With the introduction of next‐generation sequencing, the genetic landscape of the complex group of B‐cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided ...important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that ‘hit’ central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B‐cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We will detail recurrent alterations affecting important signalling pathways, that is the B‐cell receptor/NF‐κB pathway, NOTCH signalling, JAK‐STAT signalling, p53/DNA damage response, apoptosis and cell cycle regulation, as well as other perhaps unexpected cellular processes, such as immune regulation, cell migration, epigenetic regulation and RNA processing. Whilst many of these pathways/processes are commonly altered in different lymphoid tumors, albeit at varying frequencies, others are preferentially targeted in selected B‐cell malignancies. Some of these genetic lesions are either involved in disease ontogeny or linked to the evolution of each disease and/or specific clinicobiological features, and some of them have been demonstrated to have prognostic and even predictive impact. Future work is especially needed to understand the therapy‐resistant disease, particularly in patients treated with targeted therapy, and to identify novel targets and therapeutic strategies in order to realize true precision medicine in this clinically heterogeneous patient group.
Content List ‐ Read more articles from the symposium: Targeted therapy in B‐cell malignancies.
Multiferroics, where (anti-) ferromagnetic, ferroelectric and ferroelastic order parameters coexist, enable manipulation of magnetic ordering by an electric field through switching of the electric ...polarization. It has been shown that realization of magnetoelectric coupling in a single-phase multiferroic such as BiFeO3 requires ferroelastic (71 , 109 ) rather than ferroelectric (180 ) domain switching. However, the control of such ferroelastic switching in a single-phase system has been a significant challenge as elastic interactions tend to destabilize small switched volumes, resulting in subsequent ferroelastic back-switching at zero electric field, and thus the disappearance of non-volatile information storage. Guided by our phase-field simulations, here we report an approach to stabilize ferroelastic switching by eliminating the stress-induced instability responsible for back-switching using isolated monodomain BiFeO3 islands. This work demonstrates a critical step to control and use non-volatile magnetoelectric coupling at the nanoscale. Beyond magnetoelectric coupling, it provides a framework for exploring a route to control multiple order parameters coupled to ferroelastic order in other low-symmetry materials.
Genetic screens are powerful tools for identifying genes responsible for diverse phenotypes. Here we describe a genome-wide CRISPR/Cas9-mediated loss-of-function screen in tumor growth and ...metastasis. We mutagenized a non-metastatic mouse cancer cell line using a genome-scale library with 67,405 single-guide RNAs (sgRNAs). The mutant cell pool rapidly generates metastases when transplanted into immunocompromised mice. Enriched sgRNAs in lung metastases and late-stage primary tumors were found to target a small set of genes, suggesting that specific loss-of-function mutations drive tumor growth and metastasis. Individual sgRNAs and a small pool of 624 sgRNAs targeting the top-scoring genes from the primary screen dramatically accelerate metastasis. In all of these experiments, the effect of mutations on primary tumor growth positively correlates with the development of metastases. Our study demonstrates Cas9-based screening as a robust method to systematically assay gene phenotypes in cancer evolution in vivo.
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•Genome-wide in vivo CRISPR-Cas9 screen in mice reveals genes regulating lung metastasis•Screen identifies loss-of-function mutations in known tumor suppressors and novel genes•Candidate metastasis genes are validated using a pooled competition assay•Effect of mutations on primary tumor growth positively correlates with metastasis
Using an in vivo genome-wide CRISPR/Cas9 screen, loss-of-function mutations that drive tumor growth and metastasis to the lung have been identified, demonstrating Cas9-based screening as a robust method to systematically assay gene phenotypes in cancer evolution.
Bovine mycoplasmosis is an important infectious disease of cattle caused by
(
) which poses a serious threat to the breeding industry. Adhesin is involved in the initial process of
colonization, ...which is closely related to the infection, cell invasion, immune escape and virulence of this pathogenic microorganism. For the reason that
lacks a cell wall, its adhesin is predominantly located on the surface of the cell membrane. The adhesins of
are usually identified by adhesion and adhesion inhibition analysis, and more than 10 adhesins have been identified so far. These adhesins primarily bind to plasminogen, fibronectin, heparin and amyloid precursor-like protein-2 of host cells. This review aims to concisely summarize the current knowledge regarding the adhesins of
and their target proteins of the host cell. Additionally, the biological characteristics of the adhesin will be briefly analyzed.
By means of a direct-current electrodeposition technique, bulk (3mm in thickness) polycrystalline Cu samples with preferentially oriented nanoscale twins have been synthesized. Strain-controlled ...pull-push fatigue tests of the nanotwinned Cu samples show that the cyclic stability is maintained after a short initially rapid cyclic hardening stage, distinct from continuous cyclic softening of ultrafine-grained Cu. The saturation stress increases with increasing strain amplitude and decreasing twin thickness, while the longer low cycle fatigue life is achieved at larger grain size. The strain-life and S-N curves reveal that the preferentially oriented nanotwins embedded in microsized grains enhance the low and high cycle fatigue property synergy for nanotwinned Cu, which has better low cycle fatigue life while maintaining higher endurance limit (90MPa at 107), compared with that of coarse-grained Cu and ultrafine-grained Cu. Besides the relatively stable microstructure, the activation of a single primary slip system, i.e. threading dislocation propagation inside nanoscale twin lamellar channels, dominates the steady state of nanotwinned samples.
