The HIV-1 reservoir is the major hurdle to a cure. We here evaluate viral and host characteristics associated with reservoir size and long-term dynamics in 1,057 individuals on suppressive antiretroviral therapy for a median of 5.4 years. At the population level, the reservoir decreases with diminishing differences over time, but increases in 26.6% of individuals. Viral blips and low-level viremia are significantly associated with slower reservoir decay. Initiation of ART within the first year of infection, pretreatment viral load, and ethnicity affect reservoir size, but less so long-term dynamics. Viral blips and low-level viremia are thus relevant for reservoir and cure studies.

Background:Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These ‘RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.Methods:We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.Results:We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4–18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.Conclusions:These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.

Alamethicin (ALA), a voltage-gated, ion channel-forming peptide mixture from Trichoderma viride, is a potent elicitor of the biosynthesis of volatile compounds in lima bean (Phaseolus lunatus). Unlike elicitation with jasmonic acid or herbivore damage, the blend of substances emitted comprises only the two homoterpenes, 4,11-dimethylnona-1,3,7-triene and 4,8,12-trimethyltrideca-1,3,7,11-tetraene, and methyl salicylate. Inhibition of octadecanoid signaling by aristolochic acid and phenidone as well as mass spectrometric analysis of endogenous jasmonate demonstrate that ALA induces the biosynthesis of volatile compounds principally via the octadecanoid-signaling pathway (20-fold increase of jasmonic acid). ALA also up-regulates salicylate biosynthesis, and the time course of the production of endogenous salicylate correlates well with the appearance of the methyl ester in the gas phase. The massive up-regulation of the SA-pathway (90-fold) interferes with steps in the biosynthetic pathway downstream of 12-oxophytodienoic acid and thereby reduces the pattern of emitted volatiles to compounds previously shown to be induced by early octadecanoids. ALA also induces tendril coiling in various species like Pisum, Lathyrus, and Bryonia, but the response appears to be independent from octadecanoid biosynthesis, because inhibitors of lipoxygenase and phospholipase A2 do not prevent the coiling reaction.

Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.