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MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that impact its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small molecule screening campaign yielded multiple scaffolds, including type-II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.
The development of super-resolution microscopy (SRM) has widened our understanding of biomolecular structure and function in biological materials. Imaging multiple targets within a single area would elucidate their spatial localization relative to the cell matrix and neighboring biomolecules, revealing multi-protein macromolecular structures and their functional co-dependencies. SRM methods are, however, limited to the number of suitable fluorophores that can be imaged during a single acquisition as well as the loss of antigens during antibody washing and restaining for organic dye multiplexing. We report the visualization of multiple protein targets within the pre- and postsynapse in 350-400 nm thick neuronal tissue sections using DNA-assisted single-molecule localization microscopy. Using antibodies labeled with short DNA oligonucleotides, multiple targets are visualized successively by sequential exchange of fluorophore-labeled complementary oligonucleotides present in the imaging buffer. The structural integrity of the tissue is maintained owing to only a single labelling step during sample preparation. Multiple targets are imaged using a single laser wavelength, minimizing chromatic aberration. This method proved robust for multi-target imaging in semi-thin tissue sections, paving the way towards structural cell biology with single-molecule super-resolution microscopy.
Two species of Dolichomitus Smith, 1877 emerged from the trunks of Juglans mandshurica Maxim. in Kuandian and Benxi Manzu Autonomous Counties, Liaoning, in the Palaearctic part of China. One new species, D. juglanse Sheng #38; Li sp. nov., reared from Menesia flavotecta Heyden, 1886 and Mesosa myops (Dalman, 1817) (Cerambycidae), is described and illustrated. A key to the species of Dolichomitus known from China is provided.
Twelve species of the subgenus Vestiplex (Diptera, Tipulidae) were previously known to occur in Tibet (= Xizang), China. Here, six species are described and illustrated as new to science: Tipula (Vestiplex) bucera sp. nov., Tipula (Vestiplex) magatama sp. nov., Tipula (Vestiplex) motuoensis sp. nov., Tipula (Vestiplex) nayogabuensis sp. nov., Tipula (Vestiplex) platyphylla sp. nov. and Tipula (Vestiplex) uncinella sp. nov. The following three species are redescribed: Tipula (Vestiplex) himalayensis Brunetti, 1911, Tipula (Vestiplex) nigroapicalis Brunetti, 1911 and Tipula (Vestiplex) zayulensis Alexander, 1963. A key to the species of Tipula (Vestiplex) from Tibet is presented.
A revision of the wild species in the genus Malus Mill. (Rosaceae) is presented based on numerical analyses and specimens from herbaria around the world, while cultivated species such as Malus domestica (Suckow) Borkh. are not included because of their complicated domestication history. Infra- and interspecific morphological variation and species delimitation are clarified based on Principal Component Analyses (PCA) and Cluster Analyses (UPGMA). We found that several morphological characters traditionally used to distinguish species have limited taxonomic value because of high phenotypic variation or plasticity. There is a substantial conflict between traditional morphological and genetic taxonomic concepts, and as a result species lineages are often morphologically indistinguishable. None of the analyses supports the recognition of infraspecific categories in Malus transitoria (Batalin) C.K.Schneid. and interspecific categories between Malus doumeri (Bois) A.Chev. and Malus leiocalyca S.Z.Huang. Based on our analyses, we recognize 26 wild species in the genus, and propose seven new synonymies.
Background: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.
Methods: In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.
Findings: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07).
Interpretation: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.
Funding: UK Medical Research Council and British Heart Foundation.
Projektionsverhältnisse zwischen Körper, Linien und Zeichen stehen im Zentrum des Beitrags von Li-Chun Lee, der sich den Visualisierungsformen von Pulskurven im europäischen und chinesischen Kontext widmet. Mit Rekurs auf Maurice Merleau-Ponty verfolgt Lee die Frage, wie die leibliche Phänomenalität des Pulses in eine für medizinische Analysen genaue Zeichenform übersetzt werden kann. Lee kann in der Gegenüberstellung von sprachlich-metaphorischen, technischen und grafischen Übersetzungsprozessen eine Situation skizzieren, in welcher unterschiedliche Zeichenregime des Pulses und Genauigkeitsvorstellungen aufeinanderstoßen.
Based on molecular and morphological data of four specimens of Pareas Wagler, 1830 collected from the type locality of P. yunnanensis (Vogt, 1922), along with examination of the type specimens of P. yunnanensis, we revalidate this poorly known, secretive species. Furthermore, based on molecular and morphological lines of evidence we also describe a new species of Pareas from Xishuangbanna Prefecture, Yunnan Province, China. Morphologically, the new species closely resembles its sister species P. nigriceps Guo & Deng, 2009. However, the new species is divergent from the latter in cytochrome b mtDNA gene sequences, and can be distinguished from all congeners by the following combination of morphological characteristics: single preocular, postocular fused with subocular, loreal not bordering orbit, vertebral scales enlarged, 3–5 rows of mid-dorsal scales keeled at the middle of the body, ventral scales 160–171; subcaudals 62–64, dorsal surface of head solid black or reddish-brown, dark nuchal band present, iris brownish-black or reddish-brown.
A new flower fly genus (Diptera, Syrphidae), Biema Huo & Zhao gen. nov. from China is described based on two new species: Biema wanglangensis Huo & Zhao gen. et sp. nov. (designated as type-species) and Biema qilianensis Huo & Liu gen. et sp. nov. The new genus can easily be distinguished by the following morphological features: head, mesonotum and scutellum black; postpronotum without pile; metasternum not reduced, posterior margin shallowly concave; katepisternum only with ventral pile patches; alula narrow, as wide as basal width of cell c; male postabdomen conspicuously more swollen than other segments, surstylus and postgonite complex, phallus unsegmented. The results of our Bayesian inference and Maximum Likelihood analysis based on sequences of the Cytochrome c oxidase subunit I (COI) gene, as well as the species delimitation tests, support the separation of Biema Huo & Zhao gen. nov. from its related taxa. Additionally, an identification key to the genera of the tribes Bacchini and Melanostomini occurring in China is provided.