Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Lichenometric studies on moraines in the Polar Urals

Lichenometry was used to study fluctuations of six glaciers in the Polar Urals over the last millennium (viz: IGAN, Obrucheva, Anuchina, Shumskogo, Avsiuka and Berga glaciers). In order to estimate the growth rate of Rhizocarpon subgenus Rhizocarpon lichens we used recently deglaciated surfaces as calibration sites. These sites, on glacier forelands, were dated using topographic maps, aerial photographs (from 1953, 1958, 1960, 1968, 1973, 1989), terrestrial photogrammetry, field photographs (from the 1960s to 2005), and satellite images (from 2000 and 2008). We also used pits and quarries abandoned between the 1940s–1980s and a road built in the early 1980s as calibration sites. Optimum diametral growth rates of Rhizocarpon subgenus Rhizocarpon are estimated by the new curve to be c. 0.25 mm/year for the last 100 years, assuming linear growth as deduced from the shape of other curves from northern Scandinavia. Due to the lack of old control points we used a reconstructed mass balance curve (from 1816 to 2008) to indirectly constrain the age of pre-twentieth-century moraines. The following moraine groups were identified near the modern fronts of glaciers: ablation moraines de-glaciated during the last 40 to 60 years; lateral moraines formed in the early twentieth century (largest lichen diameter (DLL) = 20 mm), ice-cored moraines, probably from the 1880s (DLL= 24–26 mm); moraines probably deposited in the middle of the nineteenth century and c. 200 years ago (DLL= 30–33 mm and 44–47 mm, respectively); as well as several more ancient moraines (DLL= 70 mm, 90 mm and 110–153 mm) deposited during glacier advances of almost identical extent. According to our tentative lichenometric-age estimates most moraines were formed during the last 450 years – consistent with upper tree-limit altitude variations previously identified for this region. Glacier fluctuations in the Polar Urals are in agreement with tree-ring based reconstructions of summer temperature spanning the last millennium, and are also in tune with glacier behaviour elsewhere in the Northern Hemisphere

‘Proxy War’: a reconceptualisation

This article presents a definitional structure for the notion of ‘proxy war’ organised around three components: (1) a material-constitutive feature, e.g. external support; (2) a processual feature explaining the modalities through which the material-constitutive component is provided; and (3) a relational feature underlying its specific type of strategic behaviour, e.g. strategic bargaining short of alliance building. In doing so, the article investigates the analytical utility of ‘proxy war’ as concept given the rapid expansion of the literature. First, the article evaluates the multiple usages of the term of ‘proxy war’ in light of its contested character. Second, it proposes a way of making sense of the literature’s conceptual turmoil by analysing the different attempts at defining the notion. To this end, it adds an important link to the methodology of concept analysis, namely the ‘semantic field’, which it re-introduces as a heuristic to identify ‘military intervention’ as a root concept for defining proxy wars. The article does so by identifying a type of semantic relationship between ‘proxy war’ and ‘military intervention’, namely sub-type inclusion

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for approximately 5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS