The nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of genes that control cell proliferation and apoptosis, as well as genes that respond to inflammation and immune ...responses. There are two means of NF-κB activation: the classical pathway, which involves the degradation of the inhibitor of κBα (IκBα), and the alternative pathway, which involves the NF-κB-inducing kinase (NIK, also known as MAP3K14). The mouse growth plate consists of the resting zone, proliferative zone, prehypertrophic zone, and hypertrophic zone. The p65 (RelA), which plays a central role in the classical pathway, is expressed throughout the cartilage layer, from the resting zone to the hypertrophic zone. Inhibiting the classical NF-κB signaling pathway blocks growth hormone (GH) or insulin-like growth factor (IGF-1) signaling, suppresses cell proliferation, and suppresses bone morphogenetic protein 2 (BMP2) expression, thereby promoting apoptosis. Since the production of autoantibodies and inflammatory cytokines, such as tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, and IL-17, are regulated by the classical pathways and are increased in rheumatoid arthritis (RA), NF-κB inhibitors are used to suppress inflammation and joint destruction in RA models. In osteoarthritis (OA) models, the strength of NF-κB-activation is found to regulate the facilitation or suppression of OA. On the other hand, RelB is involved in the alternative pathway, and is expressed in the periarticular zone during the embryonic period of development. The alternative pathway is involved in the generation of chondrocytes in the proliferative zone during physiological conditions, and in the development of RA and OA during pathological conditions. Thus, NF-κB is an important molecule that controls normal development and the pathological destruction of cartilage.
Many genetic variants that influence phenotypes of interest are located outside of protein-coding genes, yet existing methods for identifying such variants have poor predictive power. Here we ...introduce a new computational method, called LINSIGHT, that substantially improves the prediction of noncoding nucleotide sites at which mutations are likely to have deleterious fitness consequences, and which, therefore, are likely to be phenotypically important. LINSIGHT combines a generalized linear model for functional genomic data with a probabilistic model of molecular evolution. The method is fast and highly scalable, enabling it to exploit the 'big data' available in modern genomics. We show that LINSIGHT outperforms the best available methods in identifying human noncoding variants associated with inherited diseases. In addition, we apply LINSIGHT to an atlas of human enhancers and show that the fitness consequences at enhancers depend on cell type, tissue specificity, and constraints at associated promoters.
Transition‐metal‐catalyzed C‐alkylation of ketones and secondary alcohols, with alcohols, avoids use of organometallic or environmentally unfriendly alkylating agents by means of borrowing hydrogen ...(BH) or hydrogen autotransfer (HA) activation of the alcohol substrates. Water is formed as the only by‐product, thus making the BH process atom‐economical and environmentally benign. Diverse homogeneous and heterogeneous transition‐metal catalysts, ketones, and alcohols can be used for this transformation, thus rendering the BH process promising for replacing those procedures that use traditional alkylating agents. This Minireview summarizes the advances during the last five years in transition‐metal‐catalyzed BH α‐alkylation of ketones, and β‐alkylation of secondary alcohols with alcohols. A discussion on the application of the BH strategy for C−C bond formation is included.
Something borrowed: The major advances during the past five years in transition‐metal‐catalyzed borrowing‐hydrogen (BH) alkylation of ketones, secondary alcohols, and related compounds with alcohols are summarized. Water is formed as the only by‐product, thus making the BH process atom‐economical and environmentally benign.
Abstract
Poly(vinylidene fluoride) (PVDF)‐based polymers demonstrate great potential for applications in flexible and wearable electronics but show low piezoelectric coefficients (e.g., −
d
33
< 30 ...pC N
−1
). The effective improvement for the piezoelectricity of PVDF is achieved by manipulating its semicrystalline structures. However, there is still a debate about which component is the primary contributor to piezoelectricity. Therefore, current methods to improve the piezoelectricity of PVDF can be classified into modulations of the amorphous phase, the crystalline region, and the crystalline–amorphous interface. Here, the basic principles and measurements of piezoelectric coefficients for soft polymers are first discussed. Then, three different categories of structural modulations are reviewed. In each category, the physical understanding and strategies to improve the piezoelectric performance of PVDF are discussed. In particular, the crucial role of the oriented amorphous fraction at the crystalline–amorphous interface in determining the piezoelectricity of PVDF is emphasized. At last, the future development of high performance piezoelectric polymers is outlooked.