Alcoholic hepatitis (AH) continues to be a disease with high mortality and no efficacious medical treatment. Although severe AH is presented as acute on chronic liver failure, what underlies this ...transition from chronic alcoholic steatohepatitis (ASH) to AH is largely unknown. To address this question, unbiased RNA sequencing and proteomic analyses were performed on livers of the recently developed AH mouse model, which exhibits the shift to AH from chronic ASH upon weekly alcohol binge, and these results are compared to gene expression profiling data from AH patients. This cross‐analysis has identified Casp11 (CASP4 in humans) as a commonly up‐regulated gene known to be involved in the noncanonical inflammasome pathway. Immunoblotting confirms CASP11/4 activation in AH mice and patients, but not in chronic ASH mice and healthy human livers. Gasdermin‐D (GSDMD), which induces pyroptosis (lytic cell death caused by bacterial infection) downstream of CASP11/4 activation, is also activated in AH livers in mice and patients. CASP11 deficiency reduces GSDMD activation, bacterial load in the liver, and severity of AH in the mouse model. Conversely, the deficiency of interleukin‐18, the key antimicrobial cytokine, aggravates hepatic bacterial load, GSDMD activation, and AH. Furthermore, hepatocyte‐specific expression of constitutively active GSDMD worsens hepatocellular lytic death and polymorphonuclear leukocyte inflammation. Conclusion: These results implicate pyroptosis induced by the CASP11/4‐GSDMD pathway in the pathogenesis of AH. (Hepatology 2018;67:1737‐1753).
•An adaptive Relevant Vector Machine is proposed for reliability assessments.•A new active learning function for RVM is proposed.•An efficient stopping criterion is adopted to terminate the active ...learning process.•The proposed method is applied to five illustrative examples, showing high accuracy and efficiency.
In this study, an adaptive relevant vector machine, which is developed within a probabilistic Bayesian learning framework, is combined with Monte Carlo simulation (MCS) to perform reliability analysis with high efficiency and accuracy. A new active learning function is proposed that comprehensively considers the probability of mis-predictions and spatial locations of the existing sampling points to search for the best next point to enrich the training samples. To avoid redundant original model evaluations, an efficient stopping criterion is adopted to terminate the active learning process in a timely manner. The proposed method is tested with five examples involving non-differentiability, high non-linearity, and practical engineering problems. The proposed method can obtain highly accurate failure probability predictions with a small number of evaluations of the original model in comparison with the direct MCS and other methods in the literature. In conclusion, the proposed method is recommended for structural reliability analyses in engineering practice.
Sleep spindles are characteristic electroencephalogram (EEG) signatures of stage 2 non-rapid eye movement sleep. Implicated in sleep regulation and cognitive functioning, spindles may represent ...heritable biomarkers of neuropsychiatric disease. Here we characterize spindles in 11,630 individuals aged 4 to 97 years, as a prelude to future genetic studies. Spindle properties are highly reliable but exhibit distinct developmental trajectories. Across the night, we observe complex patterns of age- and frequency-dependent dynamics, including signatures of circadian modulation. We identify previously unappreciated correlates of spindle activity, including confounding by body mass index mediated by cardiac interference in the EEG. After taking account of these confounds, genetic factors significantly contribute to spindle and spectral sleep traits. Finally, we consider topographical differences and critical measurement issues. Taken together, our findings will lead to an increased understanding of the genetic architecture of sleep spindles and their relation to behavioural and health outcomes, including neuropsychiatric disorders.
Psychiatric disorders have clear heritable risk. Several large-scale genome-wide association studies have revealed a strong association between susceptibility for psychiatric disorders, including ...bipolar disease, schizophrenia and major depression, and a haplotype located in an intronic region of the L-type voltage-gated calcium channel (VGCC) subunit gene CACNA1C (peak associated SNP rs1006737), making it one of the most replicable and consistent associations in psychiatric genetics. In the current study, we used induced human neurons to reveal a functional phenotype associated with this psychiatric risk variant. We generated induced human neurons, or iN cells, from more than 20 individuals harboring homozygous risk genotypes, heterozygous or homozygous non-risk genotypes at the rs1006737 locus. Using these iNs, we performed electrophysiology and quantitative PCR experiments that demonstrated increased L-type VGCC current density as well as increased mRNA expression of CACNA1C in iNs homozygous for the risk genotype, compared with non-risk genotypes. These studies demonstrate that the risk genotype at rs1006737 is associated with significant functional alterations in human iNs, and may direct future efforts at developing novel therapeutics for the treatment of psychiatric disease.
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