Ultrastructural insights into cellular organization, energy storage and ribosomal dynamics of an ammonia-oxidizing archaeon from oligotrophic oceans.

Introduction: Nitrososphaeria, formerly known as Thaumarchaeota, constitute a diverse and widespread group of ammonia-oxidizing archaea (AOA) inhabiting ubiquitously in marine and terrestrial environments, playing a pivotal role in global nitrogen cycling. Despite their importance in Earth's ecosystems, the cellular organization of AOA remains largely unexplored, leading to a significant unanswered question of how the machinery of these organisms underpins metabolic functions. Methods: In this study, we combined spherical-chromatic-aberration-corrected cryo-electron tomography (cryo-ET), scanning transmission electron microscopy (STEM), and energy dispersive X-ray spectroscopy (EDS) to unveil the cellular organization and elemental composition of Nitrosopumilus maritimus SCM1, a representative member of marine Nitrososphaeria. Results and Discussion: Our tomograms show the native ultrastructural morphology of SCM1 and one to several dense storage granules in the cytoplasm. STEM-EDS analysis identifies two types of storage granules: one type is possibly composed of polyphosphate and the other polyhydroxyalkanoate. With precise measurements using cryo-ET, we observed low quantity and density of ribosomes in SCM1 cells, which are in alignment with the documented slow growth of AOA in laboratory cultures. Collectively, these findings provide visual evidence supporting the resilience of AOA in the vast oligotrophic marine environment.

Study on the Overmolding Process of Carbon-Fiber-Reinforced Poly (Aryl Ether Ketone) (PAEK)/Poly (Ether Ether Ketone) (PEEK) Thermoplastic Composites.

This paper used poly (aryl ether ketone) (PAEK) resin with a low melting temperature to prepare laminate via the compression-molding process for continuous-carbon-fiber-reinforced composites (CCF-PAEK). Then, poly (ether ether ketone) (PEEK), or a short-carbon-fiber-reinforced poly (ether ether ketone) (SCF-PEEK) with a high melting temperature, was injected to prepare the overmolding composites. The shear strength of short beams was used to characterize the interface bonding strength of composites. The results showed that the interface properties of the composite were affected by the interface temperature, which was adjusted by mold temperature. PAEK and PEEK formed a better interfacial bonding at higher interface temperatures. The shear strength of the SCF-PEEK/CCF-PAEK short beam was 77 MPa when the mold temperature was 220 °C and 85 MPa when the mold temperature was raised to 260 °C. The melting temperature did not significantly affect the shear strength of SCF-PEEK/CCF-PAEK short beams. For the melting temperature increasing from 380 °C to 420 °C, the shear strength of the SCF-PEEK/CCF-PAEK short beam ranged from 83 MPa to 87 MPa. The microstructure and failure morphology of the composite was observed using an optical microscope. A molecular dynamics model was established to simulate the adhesion of PAEK and PEEK at different mold temperatures. The interfacial bonding energy and diffusion coefficient agreed with the experimental results.

Beta-adrenergic receptor blocker propranolol triggers anti-tumor immunity and enhances irinotecan therapy in mice colorectal cancer.

Colorectal cancer (CRC) stands as the second leading cause of cancer-related deaths worldwide with limited available medicines. While drug repurposing comes as a promising strategy for cancer treatment, we discovered that propranolol (Prop), a non-selective ß1 and ß2 adrenergic receptor blocker, significantly inhibited the development of subcutaneous CT26 CRC and AOM/DSS-induced CRC models. The RNA-seq analysis highlighted the activated immune pathways after Prop treatment, with KEGG analysis enriched in T-cell differentiation. Routine analyses of blood revealed a decrease in neutrophil to lymphocyte ratio, a biomarker of systemic inflammation, and a prognostic indicator in the Prop-treated groups in both CRC models. Analysis of the tumor-infiltrating immune cells exhibited that Prop regressed the exhaustion of CD4+ and CD8+ T cells in the CT26-derived graft models, which was further corroborated in the AOM/DSS-induced models. Furthermore, bioinformatic analysis fitted well with the experimental data, showing that ß2 adrenergic receptor (ADRB2) was positively correlated with T-cell exhaustion signature in various tumors. The in vitro experiment showed no direct effect of Prop on CT26 cell viability, while T cells were activated with significantly-upregulated production of IFN-γ and Granzyme B. Consistently, Prop was unable to restrain CT26 tumor growth in nude mice. At last, the combination of Prop and the chemotherapeutic drug Irinotecan acted out the strongest inhibition in CT26 tumor progress. Collectively, we repurpose Prop as a promising and economical therapeutic drug for CRC treatment and highlight T-cell as its target.

TRPC absence induces pro-inflammatory macrophages and gut microbe disorder, sensitizing mice to colitis.

