Duration of untreated bipolar disorder: A multicenter study

Little is known about the demographic and clinical differences between short and long duration of untreated bipolar disorder (DUB) in Chinese patients. This study examined the demographic and clinical features of short (≤2 years) and long DUB (\u3e2 years) in China. A consecutively recruited sample of 555 patients with bipolar disorder (BD) was examined in 7 psychiatric hospitals and general hospital psychiatric units across China. Patients’ demographic and clinical characteristics were collected using a standardized protocol and data collection procedure. The mean DUB was 3.2 ± 6.0 years; long DUB accounted for 31.0% of the sample. Multivariate analyses revealed that longer duration of illness, diagnosis of BD type II, and earlier misdiagnosis of BD for major depressive disorder or schizophrenia were independently associated with long DUB. The mean DUB in Chinese BD patients was shorter than the reported figures from Western countries. The long-term impact of DUB on the outcome of BD is warranted

Screening of DUB activity and specificity by MALDI-TOF mass spectrometry

Deubiquitylases (DUBs) are key regulators of the ubiquitin system which cleave ubiquitin moieties from proteins and polyubiquitin chains. Several DUBs have been implicated in various diseases and are attractive drug targets. We have developed a sensitive and fast assay to quantify in vitro DUB enzyme activity using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Unlike other current assays, this method uses unmodified substrates, such as diubiquitin topoisomers. By analyzing 42 human DUBs against all diubiquitin topoisomers we provide an extensive characterization of DUB activity and specificity. Our results confirm the high specificity of many members of the OTU and JAMM DUB families and highlight that all USPs tested display low linkage selectivity. We also demonstrate that this assay can be deployed to assess the potency and specificity of DUB inhibitors by profiling 11 compounds against a panel of 32 DUBs

Ubiquitin-based probes prepared by total synthesis to profile the activity of deubiquitinating enzymes

Epitope-tagged active-site-directed probes are widely used to visualize the activity of deubiquitinases (DUBs) in cell extracts, to investigate the specificity and potency of small-molecule DUB inhibitors, and to isolate and identify DUBs by mass spectrometry. With DUBs arising as novel potential drug targets, probes are required that can be produced in sufficient amounts and to meet the specific needs of a given experiment. The established method for the generation of DUB probes makes use of labor-intensive intein-based methods that have inherent limitations concerning the incorporation of unnatural amino acids and the amount of material that can be obtained. Here, we describe the total chemical synthesis of active-site-directed probes and their application to activity-based profiling and identification of functional DUBs. This synthetic methodology allowed the easy incorporation of desired tags for specific applications, for example, fluorescent reporters, handles for immunoprecipitation or affinity pull-down, and cleavable linkers. Additionally, the synthetic method can be scaled up to provide significant amounts of probe. Fluorescent ubiquitin probes allowed faster, in-gel detection of active DUBs, as compared to (immuno)blotting procedures. A biotinylated probe holding a photocleavable linker enabled the affinity pull-down and subsequent mild, photorelease of DUBs. Also, DUB activity levels were monitored in response to overexpression or knockdown, and to inhibition by small molecules. Furthermore, fluorescent probes revealed differential DUB activity profiles in a panel of lung and prostate cancer cells

Maps preserving common zeros between subspaces of vector-valued continuous functions

For metric spaces $X$ and $Y$, normed spaces $E$ and $F$, and certain subspaces $A(X,E)$ and $A(Y,F)$ of vector-valued continuous functions, we obtain a complete characterization of linear and bijective maps $T:A(X,E)\to A(Y,F)$ preserving common zeros, that is, maps satisfying the property \setcounter{equation}{15} \label{dub} Z(f)\cap Z(g)\neq \emptyset \Longleftrightarrow Z(Tf)\cap Z(Tg)\neq \emptyset for any $f,g\in A(X,E)$, where $Z(f)=\{x\in X:f(x)=0\}$. Moreover, we provide some examples of subspaces for which the automatic continuity of linear bijections having the property (\ref{dub}) is derived.Comment: 10 page

Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function

BRCC36 is a Zn²⁺-dependent deubiquitinating enzyme (DUB) that hydrolyzes lysine-63-linked ubiquitin chains as part of distinct macromolecular complexes that participate in either interferon signaling or DNA-damage recognition. The MPN⁺ domain protein BRCC36 associates with pseudo DUB MPN⁻ proteins KIAA0157 or Abraxas, which are essential for BRCC36 enzymatic activity. To understand the basis for BRCC36 regulation, we have solved the structure of an active BRCC36-KIAA0157 heterodimer and an inactive BRCC36 homodimer. Structural and functional characterizations show how BRCC36 is switched to an active conformation by contacts with KIAA0157. Higher-order association of BRCC36 and KIAA0157 into a dimer of heterodimers (super dimers) was required for DUB activity and interaction with targeting proteins SHMT2 and RAP80. These data provide an explanation of how an inactive pseudo DUB allosterically activates a cognate DUB partner and implicates super dimerization as a new regulatory mechanism underlying BRCC36 DUB activity, subcellular localization, and biological function

