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Cognitive dysfunction in aging is a major biomedical challenge. Whether treatment with klotho, a longevity factor, could enhance cognition in human-relevant models such as in nonhuman primates is unknown and represents a major knowledge gap in the path to therapeutics. We validated the rhesus form of the klotho protein in mice showing it increased synaptic plasticity and cognition. We then found that a single administration of low-dose, but not high-dose, klotho enhanced memory in aged nonhuman primates. Systemic low-dose klotho treatment may prove therapeutic in aging humans.

The nuclear factor I/X (NFIX) gene encodes a ubiquitously expressed transcription factor whose mutations lead to two allelic disorders characterized by developmental, skeletal, and neural abnormalities, namely, Malan syndrome (MAL) and Marshall-Smith syndrome (MSS). NFIX mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense-mediated decay (NMD) leading to NFIX haploinsufficiency, whereas NFIX mutations associated with MSS are clustered in exons 6-10 and escape NMD and result in the production of dominant-negative mutant NFIX proteins. Thus, different NFIX mutations have distinct consequences on NFIX expression. To elucidate the in vivo effects of MSS-associated NFIX exon 7 mutations, we used CRISPR-Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides (Nfix Del2); in-frame deletion of 24 nucleotides (Nfix Del24); and deletion of 140 nucleotides (Nfix Del140). Nfix +/Del2, Nfix +/Del24, Nfix +/Del140, Nfix Del24/Del24, and Nfix Del140/Del140 mice were viable, normal, and fertile, with no skeletal abnormalities, but Nfix Del2/Del2 mice had significantly reduced viability (p

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

This paper investigates performative manifestations of sincerity across Anglo-Norman and Middle English. In particular, it locates adverbial sincerity markers used to qualify performative speech act verbs in late medieval letters (fourteenth and fifteenth centuries), at a point when Middle English was rapidly replacing Anglo-Norman as the vernacular of epistolarity in England. Employing historical dictionaries and corpora, the study (1) locates the range of words for 'sincerity' from a time when the modern lexeme had yet to be borrowed in either vernacular, and (2) demonstrates that while it is clear that Middle English epistolarity was greatly influenced by Anglo-Norman, quantitative and qualitative analyses suggest that sincerity markers were much less commonplace in Middle English performatives, which further suggests ways in which the communicative ideal and practice of sincerity were reanalyzed from one language to the next.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Palynomorphs are one of the few groups of fossils that provide biostratigraphic control in marine to nonmarine rocks and can be applied as proxies for paleoenvironmental and paleoclimatic interpretations. Their utility is enhanced by their microscopic size, which is usually less than 200 micrometres; they are thus easily recovered from small rock samples. They occur throughout the Phanerozoic and are therefore invaluable in refining biostratigraphic control of Arctic successions in Alaska, Arctic Canada, Greenland, northern Europe, and northern Russia. The objective of the Circum-Arctic Palynological Event (CAPE) Stratigraphy series of papers is to integrate data published on Arctic palynomorphs to delineate palynological events (palynoevents) across the Arctic for the Silurian to Cenozoic. Once the series of papers is complete, the data will also be used to compile a TimeScale Creator datapack that can be updated and calibrated on an ongoing basis. Palynoevents include taxon originations (first occurrences or FOs) and extinctions (last occurrences, or I.Os) and some abundance events. The palynoevents are correlated with established chronostratigraphic horizons such as bases of ammonoid zones or stages, and hence their chronostratigraphy is independent of the absolute time scale in millions of years. In addition to the palynostratigraphic papers, the series includes a paper detailing the paleogeography of the circum-Arctic regions, including informative maps, as well as a paper providing a palynological perspective of the Cenozoic shift from greenhouse to icehouse conditions. Les palynomorphes sont l'un des rares groupes de fossiles qui permettent un controle biostratigraphique dans les roches marines et non marines et qui peuvent servir de temoins pour les interpretations paleoenvironnementales et paleoclimatiques. Leur utilite se trouve amelioree par leur taille microscopique, qui est habituellement de moins de 200 micrometres; ils sont ainsi facilement recuperes des petits echantillons de roches. Ils sont presents durant tout le Phanerozoique et sont par consequent d'une valeur inestimable pour le raffinement du controle biostratigraphique des successions arctiques en Alaska, dans l'Arctique canadien, au Groenland, dans le nord de l'Europe et dans le nord de la Russie. La serie d'articles sur la stratigraphie des phenomenes palynologiques circumarctiques (PPC) vise l'integration des donnees publiees sur les palynomorphes arctiques afin de degager les phenomenes palynologiques (palynophenomenes) dans l'Arctique durant la periode du Silurien au Cenozoique. Une fois la serie d'articles terminee, les donnees serviront a la compilation d'un dossier de donnees TimeScale Creator pouvant etre mis a jour et etalonne de facon continue. Les palynophenomenes englobent les apparitions (premieres manifestations ou PM) et les extinctions (dernieres manifestations ou DM) de taxons, et certains phenomenes d'abondance. Les palynophenomenes sont correles avec des horizons chronostratigraphiques etablis comme les bases de zones ou d'etages d'ammonites, et leur chronostratigraphie est done independante de l'echelle chronologique absolue en millions d'annees. Outre les articles palynostratigraphiques, la serie comprend un article detaillant la paleogeographie des regions circumarctiques, y compris des cartes informatives, ainsi qu'un article fournissant une perspective palynologique du passage d'une periode a effet de serre a des conditions a faible effet de serre durant le Cenozoique. [Traduit par la redaction], INTRODUCTION In the Circum-Arctic Palynological Event Stratigraphy project (CAPE), specialists were asked to document selected palynological events (for example taxon originations and extinctions) with correlation potential from the Silurian to [...]

ImportanceAssociations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking.ObjectiveTo assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures.Data sources and study selectionThe databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures.Data extractionIndividual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH