Activation of caspase-9 on the apoptosome as studied by methyl-TROSY NMR.

Mitochondrial apoptotic signaling cascades lead to the formation of the apoptosome, a 1.1-MDa heptameric protein scaffold that recruits and activates the caspase-9 protease. Once activated, caspase-9 cleaves and activates downstream effector caspases, triggering the onset of cell death through caspase-mediated proteolysis of cellular proteins. Failure to activate caspase-9 enables the evasion of programmed cell death, which occurs in various forms of cancer. Despite the critical apoptotic function of caspase-9, the structural mechanism by which it is activated on the apoptosome has remained elusive. Here, we used a combination of methyl-transverse relaxation-optimized NMR spectroscopy, protein engineering, and biochemical assays to study the activation of caspase-9 bound to the apoptosome. In the absence of peptide substrate, we observed that both caspase-9 and its isolated protease domain (PD) only very weakly dimerize with dissociation constants in the millimolar range. Methyl-NMR spectra of isotope-labeled caspase-9, within the 1.3-MDa native apoptosome complex or an engineered 480-kDa apoptosome mimic, reveal that the caspase-9 PD remains monomeric after recruitment to the scaffold. Binding to the apoptosome, therefore, organizes caspase-9 PDs so that they can rapidly and extensively dimerize only when substrate is present, providing an important layer in the regulation of caspase-9 activation. Our work highlights the unique role of NMR spectroscopy to structurally characterize protein domains that are flexibly tethered to large scaffolds, even in cases where the molecular targets are in excess of 1 MDa, as in the present example.

A curated rotamer library for common post-translational modifications of proteins.

MOTIVATION: Sidechain rotamer libraries of the common amino acids of a protein are useful for folded protein structure determination and for generating ensembles of intrinsically disordered proteins (IDPs). However, much of protein function is modulated beyond the translated sequence through the introduction of post-translational modifications (PTMs). RESULTS: In this work, we have provided a curated set of side chain rotamers for the most common PTMs derived from the RCSB PDB database, including phosphorylated, methylated, and acetylated sidechains. Our rotamer libraries improve upon existing methods such as SIDEpro, Rosetta, and AlphaFold3 in predicting the experimental structures for PTMs in folded proteins. In addition, we showcase our PTM libraries in full use by generating ensembles with the Monte Carlo Side Chain Entropy (MCSCE) for folded proteins, and combining MCSCE with the Local Disordered Region Sampling algorithms within IDPConformerGenerator for proteins with intrinsically disordered regions. AVAILABILITY AND IMPLEMENTATION: The codes for dihedral angle computations and library creation are available at https://github.com/THGLab/ptm_sc.git.

Highly Stable Solid Contact Calcium Ion-Selective Electrodes: Rapid Ion-Electron Transduction Triggered by Lipophilic Anions Participating in Redox Reactions of CunS Nanoflowers.

Solid contact (SC) calcium ion-selective electrodes (Ca2+-ISEs) have been widely applied in the analysis of water quality and body fluids by virtue of the unique advantages of easy operation and rapid response. However, the potential drift during the long-term stability test hinders their further practical applications. Designing novel redox SC layers with large capacitance and high hydrophobicity is a promising approach to stabilize the potential stability, meanwhile, exploring the transduction mechanism is also of great guiding significance for the precise design of SC layer materials. Herein, flower-like copper sulfide (CunS-50) composed of nanosheets is meticulously designed as the redox SC layer by modification with the surfactant (CTAB). The CunS-50-based Ca2+-ISE (CunS-50/Ca2+-ISE) demonstrates a near-Nernstian slope of 28.23 mV/dec for Ca2+ in a wide activity linear range of 10-7 to 10-1 M, with a low detection limit of 3.16 × 10-8 M. CunS-50/Ca2+-ISE possesses an extremely low potential drift of only 1.23 ± 0.13 µV/h in the long-term potential stability test. Notably, X-ray absorption fine-structure (XAFS) spectra and electrochemical experiments are adopted to elucidate the transduction mechanism that the lipophilic anion (TFPB-) participates in the redox reaction of CunS-50 at the solid-solid interface of ion-selective membrane (ISM) and redox inorganic SC layer (CunS-50), thereby promoting the generation of free electrons to accelerate ion-electron transduction. This work provides an in-depth comprehension of the transduction mechanism of the potentiometric response and an effective strategy for designing redox materials of ion-electron transduction triggered by lipophilic anions.

Formulating N-Doped Carbon Hollow Nanospheres with Highly Accessible Through-Pores to Isolate Fe Single-Atoms for Efficient Oxygen Reduction.

It is challenging yet promising to design highly accessible N-doped carbon skeletons to fully expose the active sites inside single-atom catalysts. Herein, mesoporous N-doped carbon hollow spheres with regulatable through-pore size can be formulated by a simple sequential synthesis procedure, in which the condensed SiO2 is acted as removable dual-templates to produce both hollow interiors and through-pores, meanwhile, the co-condensed polydopamine shell is served as N-doped carbon precursor. After that, Fe─N─C hollow spheres (HSs) with highly accessible active sites can be obtained after rationally implanting Fe single-atoms. Microstructural analysis and X-ray absorption fine structure analysis reveal that high-density Fe─N4 active sites together with tiny Fe clusters are uniformly distributed on the mesoporous carbon skeleton with abundant through-pores. Benefitted from the highly accessible Fe─N4 active sites arising from the unique through-pore architecture, the Fe─N─C HSs demonstrate excellent oxygen reduction reaction (ORR) performance in alkaline media with a half-wave potential up to 0.90 V versus RHE and remarkable stability, both exceeding the commercial Pt/C. When employing Fe─N─C HSs as the air-cathode catalysts, the assembled Zn-air batteries deliver a high peak power density of 204 mW cm-2 and stable discharging voltage plateau over 140 h.

Local Disordered Region Sampling (LDRS) for ensemble modeling of proteins with experimentally undetermined or low confidence prediction segments.

SUMMARY: The Local Disordered Region Sampling (LDRS, pronounced loaders) tool is a new module developed for IDPConformerGenerator, a previously validated approach to model intrinsically disordered proteins (IDPs). The IDPConformerGenerator LDRS module provides a method for generating all-atom conformations of intrinsically disordered protein regions at N- and C-termini of and in loops or linkers between folded regions of an existing protein structure. These disordered elements often lead to missing coordinates in experimental structures or low confidence in predicted structures. Requiring only a pre-existing PDB or mmCIF formatted structural template of the protein with missing coordinates or with predicted confidence scores and its full-length primary sequence, LDRS will automatically generate physically meaningful conformational ensembles of the missing flexible regions to complete the full-length protein. The capabilities of the LDRS tool of IDPConformerGenerator include modeling phosphorylation sites using enhanced Monte Carlo-Side Chain Entropy, transmembrane proteins within an all-atom bilayer, and multi-chain complexes. The modeling capacity of LDRS capitalizes on the modularity, the ability to be used as a library and via command-line, and the computational speed of the IDPConformerGenerator platform. AVAILABILITY AND IMPLEMENTATION: The LDRS module is part of the IDPConformerGenerator modeling suite, which can be downloaded from GitHub at https://github.com/julie-forman-kay-lab/IDPConformerGenerator. IDPConformerGenerator is written in Python3 and works on Linux, Microsoft Windows, and Mac OS versions that support DSSP. Users can utilize LDRS's Python API for scripting the same way they can use any part of IDPConformerGenerator's API, by importing functions from the "idpconfgen.ldrs_helper" library. Otherwise, LDRS can be used as a command line interface application within IDPConformerGenerator. Full documentation is available within the command-line interface as well as on IDPConformerGenerator's official documentation pages (https://idpconformergenerator.readthedocs.io/en/latest/).

Association of Socioeconomic Disparities With Nasopharyngeal Carcinoma Survival in an Endemic Area, China.

OBJECTIVES: This retrospective cohort study investigated the association of socioeconomic status with survival outcomes among patients with nasopharyngeal carcinoma in an endemic area of China. METHODS: The primary endpoint was overall survival. Survival outcomes were estimated by the Kaplan-Meier method and compared by the log-rank test, and the multivariate Cox proportional hazards model was used to estimate hazard ratios, 95% CIs, and independent prognostic factors. RESULTS: A total of 11 069 adult patients with NPC were enrolled and included in the analysis. Kaplan-Meier survival analysis revealed that overall survival was significantly different among socioeconomic status. Compared with high socioeconomic status patients, low socioeconomic status patients (HR, 1.190; 95% CI, 1.063-1.333) and medium socioeconomic status patients (HR, 1.111; 95% CI, 1.006-1.226) were associated with increased hazard ratio (HR) of overall survival. CONCLUSION: This analysis highlights patients with nasopharyngeal carcinoma who had high socioeconomic status had better overall survival compared with those who had low and medium socioeconomic status.

Learning to evolve structural ensembles of unfolded and disordered proteins using experimental solution data.

The structural characterization of proteins with a disorder requires a computational approach backed by experiments to model their diverse and dynamic structural ensembles. The selection of conformational ensembles consistent with solution experiments of disordered proteins highly depends on the initial pool of conformers, with currently available tools limited by conformational sampling. We have developed a Generative Recurrent Neural Network (GRNN) that uses supervised learning to bias the probability distributions of torsions to take advantage of experimental data types such as nuclear magnetic resonance J-couplings, nuclear Overhauser effects, and paramagnetic resonance enhancements. We show that updating the generative model parameters according to the reward feedback on the basis of the agreement between experimental data and probabilistic selection of torsions from learned distributions provides an alternative to existing approaches that simply reweight conformers of a static structural pool for disordered proteins. Instead, the biased GRNN, DynamICE, learns to physically change the conformations of the underlying pool of the disordered protein to those that better agree with experiments.

3-Methyladenine ameliorates surgery-induced anxiety-like behaviors in aged mice by inhibiting autophagy-induced excessive oxidative stress.

BACKGROUND: Postoperative anxiety is a common surgical complication in older patients. Research has recently linked excessive autophagy to several neurological disorders, including anxiety. This study aimed to determine whether 3-Methyladenine (3-MA) administration reduced anxiety-like behaviors in a mouse model following abdominal exploratory laparotomy. METHODS: An abdominal exploratory laparotomy model of postoperative anxiety was established using male C57BL/6 mice aged 20 months. 3-MA (6, 30, and 150 mg/ml) was administered via intracerebroventricular immediately following surgery. The mice were assessed 14 days after surgery using the marble burying, elevated plus maze tests, and local field potential recording in the amygdala. The levels of expression of phosphorylated-Akt, Beclin-1, LC3B, nuclear factor erythroid 2-related factor 2 (Nrf2)-occupied regions in NeuN-positive cells, superoxide dismutase (SOD) activity, malondialdehyde (MDA), and glutathione (GSH) were measured at 24 h after surgery. RESULTS: The injection of 3-MA reversed the increased number of marbles buried, decreased time spent in the open arm, and enhanced θ oscillation power after 14 days of abdominal exploratory laparotomy. In addition, administration of 3-MA reduced the ratio of phosphorylated- to total-Akt, decreased expression in Beclin-1 and LC3B, attenuated MDA levels, and increased the ratio of Nrf2-occupied areas in NeuN-positive cells, SOD activity, and GSH levels under abdominal exploratory laparotomy conditions. CONCLUSIONS: 3-MA improved anxiety-like behaviors in aged mice undergoing abdominal exploratory laparotomy by inhibiting excessive autophagy-induced oxidative stress. These results suggest that 3-MA could be an effective treatment for postoperative anxiety.

Outcomes of different zero-profile spacers in the treatment of two-level cervical degenerative disk disease.

PURPOSE: The purpose of this study was to analyze the clinical and radiological outcomes of two different zero-profile spacers (ROI-C and anchor-C) in contiguous two-level ACDF for CDDD patients. METHODS: We retrospectively analyzed patients who underwent contiguous two-level ACDF due to CDDD between January 2015 and December 2020 in our hospital. Patients who received ROI-C and anchor-C were included as the study groups, and those who underwent plate-cage construct (PCC) were included as the control group. The primary outcome measures were radiographical parameters, and the secondary outcome measures were dysphagia, JOA scores and VAS scores for these patients. RESULTS: A total of 91 patients were enrolled in the study; there were 31, 21 and 39 patients in the ROI-C, anchor-C and PCC groups, respectively. The mean follow-up duration was 24.52 months (range, 18-48 months) in the ROI-C group, 24.38 months (range, 16-52 months) in the anchor-C group and 25.18 months (range, 15-54 months) in the PCC group. The loss of the intervertebral space height and cage subsidence rate in the ROI-C group were significantly higher than those in the anchor-C group and PCC group at the final follow-up (P < 0.05). The ROI-C group showed a lower incidence of adjacent segment degeneration than the anchor-C group and PCC group, but the difference was not significant. The fusion rates were not different among these three groups. The early dysphagia rate was significantly lower in the patients with zero-profile spacers than in the PCC group (P < 0.05), but the difference was not significant at the last follow-up. No relevant differences were found in the JOA scores and VAS scores. CONCLUSIONS: Zero-profile spacers showed promising clinical outcomes in CDDD patients having contiguous two-level ACDF. However, ROI-C resulted in a higher intervertebral space height loss and a higher cage subsidence rate than anchor-C during the follow-up.

IDPConformerGenerator: A Flexible Software Suite for Sampling the Conformational Space of Disordered Protein States.

The power of structural information for informing biological mechanisms is clear for stable folded macromolecules, but similar structure-function insight is more difficult to obtain for highly dynamic systems such as intrinsically disordered proteins (IDPs) which must be described as structural ensembles. Here, we present IDPConformerGenerator, a flexible, modular open-source software platform for generating large and diverse ensembles of disordered protein states that builds conformers that obey geometric, steric, and other physical restraints on the input sequence. IDPConformerGenerator samples backbone phi (φ), psi (ψ), and omega (ω) torsion angles of relevant sequence fragments from loops and secondary structure elements extracted from folded protein structures in the RCSB Protein Data Bank and builds side chains from robust Monte Carlo algorithms using expanded rotamer libraries. IDPConformerGenerator has many user-defined options enabling variable fractional sampling of secondary structures, supports Bayesian models for assessing the agreement of IDP ensembles for consistency with experimental data, and introduces a machine learning approach to transform between internal and Cartesian coordinates with reduced error. IDPConformerGenerator will facilitate the characterization of disordered proteins to ultimately provide structural insights into these states that have key biological functions.

[Outcome indicators in randomized controlled trials on traditional Chinese medicine intervention of sepsis-induced myocardial injury in recent five years].

This study aims to analyze the outcome indicators of randomized controlled trial(RCT) on traditional Chinese medicine(TCM) intervention of sepsis-induced myocardial injury(SIMI) in recent five years, which is expected to lay a basis for the construction of core outcome set(COS) for this disease treated by TCM. To be specific, RCT on the treatment of SIMI with TCM was retrieved from 4 Chinese databases, 3 English databases, and 2 clinical trial protocol registries. The quality of the included studies was evaluated with Cochrane risk-of-bias(ROB) tool, and the outcome indicators were analyzed. Finally, 42 RCTs were included, of which 2 were clinical trial registration schemes. The study found that 42 RCTs had a high risk of bias, and reported a total of 86 indicators in "clinical effective rate, disease severity, TCM syndrome score, inflammation, myocardium, cardiac structure and hemodynamics, electrocardiogram, immunology, metabolism and liver and kidney function, and safety". Outcome indicators on myocardium had the highest emergence frequency, followed by indicators on the cardiac structure and hemodynamics. A total of 8 RCTs reported TCM syndrome scores. Further analysis suggested the following problems in the selection of outcome indicators in the RCTs on TCM intervention of SIMI: no classification of primary and secondary indicators, disregard of endpoint indicators, irrational selection of alternative indicators, neglection of TCM characteristics, no assessment of patients' immune status, and no emphasis on economic indicators and safety indicators. Therefore, according to the recommendations of the core outcome measures in effectiveness trials(COMET) working group, a COS for TCM intervention of TCM for SIMI should be developed, so as to facilitate clinical researchers to select appropriate outcome indicators, the combination of conclusions of similar clinical studies, and the promotion of TCM interventions.

Forensic Analysis of Sudden Death Associated with Sexual Activity.

