A study on commuters' public transportation mode choice behavior in river valley-type cities considering terrain spatial perception: evidence from Lanzhou, China.

Existing research rarely examines the subjective and objective built environment of river valley-type cities in relation to travel mode choice, particularly overlooking the heterogeneity among travelers in these cities. In this paper, based on questionnaire survey data and built environment data, terrain spatial perception (TSP) is introduced to expand the theory of planned behavior (TPB), and a Structural Equation Model (SEM) is established. Factor analysis and path analysis are conducted using SPSS and AMOS to estimate latent variables. An integrated model of SEM and random parameter Logit model (RPLM), which can not only analyze the psychological perception factors of commuters in river valley-type cities but also consider the heterogeneity of psychological perception, was constructed to analyze the impact of personal attributes, objective built environment factors, and psychological latent variables on the commuting mode choice behavior of public transport users in river valley-type cities. The results indicate that the five observation indicators corresponding to the proposed terrain spatial perception latent variables can better explain the terrain spatial perception of commuters in river valley-type cities. Different from plain cities, the subjective and objective built environment of river valley-type cities notably influence the travel behavior of commuters. Moreover, the parameters of terrain spatial perception follow a normal distribution, indicating that the sensitivity of different commuters to the terrain spatial perception of river valley-type cities is heterogeneous. The results of our study can provide a reference for alleviating traffic issues in valley cities.

Diverse modes of H3K36me3-guided nucleosomal deacetylation by Rpd3S.

Context-dependent dynamic histone modifications constitute a key epigenetic mechanism in gene regulation1-4. The Rpd3 small (Rpd3S) complex recognizes histone H3 trimethylation on lysine 36 (H3K36me3) and deacetylates histones H3 and H4 at multiple sites across transcribed regions5-7. Here we solved the cryo-electron microscopy structures of Saccharomyces cerevisiae Rpd3S in its free and H3K36me3 nucleosome-bound states. We demonstrated a unique architecture of Rpd3S, in which two copies of Eaf3-Rco1 heterodimers are asymmetrically assembled with Rpd3 and Sin3 to form a catalytic core complex. Multivalent recognition of two H3K36me3 marks, nucleosomal DNA and linker DNAs by Eaf3, Sin3 and Rco1 positions the catalytic centre of Rpd3 next to the histone H4 N-terminal tail for deacetylation. In an alternative catalytic mode, combinatorial readout of unmethylated histone H3 lysine 4 and H3K36me3 by Rco1 and Eaf3 directs histone H3-specific deacetylation except for the registered histone H3 acetylated lysine 9. Collectively, our work illustrates dynamic and diverse modes of multivalent nucleosomal engagement and methylation-guided deacetylation by Rpd3S, highlighting the exquisite complexity of epigenetic regulation with delicately designed multi-subunit enzymatic machineries in transcription and beyond.

Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel.

Cyclic nucleotide-gated (CNG) channels transduce chemical signals into electrical signals in sensory receptors and neurons. They are activated by cGMP or cAMP, which bind to the cyclic nucleotide-binding domain (CNBD) to open a gate located 50-60 Å away in the central cavity. Structures of closed and open vertebrate CNG channels have been solved, but the conformational landscape of this allosteric gating remains to be elucidated and enriched. Here, we report structures of the cGMP-activated human cone photoreceptor CNGA3/CNGB3 channel in closed, intermediate, pre-open and open states in detergent or lipid nanodisc, all with fully bound cGMP. The pre-open and open states are obtained only in the lipid nanodisc, suggesting a critical role of lipids in tuning the energetic landscape of CNGA3/CNGB3 activation. The different states exhibit subunit-unique, incremental and distinct conformational rearrangements that originate in the CNBD, propagate through the gating ring to the transmembrane domain, and gradually open the S6 cavity gate. Our work illustrates a spatial conformational-change wave of allosteric gating of a vertebrate CNG channel by its natural ligand and provides an expanded framework for studying CNG properties and channelopathy.

ZnO/Ge core-shell nanowires and Ge nanotubes fabricated by chemical vapor deposition and wet etching.

One-dimensional germanium (Ge)-related nanostructures including core-shell nanowires and nanotubes with high specific surface area show enhanced performance in energy storage and electronic devices, and their structural control is important for further improving their performance and stability. In this work, we fabricated vertically formed ZnO/Ge core-shell nanowires with different shell thicknesses. The dependence of morphology, crystallinity, and internal stress of the nanowires on the shell growth time and temperature was investigated. By applying the wet-etching method to the ZnO/Ge core-shell heterojunction nanowires, we demonstrated the Ge nanotube fabrication and stress relaxation in Ge after ZnO core removal.

Undifferentiated-predominant mixed-type early gastric cancer is more aggressive than pure undifferentiated type: a systematic review and meta-analysis.

BACKGROUND: Studies have shown that differentiated-predominant mixed-type early gastric cancer (EGC) is more aggressive than pure differentiated-type EGC. However, the biological behaviour of undifferentiated-predominant mixed-type (MU) EGC and pure undifferentiated-type (PU) EGC are controversial. This study was conducted to compare the biological behaviour of MU EGC and PU EGC. METHODS: A systematic review and meta-analysis of observational studies was conducted using literature published through PubMed and Embase from inception to 9 November 2021. Inclusion criteria were: (1) a direct or indirect comparison of MU and PU; (2) patients with EGC; (3) a specified outcome of lymph node metastasis (LNM), lymphovascular invasion, submucosal invasion and/or ulcer findings; and (4) the primary lesion was obtained. The literature search, data extraction and quality assessment were performed by two independent reviewers. The meta-analysis was conducted with a random-effect model using the Mantel-Haenszel method. RESULTS: Twelve publications with 5644 patients were included. Patients with MU EGC had significantly higher risk of LNM (OR 2.28; 95% CI 1.72 to 3.03) and submucosal invasion (OR 2.19; 95% CI 1.90 to 2.52) compared with patients with PU EGC. No difference was found between patients with MU and PU EGC with respect to lymphovascular invasion risk (OR 1.81; 95% CI 0.84 to 3.87). After stratifying the data according to depth of tumour invasion, a significantly higher risk for LNM was associated with intramucosal MU EGC (OR 2.56; 95% CI 1.66 to 3.95) and submucosal MU EGC (OR 2.63; 95% CI 2.06 to 3.06). Submucosal MU EGC also had a significantly higher risk of lymphovascular invasion (OR 2.40; 95% CI 1.79 to 3.21) compared with submucosal PU EGC. DISCUSSION: Patients with MU EGC had an increased risk of submucosal invasion and LNM compared with patients with PU EGC . MU patients with submucosal EGC also had an increased lymphovascular invasion risk compared with PU patients. Therefore, attention should be focused on the clinical management of patients with MU EGC.

Structural and functional characterization of an achromatopsia-associated mutation in a phototransduction channel.

Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the structural basis and molecular/cellular effects of R410W, an achromatopsia-associated, presumed loss-of-function mutation in human CNGA3. Cryo-EM structures of the Caenorhabditis elegans TAX-4 CNG channel carrying the analogous mutation, R421W, show that most apo channels are open. R421, located in the gating ring, interacts with the S4 segment in the closed state. R421W disrupts this interaction, destabilizes the closed state, and stabilizes the open state. CNGA3_R410W/CNGB3 and TAX4_R421W channels are spontaneously active without cGMP and induce cell death, suggesting cone degeneration triggered by spontaneous CNG channel activity as a possible cause of achromatopsia. Our study sheds new light on CNG channel allosteric gating, provides an impetus for a reevaluation of reported loss-of-function CNG channel missense disease mutations, and has implications for mutation-specific treatment of retinopathy.

Structure of the human cone photoreceptor cyclic nucleotide-gated channel.

Cyclic nucleotide-gated (CNG) channels transduce light-induced chemical signals into electrical signals in retinal cone and rod photoreceptors. Structures of native CNG channels, which are heterotetramers formed by CNGA and CNGB subunits, have not been obtained. In the present study, we report a high-resolution cryo-electron microscopy structure of the human cone CNG channel in the apo closed state. The channel contains three CNGA3 and one CNGB3 subunits. Arg403 in the pore helix of CNGB3 projects into an asymmetric selectivity filter and forms hydrogen bonds with two pore-lining backbone carbonyl oxygens. Arg442 in S6 of CNGB3 protrudes into and occludes the pore below the hydrophobic cavity gate previously observed in homotetrameric CNGA channels. It is interesting that Arg403Gln is a disease mutation, and Arg442 is replaced by glutamine in some animal species with dichromatic or monochromatic vision. These and other unique structural features and the disease link conferred by CNGB3 indicate a critical role of CNGB3 in shaping cone photoresponses.

