Cartan subalgebras in C*-algebras of Hausdorff etale groupoids

The reduced $C^*$-algebra of the interior of the isotropy in any Hausdorff \'etale groupoid $G$ embeds as a $C^*$-subalgebra $M$ of the reduced $C^*$-algebra of $G$. We prove that the set of pure states of $M$ with unique extension is dense, and deduce that any representation of the reduced $C^*$-algebra of $G$ that is injective on $M$ is faithful. We prove that there is a conditional expectation from the reduced $C^*$-algebra of $G$ onto $M$ if and only if the interior of the isotropy in $G$ is closed. Using this, we prove that when the interior of the isotropy is abelian and closed, $M$ is a Cartan subalgebra. We prove that for a large class of groupoids $G$ with abelian isotropy---including all Deaconu--Renault groupoids associated to discrete abelian groups---$M$ is a maximal abelian subalgebra. In the specific case of $k$-graph groupoids, we deduce that $M$ is always maximal abelian, but show by example that it is not always Cartan.Comment: 14 pages. v2: Theorem 3.1 in v1 incorrect (thanks to A. Kumjain for pointing out the error); v2 shows there is a conditional expectation onto $M$ iff the interior of the isotropy is closed. v3: Material (including some theorem statements) rearranged and shortened. Lemma~3.5 of v2 removed. This version published in Integral Equations and Operator Theor

Dynamic changes in gene expression in vivo predict prognosis of tamoxifen-treated patients with breast cancer

Introduction: Tamoxifen is the most widely prescribed anti-estrogen treatment for patients with estrogen receptor (ER)-positive breast cancer. However, there is still a need for biomarkers that reliably predict endocrine sensitivity in breast cancers and these may well be expressed in a dynamic manner. Methods: In this study we assessed gene expression changes at multiple time points (days 1, 2, 4, 7, 14) after tamoxifen treatment in the ER-positive ZR-75-1 xenograft model that displays significant changes in apoptosis, proliferation and angiogenesis within 2 days of therapy. Results: Hierarchical clustering identified six time-related gene expression patterns, which separated into three groups: two with early/transient responses, two with continuous/late responses and two with variable response patterns. The early/transient response represented reductions in many genes that are involved in cell cycle and proliferation (e.g. BUB1B, CCNA2, CDKN3, MKI67, UBE2C), whereas the continuous/late changed genes represented the more classical estrogen response genes (e.g. TFF1, TFF3, IGFBP5). Genes and the proteins they encode were confirmed to have similar temporal patterns of expression in vitro and in vivo and correlated with reduction in tumour volume in primary breast cancer. The profiles of genes that were most differentially expressed on days 2, 4 and 7 following treatment were able to predict prognosis, whereas those most changed on days 1 and 14 were not, in four tamoxifen treated datasets representing a total of 404 patients. Conclusions: Both early/transient/proliferation response genes and continuous/late/estrogen-response genes are able to predict prognosis of primary breast tumours in a dynamic manner. Temporal expression of therapy-response genes is clearly an important factor in characterising the response to endocrine therapy in breast tumours which has significant implications for the timing of biopsies in neoadjuvant biomarker studies.Publisher PDFPeer reviewe

Super-heavy fermion material as metallic refrigerant for adiabatic demagnetization cooling

Low-temperature refrigeration is of crucial importance in fundamental research of condensed matter physics, as the investigations of fascinating quantum phenomena, such as superconductivity, superfluidity and quantum criticality, often require refrigeration down to very low temperatures. Currently, cryogenic refrigerators with $^3$He gas are widely used for cooling below 1 Kelvin. However, usage of the gas is being increasingly difficult due to the current world-wide shortage. Therefore, it is important to consider alternative methods of refrigeration. Here, we show that a new type of refrigerant, super-heavy electron metal, YbCo$_2$Zn$_{20}$, can be used for adiabatic demagnetization refrigeration, which does not require 3He gas. A number of advantages includes much better metallic thermal conductivity compared to the conventional insulating refrigerants. We also demonstrate that the cooling performance is optimized in Yb$_{1-x}$Sc$_x$Co$_2$Zn$_{20}$ by partial Sc substitution with $x\sim$0.19. The substitution induces chemical pressure which drives the materials close to a zero-field quantum critical point. This leads to an additional enhancement of the magnetocaloric effect in low fields and low temperatures enabling final temperatures well below 100 mK. Such performance has up to now been restricted to insulators. Since nearly a century the same principle of using local magnetic moments has been applied for adiabatic demagnetization cooling. This study opens new possibilities of using itinerant magnetic moments for the cryogen-free refrigeration

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loc

Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicin

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead