The Road to Artificial Super-Intelligence: Has International Law a Role to Play?

Part I of this article deals with the road to artificial general super-intelligence. Part II addresses the controls, if any, that should be exercised over the production and use of partially or fully autonomous machines of artificial intelligence before and after they become super-intelligent. More particularly, should there be legal and ethical limits to their use and to what extent should international law play a role in this connection

The Operational Impacts of Chief Supply Chain Officers in Manufacturing Firms

Many firms have elevated their supply chain management decision-making responsibilities through the creation of ‘Chief Supply Chain Officer’ (CSCO) positions. This is widely attributed to the recognition that superior supply chain operations can generate a competitive advantage. Prior studies have found that firms with CSCOs outperform firms without CSCOs along many financial dimensions. However, these prior efforts did not examine the pathways by which these improvements occur. This study addresses this gap in the literature by investigating whether supply chain characteristics of manufacturing firms differ within firms with CSCOs. To explore this, we investigate the relationship between CSCOs and operational dimensions of supply chain performance using data from the 10-year period between 2008 and 2017. We find that the presence of a CSCO in a firm is associated with shorter cash conversion cycles, lower levels of operational slack, and larger buffers of inventory during periods of high market instability

The impact of sex on gene expression across human tissues

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation

The impact of sex on gene expression across human tissues

Many complex human phenotypes exhibit sex-differentiated characteristics, however the underlying molecular mechanisms of these differences remain largely unknown. Here, we present an extensive catalog of both sex differences in gene expression and its genetic regulation across 44 human tissue sources surveyed by GTEx (v8 release). We demonstrate that sex strongly influences gene expression levels and cellular composition of tissue samples across the human body. The effect of sex on gene expression is widespread, with a total of 37% of all genes exhibiting sex-biased expression in at least one tissue. This suggests that many if not most biological processes, and thus complex traits and diseases, are impacted by sex effects on the transciptome. We expand the identification of cis-eQTLs with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation in a single sex, including novel associations not detected with sex-agnostic approaches. Altogether we provide the most comprehensive characterization of sex differences in the human transcriptome and its regulation to date.Peer ReviewedPreprin

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Oxygen redox chemistry without excess alkali-metal ions in Na2/3_{2/3}[Mg0.28_{0.28}Mn0.72_{0.72}]O2_2

The search for improved energy-storage materials has revealed Li- and Na-rich intercalation compounds as promising high-capacity cathodes. They exhibit capacities in excess of what would be expected from alkali-ion removal/reinsertion and charge compensation by transition-metal (TM) ions. The additional capacity is provided through charge compensation by oxygen redox chemistry and some oxygen loss. It has been reported previously that oxygen redox occurs in O 2$p$ orbitals that interact with alkali ions in the TM and alkali-ion layers (that is, oxygen redox occurs in compounds containing Li$^+$–O(2$p$)–Li$^+$ interactions). Na$_{2/3}$[Mg$_{0.28}$Mn$_{0.72}$]O$_2$ exhibits an excess capacity and here we show that this is caused by oxygen redox, even though Mg$^{2+}$ resides in the TM layers rather than alkali-metal (AM) ions, which demonstrates that excess AM ions are not required to activate oxygen redox. We also show that, unlike the alkali-rich compounds, Na$_{2/3}$[Mg$_{0.28}$Mn$_{0.72}$]O$_2$ does not lose oxygen. The extraction of alkali ions from the alkali and TM layers in the alkali-rich compounds results in severely underbonded oxygen, which promotes oxygen loss, whereas Mg$^{2+}$ remains in Na$_{2/3}$[Mg$_{0.28}$Mn$_{0.72}$]O$_2$, which stabilizes oxygen

Functional diversity and co-operativity between subclonal populations of paediatric glioblastoma and diffuse intrinsic pontine glioma cells

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments