Crystallographic and Spectroscopic Snapshots Reveal a Dehydrogenase in Action

Aldehydes are ubiquitous intermediates in metabolic pathways and their innate reactivity can often make them quite unstable. There are several aldehydic intermediates in the metabolic pathway for tryptophan degradation that can decay into neuroactive compounds that have been associated with numerous neurological diseases. An enzyme of this pathway, 2-aminomuconate-6-semialdehyde dehydrogenase, is responsible for ‘disarming’ the final aldehydic intermediate. Here we show the crystal structures of a bacterial analogue enzyme in five catalytically relevant forms: resting state, one binary and two ternary complexes, and a covalent, thioacyl intermediate. We also report the crystal structures of a tetrahedral, thiohemiacetal intermediate, a thioacyl intermediate and an NADþ-bound complex from an active site mutant. These covalent intermediates are characterized by single-crystal and solution-state electronic absorption spectroscopy. The crystal structures reveal that the substrate undergoes an E/Z isomerization at the enzyme active site before an sp3-to-sp2 transition during enzyme-mediated oxidation

Ba6RE2Ti4O17 (RE= Nd, Sm,Gd, Dy-Yb): A family of quasi-two-dimensional triangular lattice magnets

Rare-earth-based triangular-lattice magnets provide the fertile ground to explore the exotic quantum magnetic state. Herein, we report a new family of RE-based triangular-lattice magnets Ba6RE2Ti4O17(RE= rare earth ions) crystallized into the hexagonal structure with space group of P63 mmc, where magnetic rare earth ions form an ideal triangular lattice within the ab-plane and stack in an AA -type fashion along the c-axis. The low-temperature magnetic susceptibility results reveal all the serial compounds have the dominant antiferromagnetic interactions and an absence of magnetic ordering down to 1.8 K. The magnetization and electron spin resonance results indicate distinct magnetic anisotropy for the compounds with different RE ions. Moreover, Ba6Nd2Ti4O17 single crystal is successfully grown and it exhibits strong Ising like anisotropy with magnetic easy-axis perpendicular to the triangle-lattice plane, being a candidate to explore quantum spin liquid state with dominant Ising-type interaction.Comment: 18 pages, 8 figure

Folate-Functionalized Mesoporous Silica Nanoparticles as a Liver Tumor-Targeted Drug Delivery System to Improve the Antitumor Effect of Paclitaxel

The aim of this study was to prepare and characterize an innovative hepatocellular carcinoma-targeted therapeutic drug delivery system based on folate-PEG-mesoporous silica nanoparticles (FA-PEG-MSNs) loaded with paclitaxel (PTX). In vitro cell experiments and an in vivo antitumor efficacy study demonstrated that FA-PEG-MSNs-PTX produced significantly higher tumor inhibition compared with pure PTX and mesoporous silica nanoparticles loaded with paclitaxel (MSNs-PTX). The biodistribution investigation of PTX in nude mice revealed that the FA-PEG-MSNs-PTX could accumulate in tumors. Folic acid functionalized MSNs resulted in a good targeting effect, confirming that FA-PEG-MSNs-PTX is a promising tumor-targeted drug delivery system for liver cancer chemotherapy

Low-mass dark matter search results from full exposure of PandaX-I experiment

We report the results of a weakly-interacting massive particle (WIMP) dark matter search using the full 80.1\;live-day exposure of the first stage of the PandaX experiment (PandaX-I) located in the China Jin-Ping Underground Laboratory. The PandaX-I detector has been optimized for detecting low-mass WIMPs, achieving a photon detection efficiency of 9.6\%. With a fiducial liquid xenon target mass of 54.0\,kg, no significant excess event were found above the expected background. A profile likelihood analysis confirms our earlier finding that the PandaX-I data disfavor all positive low-mass WIMP signals reported in the literature under standard assumptions. A stringent bound on the low mass WIMP is set at WIMP mass below 10\,GeV/c$^2$, demonstrating that liquid xenon detectors can be competitive for low-mass WIMP searches.Comment: v3 as accepted by PRD. Minor update in the text in response to referee comments. Separating Fig. 11(a) and (b) into Fig. 11 and Fig. 12. Legend tweak in Fig. 9(b) and 9(c) as suggested by referee, as well as a missing legend for CRESST-II legend in Fig. 12 (now Fig. 13). Same version as submitted to PR

