The molecular basis of frontotemporal dementia

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. Familial FTD has been linked to mutations in several genes, including those encoding the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B). The associated neuropathology is characterised by selective degeneration of the frontal and temporal lobes (frontotemporal lobar degeneration, FTLD), usually with the presence of abnormal intracellular protein accumulations. The current classification of FTLD neuropathology is based on the identity of the predominant protein abnormality, in the belief that this most closely reflects the underlying pathogenic process. Major subgroups include those characterised by the pathological tau, TDP-43, intermediate filaments and a group with cellular inclusions composed of an unidentified ubiquitinated protein. This review will focus on the current understanding of the molecular basis of each of the major FTLD subtypes. It is anticipated that this knowledge will provide the basis of future advances in the diagnosis and treatment of FT

Negotiating the Slope: Prefabricated Hillside Dwellings Meet Nordic Influence

In Wellington we are faced with the difficult task of building on our undulating topography. It does however offer inhabitants stunning vistas and to architects the rare opportunity to explore new ways of building, generating distinctive typologies. However, it is questionable whether a bespoke construction method is the most appropriate means for building houses on hillsides in present times. Prefabrication has been a prevalent housing construction method in Scandinavia and for many years and offers a number of advantages, particularly to difficult sites (Smith 255). It is emerging as an option for housing in New Zealand but faces significant problems when confronted with sloped topography (Rouillard 137). The prefabrication movement has become synonymous with the stylistic outcome of modernist detached dwellings, and while this marriage may be an outgrowth of intention rather than a technical requirement, challenging the rectilinear is relatively unheard of (Smith 251). The stylistic concerns embedded by fanciers of 50’s modernism are inherent to the representation of manufactured housing (Smith 251). For prefabrication to become popular in present day society misconceptions regarding stylistic limitations must be resolved. Residential architecture has the potential to shape our architectural identity more significantly than civic buildings. I propose this because we form a closer relationship to ‘home,’ and as a typology they cover a significant proportion of our landscape. To understand how to form an architectural response in the context of Wellington, I looked to contemporary Norwegian architecture which demonstrates contextualising architecture to the landscape. The stylistic character of Norwegian design, and parallels which made their principles applicable to New Zealand, were additional incentives for this focus. This thesis is broken into four parts; background research, design explorations, design discussions and conclusion. In background research, I establish parameters for constructing houses on hill sites. Technical limitations are presented and a range of hillside typologies are identified. Prefabricated systems internationally offered are documented accompanied by the technologies available specifically in New Zealand. The design exploration section illustrates two designs which explore how a hillside typology can be augmented with a prefabricated system. Each is assessed in relation to response to topography and adaptation of Norwegian ideologies. The design discussion revolves around a hillside development of five residential structures and their interconnectivity. Leading into the discussion is a detailed analysis of the prefabrication system implemented, and the modifications to that system which were tested through design. Here, the construction sequence is mapped. This is followed by an architectural discussion on site, access, planning and materials. The conclusions drawn in the final section tie together all these elements

The expression profiles of ADME genes in human cancers and their associations with clinical outcomes

ADME genes are a group of genes that are involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes within tumours is proposed to impact on cancer patient survival; however, this has not been systematically examined. In this study, our comprehensive analyses of pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed di erential intratumoral expression profiles for ADME genes in 21 di erent cancer types. Most genes also showed high interindividual variability within cancer-specific patient cohorts. Using Kaplan-Meier plots and logrank tests, we showed that intratumoral expression levels of twenty of the thirty-two core ADME genes were associated with overall survival (OS) in these cancers. Of these genes, five showed significant association with unfavourable OS in three cancers, including SKCM (ABCC2, GSTP1), KIRC (CYP2D6, CYP2E1), PAAD (UGT2B7); sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (UGT2B15), BRCA (CYP2D6), COAD (NAT1), HNSC (ABCB1), KIRC (ABCG2, CYP3A4, SLC22A2, SLC22A6), KIRP (SLC22A2), LIHC (CYP2C19, CYP2C8, CYP2C9, CYP3A5, SLC22A1),LUAD(SLC15A2), LUSC (UGT1A1), PAAD (ABCB1), SARC (ABCB1), and SKCM (ABCB1, DYPD). Overall, these data provide compelling evidence supporting ADME genes as prognostic biomarkers and potential therapeutic targets. We propose that intratumoral expression of ADME genes may impact cancer patient survival by multiple mechanisms that can include metabolizing/transporting anticancer drugs, activating anticancer drugs, and metabolizing/transporting a variety of endogenous molecules involved in metabolically fuelling cancer cells and/or controlling pro-growth signalling pathways.Dong Gui Hu, Peter I. Mackenzie, Pramod C. Nair, Ross A. McKinnon and Robyn Meec

Detailed study of the ac susceptibility of Sr2RuO4 in oriented magnetic fields

We have investigated the ac susceptibility of the spin triplet superconductor Sr$_2$RuO$_4$ as a function of magnetic field in various directions at temperatures down to 60 mK. We have focused on the in-plane field configuration (polar angle $\theta \simeq 90^{\circ}$), which is a prerequisite for inducing multiple superconducting phases in Sr$_2$RuO$_4$. We have found that the previous attribution of a pronounced feature in the ac susceptibility to the second superconducting transition itself is not in accord with recent measurements of the thermal conductivity or of the specific heat. We propose that the pronounced feature is a consequence of additional involvement of vortex pinning originating from the second superconducting transition.Comment: Accepted for publication in Phys. Rev.

