Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy

Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.     

Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL

Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.     

Borelli’s edition of books V–VII of Apollonius’s Conics,and Lemma 12 in Newton’s Principia

To solve the direct problem of central forces when the trajectory is an ellipse and the force is directed to its centre, Newton made use of the famous Lemma 12 (Principia, I, sect. II) that was later recognized equivalent to proposition 31 of book VII of Apollonius’s Conics. In this paper, in which we look for Newton’s possible sources for Lemma 12, we compare Apollonius’s original proof, as edited by Borelli, with those of other authors, including that given by Newton himself. Moreover, after having retraced its editorial history, we evaluate the dissemination of Borelli's edition of books V-VII of Apollonius’s Conics before the printing of the Principia.

     

From secondary causes to artificial instruments: Pierre-Sylvain Régis's rethinking of scholastic accounts of causation

Although several of Descartes's disciples established occasionalism as the natural outcome of Cartesianism, Pierre-Sylvain Régis forcefully resisted this conclusion by developing an account of secondary causes in which God does not immediately intervene in the natural world. In order to understand this view, it has been argued that Régis melds Aquinas's concurrentism with the new, mechanist natural philosophy defended in Cartesian physics. In this paper, I contend that such a reading of Régis's position is misleading for our understanding of both his account of secondary causality and the relationship between medieval debates and seventeenth century natural philosophy. I show that Régis's account of secondary causality denies two fundamental features at the core of the account proposed by Aquinas, namely that God acts immediately in nature and that secondary causes are per se causes. I contend that Régis's view more closely resembles a specific account of artificial instrumental causality developed by Duns Scotus. The comparison with Scotus shows that Régis is still dealing with conceptual tools that can be traced back to the scholastic tradition. Yet, Régis implements these tools to establish an account of causation that is fundamentally irreconcilable with scholastic natural philosophy.     

Cholesky–ANN models for predicting multivariate realized volatility

Accurately forecasting multivariate volatility plays a crucial role for the financial industry. The Cholesky–artificial neural networks specification here presented provides a twofold advantage for this topic. On the one hand, the use of the Cholesky decomposition ensures positive definite forecasts. On the other hand, the implementation of artificial neural networks allows us to specify nonlinear relations without any particular distributional assumption. Out-of-sample comparisons reveal that artificial neural networks are not able to strongly outperform the competing models. However, long-memory detecting networks, like nonlinear autoregressive model process with exogenous input and long short-term memory, show improved forecast accuracy with respect to existing econometric models.     

Pollen evidence of historical forest disturbance on the Wasatch Plateau, Utah

Environmental indicators from lake sediments provide excellent opportunities to improve understanding of forest disturbance processes and corresponding changes in forest composition. Our research provides a methodology for assessing recent, historic, and prehistoric disturbances using lacustrine sediment records. We collected sediment cores from Blue Lake, a small subalpine lake on the Wasatch Plateau in central Utah. These cores record environmental changes caused by both spruce beetle ( Dendroctonus rufipennis Kirby) and human (logging and livestock grazing) modification. We observed deteriorated insect remains in the lake sediments. These remains correspond temporally with a historic spruce beetle outbreak, though alkaline conditions in the lake water may have inhibited preservation of bark beetle remains. Pollen data reveal that despite the unprecedented level of mortality among Engelmann spruce ( Picea engelmannii Parry ex Engelm.) resulting from the spruce beetle epidemic, logging activities subsequent to Euro-American settlement appear to be the most severe disturbance to the Blue Lake watershed over the last 750 years.     

The development and function of regulatory T cells

Regulatory T cells (Tregs) are a critical subset of T cells that mediate peripheral tolerance. There are two types of Tregs: natural Tregs, which develop in the thymus, and induced Tregs, which are derived from naive CD4⁺ T cells in the periphery. Tregs utilize a variety of mechanisms to suppress the immune response. While Tregs are critical for the peripheral maintenance of potential autoreactive T cells, they can also be detrimental by preventing effective anti-tumor responses and sterilizing immunity against pathogens. In this review, we will discuss the development of natural and induced Tregs as well as the role of Tregs in a variety of disease settings and the mechanisms they utilize for suppression. C. J. Workman, A. L. Szymczak-Workman, L. W. Collison, and M. R. Pillai contributed equally.     

PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR

Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml-/- cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis.