studies demonstrate for the first time that, under physiological and unstimulated conditions, the variable expression of neural stress responses has cross-tissue consequences for fitness at the individual worm level, suggesting an adaptive role under variable environmental conditions.