Kronos: A Secure and Generic Sharding Blockchain Consensus with Optimized Overhead

Sharding enhances blockchain scalability by dividing the network into shards, each managing specific unspent transaction outputs or accounts. As an introduced new transaction type, cross-shard transactions pose a critical challenge to the security and efficiency of sharding blockchains. Currently, there is a lack of a generic sharding consensus pattern that achieves both security and low overhead. In this paper, we present Kronos, a secure sharding blockchain consensus achieving optimized overhead. In particular, we propose a new secure sharding consensus pattern, based on a buffer managed jointly by shard members. Valid transactions are transferred to the payee via the buffer, while invalid ones are rejected through happy or unhappy paths. Kronos is proved to achieve security with atomicity under malicious clients with optimal intra-shard overhead $k\mathcal{B}$ ($k$ for involved shard number and $\mathcal{B}$ for a Byzantine fault tolerance (BFT) cost). Efficient rejection even requires no BFT execution in happy paths, and the cost in unhappy paths is still lower than a two-phase commit. Besides, we propose secure cross-shard certification methods based on batch certification and reliable cross-shard transfer. The former combines hybrid trees or vector commitments, while the latter integrates erasure coding. Handling $b$ transactions, Kronos is proved to achieve reliability with low cross-shard overhead $\mathcal{O}(n b \lambda)$ ($n$ for shard size and $\lambda$ for the security parameter). Notably, Kronos imposes no restrictions on BFT and does not rely on time assumptions, offering optional constructions in various modules. Kronos could serve as a universal framework for enhancing the performance and scalability of existing BFT protocols, supporting generic models, including asynchronous networks, increasing the throughput by several orders of magnitude. We implement Kronos using two prominent BFT protocols: asynchronous Speeding Dumbo (NDSS\u2722) and partial synchronous Hotstuff (PODC\u2719). Extensive experiments (over up to 1000 AWS EC2 nodes across 4 AWS regions) demonstrate Kronos scales the consensus nodes to thousands, achieving a substantial throughput of 320 ktx/sec with 2.0 sec latency. Compared with the past solutions, Kronos outperforms, achieving up to a 12$\times$ improvement in throughput and a 50% reduction in latency when cross-shard transactions dominate the workload

Comprehensive serial molecular profiling of an “N of 1” exceptional non-responder with metastatic prostate cancer progressing to small cell carcinoma on treatment

Abstract Importance Small cell carcinoma/neuroendocrine prostate cancer (NePC) is a lethal, poorly understood prostate cancer (PCa) subtype. Controversy exists about the origin of NePC in this setting. Objective To molecularly profile archived biopsy specimens from a case of early-onset PCa that rapidly progressed to NePC to identify drivers of the aggressive course and mechanisms of NePC origin and progression. Design, setting, and participants A 47-year-old patient presented with metastatic prostatic adenocarcinoma (Gleason score 9). After a 6-month response to androgen deprivation therapy, the patient developed jaundice and liver biopsy revealed exclusively NePC. Targeted next generation sequencing (NGS) from formalin-fixed paraffin-embedded (FFPE)-isolated DNA was performed from the diagnostic prostate biopsy and the liver biopsy at progression. Intervention Androgen deprivation therapy for adenocarcinoma followed by multiagent chemotherapy for NePC. Main outcomes and measures Identification of the mutational landscape in primary adenocarcinoma and NePC liver metastasis. Whether the NePC arose independently or was derived from the primary adenocarcinoma was considered based on mutational profiles. Results A deleterious somatic SMAD4 L535fs variant was present in both prostate and liver specimens; however, a TP53 R282W mutation was exclusively enriched in the liver specimen. Copy number analysis identified concordant, low-level alterations in both specimens, with focal MYCL amplification and homozygous PTEN, RB1, and MAP2K4 losses identified exclusively in the NePC specimen. Integration with published genomic profiles identified MYCL as a recurrently amplified in NePC. Conclusions and relevance NGS of routine biopsy samples from an exceptional non-responder identified SMAD4 as a driver of the aggressive course and supports derivation of NePC from primary adenocarcinoma (transdifferentiation).http://deepblue.lib.umich.edu/bitstream/2027.42/113670/1/13045_2015_Article_204.pd