OBJECTIVES: To analyze the characteristics of sudden death associated with sexual activity to provide recommendations for forensic identification. METHODS: A retrospective analysis was conducted on autopsy cases accepted by Forensic Identification Center of Huazhong University of Science and Technology from 1998 to 2018, and a total of 15 cases of sudden death associated with sexual activity were screened out. The general information, case data and pathological changes of 15 cases were collected to find the relationship between sexual activity and sudden death. RESULTS: The ratio of male to female was 1.5∶1. The average age of males was 50.1 years and that of females was 35.0 years. Coronary artery diseases and brain diseases accounted for most of the cases (12/15). Sexual partners were associated with locations of deaths and body dumping behaviors. CONCLUSIONS: Sudden death associated with sexual activity, although rare, may occur in people over 30 years old with pre-existing heart or brain diseases, which should be paid attention to in forensic practice.

[Effect of Schizonepetae Herba and Saposhnikoviae Radix on expression of AQP4 and AQP8 in colonic mucosa of rats with ulcerative colitis].

The aim of this paper was to investigate the effect of Schizonepetae Herba and Saposhnikoviae Radix(wind medicine) on the expression of AQP4 and AQP8 in colonic mucosa in rats with ulcerative colitis(UC). A total of 35 healthy SD male rats were randomly divided into normal group(gavaged with normal saline), DSS model group, as well as low, middle, and high dose wind medicine groups(Schizonepeta and Saposhnikovia 1∶1, gavaged at dosages of 6, 12, and 24 g·kg~(-1)·d~(-1)), with 7 in each group. UC rat model was established by free drinking of 3% dextran sulphate sodium(DSS) solution for 10 days. At the end of the 10 th day after the treatment, mice were put to death to collect colonic mucosa. The length of colon was measured; the colonic mucosal injury index(CMDI) and pathological changes of colon were observed. ELISA method was used for measuring the content of serum IL-1, IL-8, and immunohistochemical method was used to measure AQP4, AQP8 protein expressions in colon mucosa. The expressions of AQP4, AQP8 mRNA were measured by Real-time PCR. As compared with the normal group, the length of colon tissue was significantly reduced(P<0.01), CMDI scores and pathological scores were significantly increased(P<0.01), the levels of serum IL-1 and IL-8 were significantly increased(P<0.05) in model group; the immunohistochemical results showed that the protein expressions of AQP4, AQP8 were lower; the color was light yellow or brown; AQP4, AQP8 mRNA expressions in colon mucosa were significantly decreased in model group(P<0.01). CMDI scores, pathological scores, and the levels of serum IL-1, IL-8 in high, middle, low dose wind medicine groups were obvious lower than those in the model group(P<0.01 or P<0.05); the protein expressions of AQP4, AQP8 were higher; the color was chocolate brown or dark brown; the length of colon tissue, and the expressions of AQP4, AQP8 mRNA were obvious higher in wind medicine groups(P<0.01 or P<0.05). Schizonepetae Herba and Saposhnikoviae Radix could significantly improve the symptoms and histopathology of UC model rats and accelerate the intestinal mucosal healing. The mechanism may be related with up-regulating the expression level of AQP4 and AQP8 in colonic mucosa.

Development and characterization of octreotide-modified curcumin plus docetaxel micelles for potential treatment of non-small-cell lung cancer.

We prepared octreotide (OCT)-modified curcumin plus docetaxel micelles to enhance active targeting and inhibit tumor metastasis by destroying vasculogenic mimicry (VM) channels. Soluplus was applied as an amphiphilic material to form micelles via film dispersion. The cytotoxic effects, active cellular targeting, and inhibitory effects on metastasis were systematically evaluated in vitro using A549 cells, and in vivo antitumor effects were evaluated using xenograft tumor-bearing mice. In vitro assays indicated that the OCT-modified curcumin plus docetaxel micelles showed robust cytotoxicity on A549 cells and effectively inhibited VM channels and tumor metastasis. Studying the mechanism of action indicated that OCT-modified curcumin plus docetaxel micelles downregulated MMP-2 and HIF-1α. In vivo assays indicated that OCT-modified curcumin plus docetaxel micelles increased drug accumulation at tumor sites and showed obvious antitumor efficacy. The developed OCT-modified curcumin plus docetaxel micelles may offer a promising treatment strategy for non-small-cell lung cancer.

[Network pharmacological study of Schizonepetae Herba and Saposhnikoviae Radix in treatment of ulcerative colitis].

