Novel conductive ultrathin graphene papers demonstrate effective EMI shielding of ∼46.3 dB (∼0.3 mm) and ∼47.7 dB (∼0.1 mm) in attenuators.

Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also, the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype and other fragment hits described herein can stimulate researchers to develop more diversified bromodomain inhibitors.

2D metal‐porphyrin frameworks (MPFs) are attractive for advanced energy storage devices. However, the inferior conductivity and low structural stability of MPFs seriously limit their application as flexible free‐standing electrodes with high performance. Here, for the first time, an interlayer hydrogen‐bonded MXene/MPFs film is proposed to overcome these disadvantages by intercalation of highly conductive MXene nanosheets into MPFs nanosheets via a vacuum‐assisted filtration technology. The alternant insertion of MXene and MPFs affords 3D interconnected “MPFs‐to‐MXene‐to‐MPFs” conductive networks to accelerate the ionic/electronic transport rates. Meanwhile, the interlayer hydrogen bonds (F···HO and O···HO) contribute a high chemical stability due to a favorable tolerance to volume change caused by phase separation and structural collapse during the charge/discharge process. The synergistic effect makes MXene/MPFs film deliver a capacitance of 326.1 F g−1 at 0.1 A g−1, 1.64 F cm−2 at 1 mA cm−2, 694.2 F cm−3 at 1 mA cm−3 and a durability of about 30 000 cycles. The flexible symmetric supercapacitor shows an areal capacitance of 408 mF cm−2, areal energy density of 20.4 µW h cm−2, and capacitance retention of 95.9% after 7000 cycles. This work paves an avenue for the further exploration of 2D MOFs in flexible energy storage devices.

Scholars from environmental psychology, geography, disaster science, and sociology have recently focused attention on evacuation and relocation behaviors and influencing factors in hazard-threatened areas. However, existing studies are mainly focused on developed countries and the influence of individual characteristics, household characteristics, and the perception of risk of urban households on evacuation and relocation behaviors. Few studies examine developing countries and the influence of farmers' sense of place in geological hazardthreatened areas. Using statistics of farming households in an area threatened by landslides, this is a pilot study to explore the relationship of sense of place to the relocation willingness of farming households while controlling for other variables. The results show that: (1) Households with higher scores of place identity and place dependence are less willing to relocate, whereas place attachment has no significant relationship to household relocation willingness; (2) Risk perception dimensions, including probability, threat, and controllability have a significant relationship to household relocation willingness, while worry and fear of the unknown have no significant relationship; (3) Household characteristics, including income, whether a household has experienced economic loss from landslides, and social support are significantly correlated with household relocation willingness, while gender, age, experience, distance to hazard sites, size of household, children, older people, and housing material are not. The results for information and education are not robust. This study contributes to the current literature by improving the understanding of the relationship of sense of place to the relocation willingness of farming households in villages threatened by geological disasters in rural China.

β-Secretase (β-site amyloid precursor protein-cleaving enzyme 1; BACE1) is a transmembrane aspartic protease that cleaves the β-amyloid precursor protein en route to generation of the amyloid β-peptide (Aβ) that is believed to be responsible for the Alzheimer's disease amyloid cascade. It is thus a prime target for the development of inhibitors which may serve as drugs in the treatment and/or prevention of Alzheimer's disease. In the following determination of the crystal structures of both apo and complexed BACE1, structural analysis of all crystal structures of BACE1 deposited in the PDB and molecular dynamics (MD) simulations of monomeric and `dimeric' BACE1 were used to study conformational changes in the active-site region of the enzyme. It was observed that a flap able to cover the active site is the most flexible region, adopting multiple conformational states in the various crystal structures. Both the presence or absence of an inhibitor within the active site and the crystal packing are shown to influence the flap's conformation. An open conformation of the flap is mostly observed in the apo structures, while direct hydrogen-bonding interaction between main-chain atoms of the flap and the inhibitor is a prerequisite for the flap to adopt a closed conformation in the crystal structures of complexes. Thus, a systematic study of the conformational flexibility of the enzyme may not only contribute to structure-based drug design of BACE1 inhibitors and of other targets with flexible conformations, but may also help to better understand the mechanistic events associated with the binding of substrates and inhibitors to the enzyme.

