CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

1. In a rapidly changing world, ecology has the potential to move from empirical and conceptual stages to application and management issues. It is now possible to make large-scale predictions up to continental or global scales, ranging from the future distribution of biological diversity to changes in ecosystem functioning and services. With these recent developments, ecology has a historical opportunity to become a major actor in the development of a sustainable human society. With this opportunity, however, also comes an important responsibility in developing appropriate predictive models, correctly interpreting their outcomes and communicating their limitations. There is also a danger that predictions grow faster than our understanding of ecological systems, resulting in a gap between the scientists generating the predictions and stakeholders using them (conservation biologists, environmental managers, journalists, policymakers). 2. Here, we use the context provided by the current surge of ecological predictions on the future of biodiversity to clarify what prediction means, and to pinpoint the challenges that should be addressed in order to improve predictive ecological models and the way they are understood and used.3. Synthesis and applications. Ecologists face several challenges to ensure the healthy development of an operational predictive ecological science: (i) clarity on the distinction between explanatory and anticipatory predictions; (ii) developing new theories at the interface between explanatory and anticipatory predictions; (iii) open data to test and validate predictions; (iv) making predictions operational; and (v) developing a genuine ethics of prediction. Supporting InformationAdditional Supporting Information may be found in the online version of this article.Appendix S1. Characteristics of mechanistic and phenomenological models in ecology.Appendix S2. Non-exhaustive list, of international initiatives of the scientific community aiming for sharing ecological data.

Abstract. The fate of octogenarians reaching end-stage renal disease (ESRD) is poorly defined, and implicit dialysis rationing may be practiced in this age group. The main objectives of this study were to analyze the characteristics of pre-ESRD octogenarians offered dialysis or not and to identify factors influencing mortality while on dialysis, to improve prognosis assessment and decision-making. In this single-center cohort, 146 consecutive pre-ESRD octogenarians were referred to a nephrology unit over a 12-yr period (1989 to 2000). Main outcome measures were baseline characteristics of patients offered dialysis and conservative therapy and overall and 1-yr survival according to effective treatment. A therapeutic decision was made for 144 patients. Octogenarians who were not proposed dialysis (n ϭ 37) differed from those who were proposed dialysis (n ϭ 107) mainly in terms of social isolation (43.3% versus 14.7%; P ϭ 0.03), late nephrologic referral (51.4% versus 28.9%; P ϭ 0.01), Karnofsky score (55 Ϯ 18 versus 63 Ϯ 20; P ϭ 0.03), and diabetic status (22.2% versus 6.5%, P ϭ 0.008). Six patients refused the dialysis proposal.During the 12-yr observation period, 99 patients died (68.7%). Median survival was 28.9 mo (95% CI, 24 to 38) in patients undergoing dialysis, compared with 8.9 mo (95% CI, 4 to

Activation of the hepatocyte growth factor (HGF) receptor in epithelial cells results in lamellipodia protrusion, spreading, migration, and tubule formation. We have previously reported that these morphogenic effects are dependent on MAPK activation at focal adhesions. In the present study we demonstrate that activated ERK phosphorylates paxillin on serine 83 and that mutation of this site eliminates HGF-stimulated increased association of paxillin and FAK in subconfluent cells. Failure to activate FAK at focal adhesions results in a loss of FAK-PI 3-kinase association and the marked reduction of Rac activation after HGF stimulation. Expression of paxillin mutants that disrupt ERK association or phosphorylation inhibits HGF-induced cell spreading, migration, and tubulogenesis. These data demonstrate that the paxillin-MAPK complex serves as a central regulator of HGF-stimulated FAK and Rac activation in the vicinity of focal adhesions, thus promoting the rapid focal adhesion turnover and lamellipodia extension that are required for migratory and tubulogenic responses.

We analyzed genetic variation among geographically diverse populations of Drosophila and showed that tropical flies are more tolerant than temperate ones to heat-induced male sterility, as assessed by the presence of both motile sperm and progeny production. In tropical populations, the temperature inducing 50% sterility (median threshold) is 1°C above the value for temperate populations (30.4 vs. 29.4°C). When transferred to a mild permissive temperature (21°C), males recover fertility. Recovery time is proportional to pre-adult culture temperature. At these temperatures, recovery time is greater for temperate than for tropical populations. Crosses between a temperate and a tropical strain (F 1, F2and successive backcrosses) revealed that the Y chromosome was responsible for much of the geographic variation. Sterile males exhibited diverse abnormalities in the shape and position of sperm nuclei. However, impairment of the spermatid elongation seems to be the major factor responsible for sperm inviability. Heatinduced male sterility seems to be quite a general phenomenon in Drosophilid species and variation of threshold temperatures may be important for explaining their geographic distributions.

The thermal range for viability is quite variable among Drosophila species and it has long been known that these variations are correlated with geographic distribution: temperate species are on average more cold tolerant but more heat sensitive than tropical species. At both ends of their viability range, sterile males have been observed in all species investigated so far. This symmetrical phenomenon restricts the temperature limits within which permanent cultures can be kept in the laboratory. Thermal heat sterility thresholds are very variable across species from 23 degrees C in heat sensitive species up to 31 degrees C in heat tolerant species. In Drosophila melanogaster, genetic variations are observed among geographic populations. Tropical populations are more tolerant to heat induced sterility and recover more rapidly than temperate ones. A genetic analysis revealed that about 50% of the difference observed between natural populations was due to the Y chromosome. Natural populations have not reached a selection limit, however: thermal tolerance was still increased by keeping strains at a high temperature, close to the sterility threshold. On the low temperature side, a symmetrical reverse phenomenon seems to exist: temperate populations are more tolerant to cold than tropical ones. Compared to Mammals, drosophilids exhibit two major differences: first, male sterility occurs not only at high temperature, but also at a low temperature; second, sterility thresholds are not evolutionarily constrained, but highly variable. Altogether, significant and sometimes major genetic variations have been observed between species, between geographic races of the same species, and even between strains kept in the laboratory under different thermal regimes. In each case, it is easily argued that the observed variations correspond to adaptations to climatic conditions, and that male sterility is a significant component of fitness and a target of natural selection.

Activation of the hepatocyte growth factor (HGF) receptor c-met results in the regulation of cell-matrix interactions, including the MAPK-dependent stimulation of epithelial cell morphogenesis. In the present study we demonstrate that HGF stimulates the localization of ERK to sites of cell-matrix interactions and that this is mediated by the tyrosine phosphorylation-dependent association of inactive ERK and the focal adhesion complex protein paxillin. In addition, paxillin was found to associate with the upstream MAP kinases Raf and MEK, resulting in a complex that can mediate localized ERK activation. Mutation of the ERK binding site in paxillin prevented HGF-stimulated ERK-paxillin association and eliminated HGF-induced cell spreading and branching process formation. These experiments reveal that paxillin-dependent ERK activation at sites of cell-matrix interaction is critical for HGF-stimulated epithelial morphogenesis.

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.