The aim of this paper was to screen the active targets of Schizonepetae Herba and Saposhnikoviae Radix in the treatment of ulcerative colitis by means of network pharmacology,and to investigate their mechanism of action. The effective components of Schizonepetae Herba and Saposhnikoviae Radix were screened out by traditional Chinese medicine systematic pharmacological( TCMSP)database,with oral bioavilability( OB) ≥30% and drug-like( DL) ≥18% selected as the thresholds. Target PPI network was built between the main components and their corresponding targets. One hundred and eighty-two human genes corresponding to the medicine target sites were obtained from Uniprot database; 3 874 genes corresponding to ulcerative colitis were obtained from Genecard database.A total of 115 intersection genes were screened from disease genes and medicine genes,and the PPI interaction analysis was conducted by using String tool. Disease-target PPI network was drawn by using Cytoscape software,and component-target-disease network was constructed. One hundred and eight nodes and 1 882 connections were found,and then Cytoscape software was used to merge the networks and filter the core network for gene GO function analysis and KEGG pathway enrichment analysis. The mechanism of Schizonepetae Herba and Saposhnikoviae Radix was then verified by animal experiment. Gene GO functional analysis suggested that biological process,molecular functions and cell components were involved,and it was found that ulcerative colitis might be related to transcription factor activity,and cytokine receptor binding,etc. Gene KEGG pathway enrichment analysis showed that the mechanism of ulcerative colitis might be associated with TNF and Toll-like receptors( TLRs) signaling pathway-mediated cytoinflammatory factors interleukin-1( IL-1) and interleukin-6( IL6). The possible mechanism of the effective components of Schizonepetae Herba and Saposhnikoviae Radix in treating ulcerative colitis might be related to intervening the cytokine receptor binding of TNF and TLRs signaling pathways,reducing the transcription of nuclear factor-kappaB( NF-κB),and inhibiting the secretion of intestinal inflammatory factors IL-1 and IL-6.

Identification of the long non-coding RNA POU3F3 in plasma as a novel biomarker for diagnosis of esophageal squamous cell carcinoma.

BACKGROUND: Recent studies have demonstrated that long non-coding RNAs (lncRNAs) were present in the blood of cancer patients and have shown great potential as powerful and non-invasive tumor markers. However, little is known about the value of lncRNAs in the diagnosis of esophageal squamous cell carcinoma (ESCC). We hypothesized that ESCC-related lncRNAs might be released into the circulation during tumor initiation and could be utilized to detect and monitor ESCC. METHODS: Ten lncRNAs (HOTAIR, AFAP1-AS1, POU3F3, HNF1A-AS1, 91H, PlncRNA1, SPRY4-IT1, ENST00000435885.1, XLOC_013104 and ENST00000547963.1) which previously found to be differently expressed in esophageal cancer were selected as candidate targets for subsequent circulating lncRNA assay. A four-stage exploratory study was conducted to test the hypothesis: (1) optimization of detected method to accurately and reproducibly measure ESCC-related lncRNAs in plasma and serum; (2) evaluation of the stability of circulating lncRNAs in human plasma or serum; (3) exploration the origin of ESCC-related lncRNAs in vitro and in vivo; (4) evaluation the diagnostic power of circulating lncRNAs for ESCC. RESULTS: ESCC-related lncRNAs were detectable and stable in plasma of cancer patients, and derived largely from ESCC tumor cells. Furthermore, plasma levels of POU3F3, HNF1A-AS1 and SPRY4-IT1 were significantly higher in ESCC patients compared with normal controls. By receiver operating characteristic curve (ROC) analysis, among the three lncRNAs investigated, plasma POU3F3 provided the highest diagnostic performance for detection of ESCC (the area under the ROC curve (AUC), 0.842; p < 0.001; sensitivity, 72.8%; specificity, 89.4%). Moreover, use of POU3F3 and SCCA in combination could provide a more effective diagnosis performance (AUC, 0.926, p < 0.001, sensitivity, 85.7%; specificity, 81.4%). Most importantly, this combination was effective to detect ESCC at an early stage (80.8%). CONCLUSIONS: Plasma POU3F3 could serve as a potential biomarker for diagnosis of ESCC, and the combination of POU3F3 and SCCA was more efficient for ESCC detection, in particular for early tumor screening.

