Mutations driving CLL and their evolution in progression and relapse.

Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.

The influence of the casting process on the internal structure and physical properties of hemp-lime.

Bio-aggregate composites such as hemp-lime offer a more sustainable alternative to traditional walling infill material. Hemp-lime, whether in situ or prefabricated, is generally either cast or sprayed, which results in a directionally dependent, typically layered, physical structure. This paper considers the impact of compaction and layering on the directional thermal conductivity, compressive strength and internal structure of the material through use of a novel image analysis method. The results presented indicate that production variables have a significant, and crucially, directionally dependent impact on the thermal and mechanical properties of cast hemp-lime.

Somatic mutation as a mechanism of Wnt/ß-catenin pathway activation in CLL.

One major goal of cancer genome sequencing is to identify key genes and pathways that drive tumor pathogenesis. Although many studies have identified candidate driver genes based on recurrence of mutations in individual genes, subsets of genes with nonrecurrent mutations may also be defined as putative drivers if they affect a single biological pathway. In this fashion, we previously identified Wnt signaling as significantly mutated through large-scale massively parallel DNA sequencing of chronic lymphocytic leukemia (CLL). Here, we use a novel method of biomolecule delivery, vertical silicon nanowires, to efficiently introduce small interfering RNAs into CLL cells, and interrogate the effects of 8 of 15 mutated Wnt pathway members identified across 91 CLLs. In HEK293T cells, mutations in 2 genes did not generate functional changes, 3 led to dysregulated pathway activation, and 3 led to further activation or loss of repression of pathway activation. Silencing 4 of 8 mutated genes in CLL samples harboring the mutated alleles resulted in reduced viability compared with leukemia samples with wild-type alleles. We demonstrate that somatic mutations in CLL can generate dependence on this pathway for survival. These findings support the notion that nonrecurrent mutations at different nodes of the Wnt pathway can contribute to leukemogenesis.

Research on Prediction Model for Durability of Straw Bale Walls in Warm (Humid) Continental Climate-A Case Study in Northeast China.

This research analyses straw degradation inside straw bale walls in the region and develops the prediction of degradation inside straw bale walls. The results show that the straw inside straw bale walls have no serious concerns of degradation in the high hygrothermal environment in the region with only moderate concerns of degradation in the area 2-3 cm deep behind the lime render. The onsite investigations indicate that the degradation isopleth model can only predict straw conditions behind the rendering layer, whereas the isothermal model fits the complete situation inside straw bale walls. This research develops the models for predicting straw degradation levels inside a straw bale building in a warm (humid) continental climate. The impact of this research will help the growth of low carbon energy efficient straw bale construction with confidence pertaining to its long-term durability characteristics both in the region and regions sharing similar climatic features globally.

Visual search patterns in neglect: comparison of peripersonal and extrapersonal space.

Previous studies of visual search patterns in visuospatial neglect have analyzed shifts of attention during search tasks using eye tracking technology and verbal reports. The purpose of the present study was to replicate and extend upon reported parameters of visual scanning patterns of neglect patients in peripersonal space (within arms reach) and to examine whether similar patterns of visual search are also apparent in extrapersonal space (beyond arms reach). Using a simple verbal visual search and target detection paradigm right-hemisphere stroke participants, with and without neglect, and healthy older volunteers named targets on scanning sheets placed in peripersonal and extrapersonal space. The healthy controls and right-hemisphere stroke group without neglect showed similar 'reading' type strategies, while the neglect group displayed an unsystematic search pattern, during search in both peripersonal and extrapersonal space. Group comparisons of search parameters support the presence of multiple cognitive deficits affecting the complex visual search patterns of neglect patients, including a rightward attentional bias, a reduced spatial scale of attention (local processing bias), and a deficit of working memory affecting both near and far space search. Ventral visual stream damage and neglect, however, were related to slower target report rate and more misidentification errors in extrapersonal space. The ease of administration of this verbal target detection task in both peripersonal and extrapersonal space, and the relationship of the measures produced to theorized attentional and executive deficits in neglect, provide impetus for further research on the severity and independence of individual scanning deficits in neglect.

Modification of hemp shiv properties using water-repellent sol-gel coatings.

For the first time, the hydrophilicity of hemp shiv was modified without the compromise of its hygroscopic properties. This research focused on the use of sol-gel method in preparation of coatings on the natural plant material, hemp shiv, that has growing potential in the construction industry as a thermal insulator. The sol-gel coatings were produced by cohydrolysis and polycondensation of tetraethyl orthosilicate (TEOS) using an acidic catalyst. Methyltriethoxysilane (MTES) was added as the hydrophobic precursor to provide water resistance to the bio-based material. Scanning electron microscopy (SEM) and focused ion beam (FIB) have been used to determine the morphological changes on the surface as well as within the hemp shiv. It was found that the sol-gel coatings caused a reduction in water uptake but did not strongly influence the moisture sorption behaviour of hemp shiv. Fourier transformed infrared (FTIR) spectroscopy shows that the coating layer on hemp shiv acts a shield, thereby lowering peak intensity in the wavelength range 1200-1800 cm-1. The sol-gel coating affected pore size distribution and cumulative pore volume of the shiv resulting in tailored porosity. The overall porosity of shiv decreased with a refinement in diameter of the larger pores. Thermal analysis was performed using TGA and stability of coated and uncoated hemp shiv have been evaluated. Hemp shiv modified with sol-gel coating can potentially develop sustainable heat insulating composites with better hygrothermal properties.

Author Correction: Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

In the version of this article originally published, an asterisk was omitted from Fig. 1a. The asterisk has been added to the figure. Additionally, a "NOTCH2" label was erroneously included in Fig. 4a. The label has been removed. The errors have been corrected in the PDF and HTML versions of this article.

Publisher Correction: Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

In the version of this article originally published, some text above the "Tri-nucleotide sequence motifs" label in Fig. 2a appeared incorrectly. The text was garbled and should have appeared as nucleotide codes.Additionally, the labels on the bars in Fig. 2c were not italicized in the original publication. These are gene symbols, and they should have been italicized.The colored labels above the graphs in Fig. 4b were also erroneously not italicized. These labels represent gene names and loci, and they should have been italicized.

Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.

A simple strategy for mitigating the effect of data variability on the identification of active chemotypes from high-throughput screening data.

Among the several goals of a high-throughput screening campaign is the identification of as many active chemotypes as possible for further evaluation. Often, however, the number of concentration response curves (e.g., IC(50)s or K(i)s) that can be collected following a primary screen is limited by practical constraints such as protein supply, screening workload, and so forth. One possible approach to this dilemma is to cluster the hits from the primary screen and sample only a few compounds from each cluster. This introduces the question as to how many compounds must be selected from a cluster to ensure that an active compound is identified, if it exists at all. This article seeks to address this question using a Monte Carlo simulation in which the dependence of the success of sampling is directly linked to screening data variability. Furthermore, the authors demonstrate that the use of replicated compounds in the screening collection can easily assess this variability and provide a priori guidance to the screener and chemist as to the extent of sampling required to maximize chemotype identification during the triage process. The individual steps of the Monte Carlo simulation provide insight into the correspondence between the percentage inhibition and eventual IC(50) curves.

Eye movements as direct tests of the GO model for the missing-letter effect.

When asked to detect target letters while reading a text, participants miss more letters in frequently occurring function words than in less frequent content words. To account for this pattern of results, known as the missing-letter effect, Greenberg, Healy, Koriat, and Kreiner proposed the guidance-organization (GO) model, which integrates the two leading models of the missing-letter effect while incorporating innovative assumptions based on the literature on eye movements during reading. The GO model was evaluated by monitoring the eye movements of participants while they searched for a target letter in a continuous text display. Results revealed the usual missing-letter effect, and many empirical benchmark effects in eye movement literature were observed. However, contrary to the predictions of the GO model, response latencies were longer for function words than for content words. Alternative models are discussed that can accommodate both error and response latency data for the missing-letter effect.