In natural and social science, many events happened at different space-times may be closely correlated. Two events, A (Alice) and B (Bob) are defined correlated if one event is determined by another, ...say, Formula: see text for suitable Formula: see text operators. Taking KdV and coupled KdV systems as examples, we can find some types of models (AB-KdV systems) to exhibit the existence on the correlated solutions linked with two events. The idea of this report is valid not only for physical problems related to KdV systems but also for problems described by arbitrary continuous or discrete models. The parity and time reversal symmetries are extended to shifted parity and delayed time reversal. The new symmetries are found to be useful not only to establish AB-systems but also to find group invariant solutions of numerous AB-systems. A new elegant form of the N-soliton solutions of the KdV equation and then the AB-KdV systems is obtained. A concrete AB-KdV system derived from the nonlinear inviscid dissipative and barotropic vorticity equation in a β-plane channel is applied to the two correlated monople blocking events which is responsible for the snow disaster in the winter of 2007/2008 happened in Southern China.
A challenge in medical genomics is to identify variants and genes associated with severe genetic disorders. Based on the premise that severe, early-onset disorders often result in a reduction of ...evolutionary fitness, several statistical methods have been developed to predict pathogenic variants or constrained genes based on the signatures of negative selection in human populations. However, we currently lack a statistical framework to jointly predict deleterious variants and constrained genes from both variant-level features and gene-level selective constraints. Here we present such a unified approach, UNEECON, based on deep learning and population genetics. UNEECON treats the contributions of variant-level features and gene-level constraints as a variant-level fixed effect and a gene-level random effect, respectively. The sum of the fixed and random effects is then combined with an evolutionary model to infer the strength of negative selection at both variant and gene levels. Compared with previously published methods, UNEECON shows improved performance in predicting missense variants and protein-coding genes associated with autosomal dominant disorders, and feature importance analysis suggests that both gene-level selective constraints and variant-level predictors are important for accurate variant prioritization. Furthermore, based on UNEECON, we observe a low correlation between gene-level intolerance to missense mutations and that to loss-of-function mutations, which can be partially explained by the prevalence of disordered protein regions that are highly tolerant to missense mutations. Finally, we show that genes intolerant to both missense and loss-of-function mutations play key roles in the central nervous system and the autism spectrum disorders. Overall, UNEECON is a promising framework for both variant and gene prioritization.
Sr3Sn2O7 is the first room‐temperature ferroelectric Sn insulator with switchable electric polarization. The ferroelastic twin domains are observed using a polarized optical microscope. The ...polarization hysteresis loop clearly demonstrates the ferroelectric property. Intriguing polarization switching kinetics are observed through an in situ poling process using a dark‐field transmission electron microscopy technique.
On the basis of successful first-principles predictions of new functional ferroelectric materials, a number of new ferroelectrics have been experimentally discovered. Using trilinear coupling of two ...types of octahedron rotation, hybrid improper ferroelectricity has been theoretically predicted in ordered perovskites and the Ruddlesden-Popper compounds (Ca3Ti2O7, Ca3Mn2O7 and (Ca/Sr/Ba)3(Sn/Zr/Ge)2O7). However, the ferroelectricity of these compounds has never been experimentally confirmed and even their polar nature has been under debate. Here we provide the first experimental demonstration of room-temperature switchable polarization in bulk crystals of Ca3Ti2O7, as well as Sr-doped Ca3Ti2O7. Furthermore, (Ca, Sr)3Ti2O7 is found to exhibit an intriguing ferroelectric domain structure resulting from orthorhombic twins and (switchable) planar polarization. The planar domain structure accompanies abundant charged domain walls with conducting head-to-head and insulating tail-to-tail configurations, which exhibit a conduction difference of two orders of magnitude. These discoveries provide new research opportunities, not only for new stable ferroelectrics of Ruddlesden-Popper compounds, but also for meandering conducting domain walls formed by planar polarization.
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