Upregulation of the long noncoding RNA PCAT-1 correlates with advanced clinical stage and poor prognosis in esophageal squamous carcinoma.

Recent studies reveal that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. Prostate cancer-associated ncRNA transcript 1 (PCAT-1) is one of the lncRNAs involved in cell apoptosis and proliferation of prostate cancer. This study aimed to assess the potential role of PCAT-1 specifically in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of PCAT-1 in matched cancerous tissues and adjacent noncancerous tissues from 130 patients with ESCC, 34 patients with non-small cell lung cancer (NSCLC), and 30 patients with gastric carcinoma (GC). The correlation of PCAT-1 with clinicopathological features and prognosis were also analyzed. The expression of PCAT-1 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (70.8%, p < 0.01), and the high level of PCAT-1 expression was significantly correlated with invasion of the tumor (p = 0.024), advanced clinical stage (p = 0.003), lymph node metastasis (p = 0.032), and poor prognosis. However, PCAT-1 mRNA expression had no significant difference between paired primary cancerous tissues and the adjacent noncancerous tissues in 34 cases of NSCLC (p = 0.293) and 30 cases of GC (p = 0.125). High expression of PCAT-1 was specifically correlated with invasion of cancer tissues, metastasis of lymph node, and advanced tumor stage of ESCC. High expression of PCAT-1 might reflect poor prognosis of ESCC and indicate a potential diagnostic target in ESCC patients. Adjuvant therapy targeting PCAT-1 molecule might be effective in treatment of ESCC.

Applying Attenuated Total Reflection-Mid-Infrared (ATR-MIR) Spectroscopy to Detect Hairtail Surimi in Mixed Surimi and Their Surimi Products.

ATR-MIR spectroscopic analysis was used to classify sliver carp surimi and surimi products adulterated with different levels of hairtail surimi. Five chemometric methods, including SIMCA (soft independent modeling class of analogies), KNN (K-nearest neighbor), SVR (support vector machines regression), PLSDA (partial least squares discriminate analysis) and ID3 (interative dicremiser version 3) Decision tree were used to build the classifying models. And the performances of the models were compared. Results showed that for both cooked and uncooked mixed surimi samples, better classifications were obtained using SIMCA model, the percentage of the correct classification reached 96.59% and 96.43%, and the corresponding RMSECV were 0.185 7 and 0.189 8, r value were 0.988 0 and 0.994 1 respectively. The results of this study demonstrated for the first time that ATR-MIR spectroscopy combined with chemometrics method can be used to classify sliver carp surimi and surimi products adulterated with different levels of hairtail surimi.

Chromosome compaction is triggered by an autonomous DNA-binding module within condensin.

The compaction of chromatin into mitotic chromosomes is essential for faithful transmission of the genome during cell division. In eukaryotes, chromosome morphogenesis is regulated by the condensin complex, though the exact mechanism used to target condensin to chromatin and initiate condensation is not understood. Here, we reveal that condensin contains an intrinsically disordered region (IDR) that modulates its association with chromatin in early mitosis and exhibits phase separation. We describe DNA-binding motifs within the IDR that, upon deletion, inflict striking defects in chromosome condensation and segregation, ill-timed condensin turnover on chromatin, and cell death. Importantly, we demonstrate that the condensin IDR can impart cell cycle regulatory functions when transferred to other subunits within the complex, indicating its autonomous nature. Collectively, our study unveils the molecular basis for the initiation of chromosome condensation in early mitosis and how this process ultimately promotes genomic stability and faultless cell division.

Computational Methods to Investigate Intrinsically Disordered Proteins and their Complexes.

In 1999 Wright and Dyson highlighted the fact that large sections of the proteome of all organisms are comprised of protein sequences that lack globular folded structures under physiological conditions. Since then the biophysics community has made significant strides in unraveling the intricate structural and dynamic characteristics of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). Unlike crystallographic beamlines and their role in streamlining acquisition of structures for folded proteins, an integrated experimental and computational approach aimed at IDPs/IDRs has emerged. In this Perspective we aim to provide a robust overview of current computational tools for IDPs and IDRs, and most recently their complexes and phase separated states, including statistical models, physics-based approaches, and machine learning methods that permit structural ensemble generation and validation against many solution experimental data types.