Topological metamagnetism : thermodynamics and dynamics of the transition in spin ice under uniaxial compression

This work was carried out within the framework of a Max-Planck independent research group on strongly correlated systems. We acknowledge financial support from the Deutsche Forschungsgemeinschaft through SFB 1143 (Project No. 247310070) and Cluster of Excellence ct.qmat (EXC 2147, Project No. 390858490), EPSRC (EP/T028637/1), ShanghaiTech University, Agencia Nacional de Promoción Científica y Tecnológica through PICT 2017-2347, and Consejo Nacional de Investigaciones Científicas y Técnicas through PIP 0446.Metamagnetic transitions are analogs of a pressure-driven gas-liquid transition in water. In insulators, they are marked by a superlinear increase in the magnetization that occurs at a field strength set by the spin exchange interactions. Here we study topological metamagnets, in which the magnetization is itself a topological quantity and for which we find a single transition line for two materials with substantially different magnetic interactions: the spin ices Dy2Ti2O7 and Ho2Ti2O7. We study single crystals under magnetic field and stress applied along the [001] direction and show that this transition, of the Kasteleyn type, has a magnetization versus field curve with upward convexity and a distinctive asymmetric peak in the susceptibility. We also show that the dynamical response of Ho2Ti2O7 is sensitive to changes in the Ho3+ environment induced by compression along [001]. Uniaxial compression may open up experimental access to equilibrium properties of spin ice at lower temperatures.Publisher PDFPeer reviewe

Angular dependence of novel magnetic quantum oscillations in a quasi-two-dimensional multiband Fermi liquid with impurities

The semiclassical Lifshitz-Kosevich-type description is given for the angular dependence of quantum oscillations with combination frequencies in a multiband quasi-two-dimensional Fermi liquid with a constant number of electrons. The analytical expressions are found for the Dingle, thermal, spin, and amplitude (Yamaji) reduction factors of the novel combination harmonics, where the latter two strongly oscillate with the direction of the field. At the "magic" angles those factors reduce to the purely two-dimensional expressions given earlier. The combination harmonics are suppressed in the presence of the non-quantized ("background") states, and they decay exponentially faster with temperature and/or disorder compared to the standard harmonics, providing an additional tool for electronic structure determination. The theory is applied to Sr$_2$RuO$_4$.Comment: 5 pages, 2 figures, minor typos correcte

From Atiyah Classes to Homotopy Leibniz Algebras

A celebrated theorem of Kapranov states that the Atiyah class of the tangent bundle of a complex manifold $X$ makes $T_X[-1]$ into a Lie algebra object in $D^+(X)$, the bounded below derived category of coherent sheaves on $X$. Furthermore Kapranov proved that, for a K\"ahler manifold $X$, the Dolbeault resolution $\Omega^{\bullet-1}(T_X^{1,0})$ of $T_X[-1]$ is an $L_\infty$ algebra. In this paper, we prove that Kapranov's theorem holds in much wider generality for vector bundles over Lie pairs. Given a Lie pair $(L,A)$, i.e. a Lie algebroid $L$ together with a Lie subalgebroid $A$, we define the Atiyah class $\alpha_E$ of an $A$-module $E$ (relative to $L$) as the obstruction to the existence of an $A$-compatible $L$-connection on $E$. We prove that the Atiyah classes $\alpha_{L/A}$ and $\alpha_E$ respectively make $L/A[-1]$ and $E[-1]$ into a Lie algebra and a Lie algebra module in the bounded below derived category $D^+(\mathcal{A})$, where $\mathcal{A}$ is the abelian category of left $\mathcal{U}(A)$-modules and $\mathcal{U}(A)$ is the universal enveloping algebra of $A$. Moreover, we produce a homotopy Leibniz algebra and a homotopy Leibniz module stemming from the Atiyah classes of $L/A$ and $E$, and inducing the aforesaid Lie structures in $D^+(\mathcal{A})$.Comment: 36 page

De Haas-van Alphen oscillations in the charge-density wave compound lanthanum tritelluride (LaTe_3)

De Haas-van Alphen oscillations were measured in lanthanum tritelluride (LaTe_3) to probe the partially gapped Fermi surface resulting from charge density wave (CDW) formation. Three distinct frequencies were observed, one of which can be correlated with a FS sheet that is unaltered by CDW formation. The other two frequencies arise from FS sheets that have been reconstructed in the CDW state.Comment: 8 page

Mathematical practice, crowdsourcing, and social machines

The highest level of mathematics has traditionally been seen as a solitary endeavour, to produce a proof for review and acceptance by research peers. Mathematics is now at a remarkable inflexion point, with new technology radically extending the power and limits of individuals. Crowdsourcing pulls together diverse experts to solve problems; symbolic computation tackles huge routine calculations; and computers check proofs too long and complicated for humans to comprehend. Mathematical practice is an emerging interdisciplinary field which draws on philosophy and social science to understand how mathematics is produced. Online mathematical activity provides a novel and rich source of data for empirical investigation of mathematical practice - for example the community question answering system {\it mathoverflow} contains around 40,000 mathematical conversations, and {\it polymath} collaborations provide transcripts of the process of discovering proofs. Our preliminary investigations have demonstrated the importance of "soft" aspects such as analogy and creativity, alongside deduction and proof, in the production of mathematics, and have given us new ways to think about the roles of people and machines in creating new mathematical knowledge. We discuss further investigation of these resources and what it might reveal. Crowdsourced mathematical activity is an example of a "social machine", a new paradigm, identified by Berners-Lee, for viewing a combination of people and computers as a single problem-solving entity, and the subject of major international research endeavours. We outline a future research agenda for mathematics social machines, a combination of people, computers, and mathematical archives to create and apply mathematics, with the potential to change the way people do mathematics, and to transform the reach, pace, and impact of mathematics research.Comment: To appear, Springer LNCS, Proceedings of Conferences on Intelligent Computer Mathematics, CICM 2013, July 2013 Bath, U