MicroRNAs (miRNAs) have been identified as major post-transcriptional regulators of the initiation and progression of human cancers, including breast cancer. However, the detail role of miR-451 has not been fully elucidated in breast cancer. In this study, we aimed to investigate the biological role and molecular mechanisms of miR-451 in drug resistance in breast cancer cell lines and in xenograft model. We show that miR-451 is decreased in human breast cancer specimens and in paclitaxel-resistant (PR) cells. Ectopic expression of miR-451 could inhibit the cell migration and invasion, promoted apoptosis, induced cell-cycle arrest Furthermore, tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ) was identified as a direct target of miR-451. Remarkably, the expression of YWHAZ is inversely correlated with the level of miR-451 in human breast cancer samples. Co-treatment with miR-451 mimics and YWHAZ-siRNA significantly enhanced YWHAZ knockdown in both SKBR3/PR and MCF-7/PR cells Moreover, miR-451 markedly inhibited expression of β-catenin via YWHAZ and subsequently inhibited downstream gene cyclin D1, c-Myc expression. The results of xenograft model in vivo showed that intratumor injection of miR-451 agomir induced a tumor-suppressive effect in SKBR3/PR drug-resistant xenograft model. Taken together, our findings suggested that miR-451 might be considered as important and potential target in paclitaxel-resistant breast cancer treatment.

Inspired by marine cyanobacterial natural products, we synthesized modified peptides with a central statine-core unit, characteristic for aspartic protease inhibition. A series of tasiamide B analogues inhibited BACE1, a therapeutic target in Alzheimer's disease. We probed the stereospecificity of target engagement and determined additional structure-activity relationships with respect to BACE1 and related aspartic proteases, cathepsins D and E. We cocrystallized selected inhibitors with BACE1 to reveal the structural basis for the activity. Hybrid molecules that combine features of tasiamide B and an isophthalic acid moiety-containing sulfonamide showed nanomolar cellular activity. Compounds were screened in a series of rigorous complementary cell-based assays. We measured secreted APP ectodomain (sAPPβ), membrane bound carboxyl terminal fragment (CTF), levels of β-amyloid (Aβ) peptides and selectivity for β-secretase (BACE1) over γ-secretase. Prioritized compounds showed reasonable stability in vitro and in vivo, and our most potent inhibitor showed efficacy in reducing Aβ levels in the rodent brain.

A population-based case-control was performed to explore familial aggregation of esophageal squamous cell carcinoma (ESCC). Family history of cancer was assessed by a structured questionnaire, and from which 2 cohorts of relatives of cases and controls were reconstructed. Unconditional logistic regression and Cox proportional hazards regression were applied for case-control design and reconstructed cohort design, respectively. We observed a close to doubled risk of ESCC associated with a positive family history of esophageal cancer among first degree relatives (odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.42–2.41), after adjusting age, sex, family size and other confounders. The excess risks of ESCC increased with the increasing of first-degree relatives affected by esophageal cancer (p < 0.001). In particular, those individuals whose both parents with esophageal cancer had an 8-fold excess risk of ESCC (95% CI: 1.74–36.32). The reconstructed cohort analysis showed that the cumulative risk of esophageal cancer to age 75 was 12.2% in the first-degree relatives of cases and 7.0% in those of controls (hazard ratio = 1.91, 95% CI: 1.54–2.37). Our results suggest family history of esophageal cancer significantly increases the risk for ESCC. Future studies are needed to understand how the shared genetic susceptibility and/or environmental exposures contribute to the observed excess risk.