Silicon Nanotubes Fabricated by Wet Chemical Etching of ZnO/Si Core-Shell Nanowires.

Silicon nanotubes (SiNTs) have garnered a great deal of interest for both their synthesis and their potential for application to high-capacity energy storage, biosensors, and selective transport. In this study, we report a convenient and low-cost route to the fabrication of vertically aligned SiNTs via a wet-etching process that enables the control of the wall thickness of SiNTs by varying the gas flux and growth temperature. Transmission electron microscopy (TEM) characterization showed the resultant SiNTs to have an amorphous nature and a hexagonal hollow core. These SiNTs can be crystallized by thermal annealing.

Mechanism of ligand activation of a eukaryotic cyclic nucleotide-gated channel.

Cyclic nucleotide-gated (CNG) channels convert cyclic nucleotide (CN) binding and unbinding into electrical signals in sensory receptors and neurons. The molecular conformational changes underpinning ligand activation are largely undefined. We report both closed- and open-state atomic cryo-EM structures of a full-length Caenorhabditis elegans cyclic GMP-activated channel TAX-4, reconstituted in lipid nanodiscs. These structures, together with computational and functional analyses and a mutant channel structure, reveal a double-barrier hydrophobic gate formed by two S6 amino acids in the central cavity. cGMP binding produces global conformational changes that open the cavity gate located ~52 Å away but do not alter the structure of the selectivity filter-the commonly presumed activation gate. Our work provides mechanistic insights into the allosteric gating and regulation of CN-gated and nucleotide-modulated channels and CNG channel-related channelopathies.

Histone Modifications Regulate Chromatin Compartmentalization by Contributing to a Phase Separation Mechanism.

Eukaryotic chromosomes contain compartments of various functions, which are marked by and enriched with specific histone modifications. However, the molecular mechanisms by which these histone marks function in chromosome compartmentalization are poorly understood. Constitutive heterochromatin is a largely silent chromosome compartment characterized in part by H3K9me2 and 3. Here, we show that heterochromatin protein 1 (HP1), an H3K9me2 and 3 "reader," interacts with SUV39H1, an H3K9me2 and 3 "writer," and with TRIM28, an abundant HP1 scaffolding protein, to form complexes with increased multivalent engagement of H3K9me2 and 3-modified chromatin. H3K9me2 and 3-marked nucleosomal arrays and associated complexes undergo phase separation to form macromolecule-enriched liquid droplets. The droplets are reminiscent of heterochromatin as they are highly dense chromatin-containing structures that are resistant to DNase and exclude the general transcription factor TFIIB. Our data suggest a general mechanism by which histone marks regulate chromosome compartmentalization by promoting phase separation.

Plant HP1 protein ADCP1 links multivalent H3K9 methylation readout to heterochromatin formation.

Heterochromatin Protein 1 (HP1) recognizes histone H3 lysine 9 methylation (H3K9me) through its conserved chromodomain and maintains heterochromatin from fission yeast to mammals. However, in Arabidopsis, Like Heterochromatin Protein 1 (LHP1) recognizes and colocalizes genome-wide with H3K27me3, and is the functional homolog of Polycomb protein. This raises the question whether genuine HP1 homologs exist in plants. Here, we report on the discovery of ADCP1, a plant-specific triple tandem Agenet protein, as a multivalent H3K9me reader in Arabidopsis, and establish that ADCP1 is essential for heterochromatin formation and transposon silencing through modulating H3K9 and DNA methylation levels. Structural studies revealed the molecular basis underlying H3K9me-specific recognition by tandem Agenet of ADCP1. Similar to human HP1α and fly HP1a, ADCP1 mediates heterochromatin phase separation. Our results demonstrate that despite its distinct domain compositions, ADCP1 convergently evolves as an HP1-equivalent protein in plants to regulate heterochromatin formation.

Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells.

Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster amplified extra centrosomes and achieve pseudobipolar division. Here, we set out to prevent clustering of extra centrosomes. Tubulin, by interacting with the centrosomal protein CPAP, negatively regulates CPAP-dependent peri-centriolar material recruitment, and concurrently microtubule nucleation. Screening for compounds that perturb CPAP-tubulin interaction led to the identification of CCB02, which selectively binds at the CPAP binding site of tubulin. Genetic and chemical perturbation of CPAP-tubulin interaction activates extra centrosomes to nucleate enhanced numbers of microtubules prior to mitosis. This causes cells to undergo centrosome de-clustering, prolonged multipolar mitosis, and cell death. 3D-organotypic invasion assays reveal that CCB02 has broad anti-invasive activity in various cancer models, including tyrosine kinase inhibitor (TKI)-resistant EGFR-mutant non-small-cell lung cancers. Thus, we have identified a vulnerability of cancer cells to activation of extra centrosomes, which may serve as a global approach to target various tumors, including drug-resistant cancers exhibiting high incidence of centrosome amplification.

Optimization of b-values in diffusion-weighted imaging for esophageal cancer: Measuring the longitudinal length of gross tumor volume and evaluating chemoradiotherapeutic efficacy.

PURPOSE: To study the optimization of b-values of magnetic resonance-diffusion-weighted (MR-DWI) in evaluating the chemoradiotherapeutic efficacy for esophageal squamous cell carcinoma (ESCC) and measuring the longitudinal length of gross tumor volume (GTV) of ESCC. MATERIALS AND METHODS: Eighteen patients with biopsy-proven ESCC were undergoing concurrent chemoradiotherapy (CCRT). Conventional magnetic resonance imaging (MRI) combined with DWI using b-values of 600 s/mm2, 800 s/mm2, and 1000 s/mm2 was performed before CCRT and after the 1st, 3rd, 5th, and 10th weeks. The apparent diffusion coefficient (ADC) values of ESCC were derived from DWI using multiple b-values. The correlations between ADC values and apoptosis positive rates of ESCC cells obtained from the endoscope biopsy were statistically analyzed. Thirty-eight patients with confirmed ESCC who underwent radical surgery were analyzed. Longitudinal length of GTV of ESCC was measured using endoscopy, esophageal barium fluoroscopy, computed tomography (CT), and T2-weighted MRI and DWI using different b-values (b = 400, 600, and 800 s/mm2) before surgery and were compared with pathologic lesion length. RESULTS: The ADC values of DWI images with different b-values are positively correlated with ESCC cell apoptosis positive ratios, the relation is significant, especially in the group of b = 1000 s/mm2 (P < 0.01). The measured length of esophageal lesions from short to long was MR-DWI b = 800 s/mm2, endoscopy, real tumor, MR-DWI b = 600 s/mm2, esophageal barium fluoroscopy, CT, and MR-DWI b = 400 s/mm2. CONCLUSION: MR-DWI b = 800 s/mm2 and b = 1000 s/mm2 are in favor of observing the chemoradiotherapeutic efficacy with time variation and evaluating the chemoradiotherapeutic efficacy, respectively. MR-DWI b = 600 s/mm2 could be used as a supplementary means in measuring the length of ESCC.

Monitoring atmospheric nitrous oxide background concentrations at Zhongshan Station, east Antarctica.

At present, continuous observation data for atmospheric nitrous oxide (N2O) concentrations are still lacking, especially in east Antarctica. In this paper, nitrous oxide background concentrations were measured at Zhongshan Station (69°22'25″S, 76°22'14″E), east Antarctica during the period of 2008-2012, and their interannual and seasonal characteristics were analyzed and discussed. The mean N2O concentration was 321.9nL/L with the range of 320.5-324.8nL/L during the five years, and it has been increasing at a rate of 0.29% year(-1). Atmospheric N2O concentrations showed a strong seasonal fluctuation during these five years. The concentrations appeared to follow a downtrend from spring to autumn, and then increased in winter. Generally the highest concentrations occurred in spring. This trend was very similar to that observed at other global observation sites. The overall N2O concentration at the selected global sites showed an increasing annual trend, and the mean N2O concentration in the Northern Hemisphere was slightly higher than that in the Southern Hemisphere. Our result could be representative of atmospheric N2O background levels at the global scale. This study provided valuable data for atmospheric N2O concentrations in east Antarctica, which is important to study on the relationships between N2O emissions and climate change.

ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes.

Histone acetylation, including acetylated H3K14 (H3K14ac), is generally linked to gene activation. Monomethylated histone H3 lysine 4 (H3K4me1), together with other gene-activating marks, denotes active genes. In contrast to usual gene-activating functions of H3K14ac and H3K4me1, we here show that the dual histone modification mark H3K4me1-H3K14ac is recognized by ZMYND8 (also called RACK7) and can function to counteract gene expression. We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D. ZMYND8 antagonized the expression of metastasis-linked genes, and its knockdown increased the cellular invasiveness in vitro and in vivo. The plant homeodomain (PHD) and Bromodomain cassette in ZMYND8 mediated the combinatorial recognition of H3K4me1-H3K14ac and H3K4me0-H3K14ac by ZMYND8. These findings uncover an unexpected role for the signature H3K4me1-H3K14ac in attenuating gene expression and reveal a metastasis-suppressive epigenetic mechanism in which ZMYND8's PHD-Bromo cassette couples H3K4me1-H3K14ac with downregulation of metastasis-linked genes.

Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase.

High-frequency point mutations of genes encoding histones have been identified recently as novel drivers in a number of tumors. Specifically, the H3K36M/I mutations were shown to be oncogenic in chondroblastomas and undifferentiated sarcomas by inhibiting H3K36 methyltransferases, including SETD2. Here we report the crystal structures of the SETD2 catalytic domain bound to H3K36M or H3K36I peptides with SAH (S-adenosylhomocysteine). In the complex structure, the catalytic domain adopts an open conformation, with the K36M/I peptide snuggly positioned in a newly formed substrate channel. Our structural and biochemical data reveal the molecular basis underying oncohistone recognition by and inhibition of SETD2.

Molecular basis for CPAP-tubulin interaction in controlling centriolar and ciliary length.

Centrioles and cilia are microtubule-based structures, whose precise formation requires controlled cytoplasmic tubulin incorporation. How cytoplasmic tubulin is recognized for centriolar/ciliary-microtubule construction remains poorly understood. Centrosomal-P4.1-associated-protein (CPAP) binds tubulin via its PN2-3 domain. Here, we show that a C-terminal loop-helix in PN2-3 targets ß-tubulin at the microtubule outer surface, while an N-terminal helical motif caps microtubule's α-ß surface of ß-tubulin. Through this, PN2-3 forms a high-affinity complex with GTP-tubulin, crucial for defining numbers and lengths of centriolar/ciliary-microtubules. Surprisingly, two distinct mutations in PN2-3 exhibit opposite effects on centriolar/ciliary-microtubule lengths. CPAP(F375A), with strongly reduced tubulin interaction, causes shorter centrioles and cilia exhibiting doublet- instead of triplet-microtubules. CPAP(EE343RR) that unmasks the ß-tubulin polymerization surface displays slightly reduced tubulin-binding affinity inducing over-elongation of newly forming centriolar/ciliary-microtubules by enhanced dynamic release of its bound tubulin. Thus CPAP regulates delivery of its bound-tubulin to define the size of microtubule-based cellular structures using a 'clutch-like' mechanism.

Molecular basis for histone N-terminal methylation by NRMT1.

NRMT1 is an N-terminal methyltransferase that methylates histone CENP-A as well as nonhistone substrates. Here, we report the crystal structure of human NRMT1 bound to CENP-A peptide at 1.3 Å. NRMT1 adopts a core methyltransferase fold that resembles DOT1L and PRMT but not SET domain family histone methyltransferases. Key substrate recognition and catalytic residues were identified by mutagenesis studies. Histone peptide profiling revealed that human NRMT1 is highly selective to human CENP-A and fruit fly H2B, which share a common "Xaa-Pro-Lys/Arg" motif. These results, along with a 1.5 Å costructure of human NRMT1 bound to the fruit fly H2B peptide, underscore the importance of the NRMT1 recognition motif.