Borderlands: dub techno’s hauntological politics of acoustic ecology

This article explores the aesthetic, social and economic relationships between dub techno and urban space. Sketching out the neoliberal economic transition from the post-war economy to a post-Fordist society, this article lingers on dub/techno trends from four cities: Kingston, London, Detroit and Berlin. An archaeology of dub techno is reconstructed into four parts, each highlighting an affective relation, or “sound map”, between music and neoliberal economic production. Starting with the hauntological melancholia of London-based Burial’s music, this article traces the history and sonic networks of the dub techno diaspora, from Detroit techno’s city of urban decay to Berlin’s divided city. Finally, dub techno is narrated through a “borderland” mapped sonically between Detroit and Berlin, suggesting a futuristic politics of dub techno’s acoustic ecology

Introducción a la poesía Dub : Linton Kwesi Johnson

Linton Kwesi Johnson, poeta jamaiquino, fue el pionero de la poesía dub con su obra Dread Beat and Blood, su primer LP. En su búsqueda estética, la calle adquiere una relevancia primordial pues la poesía dub ha comunicado todo el resentimiento que desemboca en el disturbio. De allí que haya inspirado a las minorías a enfrentarse con las fuerzas del orden en las calles. Emparentada con el reggae, la poesía dub se yergue como estrategia de liberación. Esta investigación explora los orígenes y el desarrollo de esta poesía dentro y fuera de las Antillas, analizando algunos ejemplos concretos.Linton Kwesi Johnson, a Jamaican poet, was the pioneer of Dub poetry with his first long play entitled Dread Beat and Blood. In his quest for a particular style, the street acquires a fundamental relevance since his dub poetry expresses all the resentment that leads to revolts. Therefore, he inspired the social minorities to confront the police force in the streets. Related to reggae, dub poetry becomes a strategy of liberation. This research explores, along with the analysis of some examples, the origins and development of this poetic expression within and beyond the West Indies.Fil: Valero, Arnaldo

The Cost of Bounded Curvature

We study the motion-planning problem for a car-like robot whose turning radius is bounded from below by one and which is allowed to move in the forward direction only (Dubins car). For two robot configurations $\sigma, \sigma'$, let $\ell(\sigma, \sigma')$ be the shortest bounded-curvature path from $\sigma$ to $\sigma'$. For $d \geq 0$, let $\ell(d)$ be the supremum of $\ell(\sigma, \sigma')$, over all pairs $(\sigma, \sigma')$ that are at Euclidean distance $d$. We study the function \dub(d) = \ell(d) - d, which expresses the difference between the bounded-curvature path length and the Euclidean distance of its endpoints. We show that \dub(d) decreases monotonically from \dub(0) = 7\pi/3 to \dub(\ds) = 2\pi, and is constant for d \geq \ds. Here \ds \approx 1.5874. We describe pairs of configurations that exhibit the worst-case of \dub(d) for every distance $d$

Discovery of a potent deubiquitinase (DUB) small molecule activity‐based probe enables broad spectrum DUB activity profiling in living cells

Deubiquitinases (DUBs) are a family of >100 proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates. This leads to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB activity has been implicated in many diseases, including cancer, neurodegeneration and auto-inflammation, and several have been recognized as attractive targets for therapeutic intervention. Ubiquitin-derived covalent activity-based probes (ABPs) provide a powerful tool for DUB activity profiling, but their large recognition element impedes cellular permeability and presents an unmet need for small molecule ABPs which can account for regulation of DUB activity in intact cells or organisms. Here, through comprehensive chemoproteomic warhead profiling, we identify cyanopyrrolidine (CNPy) probe IMP-2373 (12) as a small molecule pan-DUB ABP to monitor DUB activity in physiologically relevant live cells. Through proteomics and targeted assays, we demonstrate that IMP-2373 quantitatively engages more than 35 DUBs across a range of non-toxic concentrations in diverse cell lines. We further demonstrate its application to quantification of changes in intracellular DUB activity during pharmacological inhibition and during MYC deregulation in a model of B cell lymphoma. IMP-2373 thus offers a complementary tool to ubiquitin ABPs to monitor dynamic DUB activity in the context of disease-relevant phenotypes