The transient receptor potential canonical (TRPC) channels, encoded in seven non-allelic genes, are important contributors to calcium fluxes, are strongly associated with various diseases. Here we explored the consequences of ablating all seven TRPCs in mice focusing on colitis. We discovered that absence of all seven TRPC proteins in mice (TRPC HeptaKO mice) promotes the development of dextran sulfate sodium (DSS)-induced colitis. RNA-sequence analysis highlighted an extremely pro-inflammatory profile in colons of DSS-treated TRPC HeptaKO mice, with an amount of increased pro-inflammatory cytokines and chemokines. Flow cytometry analysis showed that the infiltration of Ly6Chi monocytes and neutrophils in colonic lamina propria was significantly increased in DSS-treated TRPC HeptaKO mice. Results also revealed that macrophages from TRPC HeptaKO mice exhibited M1 polarization and enhanced secretion of pro-inflammatory factors. In addition, the composition of gut microbiota was markedly disturbed in DSS-treated TRPC HeptaKO mice. However, upon antibiotic cocktail (Abx)-treatment, TRPC HeptaKO mice showed no significant differences with WT mice in disease severity. Collectively, these data suggest that ablation of all TRPCs promotes the development of DSS-induced colitis by inducing pro-inflammatory macrophages and gut microbiota disorder.

Hexachloro-1,3-butadiene as a Functional Additive for Constructing an Efficient Solid Electrolyte Interface Layer for Long-Life Stable Li Anodes.

Lithium (Li) metal is considered as one of the attractive anodes for next-generation high-energy-density batteries due to its ultrahigh theoretical specific capacity and low potential. However, many great challenges including uncontrolled dendrite growth and undesired side reactions during repeated cycling still seriously hinder its practical application in Li metal secondary batteries. Herein, we report the hexachloro-1,3-butadiene (HCBD) molecule as a functional additive to stabilize the Li anode by forming a stable solid electrolyte interface (SEI) layer with high Li ion conductivity via in situ surface and electrochemical reactions. Density functional theory calculations demonstrate that HCBD can preferentially react with the Li anode, which generates an ionic conducting species (LiCl) into an SEI layer. The LiCl-rich SEI layer effectively regulates Li+ deposition/stripping kinetics and then induces uniform nucleation of Li+ and reduces the side reactions between the Li anode and electrolyte. With an optimal amount of HCBD in an ether-based electrolyte, an excellent cycling lifespan (7000 h) was achieved with a low hysteresis voltage of ∼10 mV at 1.0 mA cm-2 in a Li||Li symmetrical cell. Furthermore, the LiFePO4-based cell with the additive-functionalized Li anode displays obviously improved cycling stability (with a high specific capacity of 141.1 mAh g-1 after 350 cycles at 1 C).

Laser Ablation Mechanism and Performance of Carbon Fiber-Reinforced Poly Aryl Ether Ketone (PAEK) Composites.

The ablation mechanism and performance of carbon fiber (CF)-reinforced poly aryl ether ketone (PAEK) thermoplastic composites were studied in this paper. The results show that the ablation damaged area is controlled by the irradiation energy, while the mass loss rate is controlled by the irradiation power density. In the ablation center, the PAEK resin and CFs underwent decomposition and sublimation in an anaerobic environment. In the transition zone, the resin experienced decomposition and remelting in an aerobic environment, and massive char leaves were present in the cross section. In the heat-affected zone, only remelting of the resin was observed. The fusion and decomposition of the resin caused delamination and pores in the composites. Moreover, oxygen appeared crucial to the ablation morphology of CFs. In an aerobic environment, a regular cross section formed, while in an anaerobic environment, a cortex-core structure formed. The cortex-core structure of CF inside the ablation pit was caused by the inhomogeneity of fibers along the radial direction and the residual carbon layer generated by resin decomposition in an anoxic environment. The description of the ablation mechanism presented in this study broadens our understanding of damage evolution in thermoplastic composites subjected to high-energy CW laser irradiation.

Eleven undescribed alkaloids from the rhizomes of Sinomenium acutum and their IDO1 and TDO inhibitory activities.

Eleven previously undescribed alkaloids, named sinometumines A-K, along with three known alkaloids, were isolated from the rhizomes of Sinomenium acutum. The chemical structures of these unreported compounds were established using extensive spectroscopic methods (IR, UV, HRESIMS, and NMR), and their absolute configurations were determined by single crystal X-ray diffraction analyses and calculated electronic circular dichroism spectroscopy (ECD). Sinometumine D was the first aporphine-type derived alkaloid inner salt with a rearranged dibenzofuran ring backbone. Sinometumine E was a rare protoberberine-type alkaloid with a complex 6/6/6/6/6/6 hexacyclic skeleton. This was the first report of alkaloids with these two skeletons isolated from S. acutum. All isolates were evaluated for their inhibitory activities against indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). Lysicamine possessed noteworthy inhibitory activities as an IDO1/TDO dual inhibitor with IC50 values of 6.22 ± 0.26 µM and 23.76 ± 2.93 µM, respectively, and liriodenine revealed moderate dual inhibition with IC50 values of 31.65 ± 4.44 µM and 15.64 ± 0.26 µM. The intermolecular interactions and binding modes between lysicamine and IDO1/TDO were elaborated by molecular docking studies.

Andrographolide Inhibits Proliferation and Promotes Apoptosis in Bladder Cancer Cells by Interfering with NF- κ B and PI3K/AKT Signaling In Vitro and In Vivo.

OBJECTIVE: To explore the influences of andrographolide (Andro) on bladder cancer cell lines and a tumor xenograft mouse model bearing 5637 cells. METHODS: For in vitro experiments, T24 cells were stimulated with Andro (0-40 µmol/L) and 5637 cells were stimulated with Andro (0 to 80 µmol/L). Cell growth, migration, and infiltration were assessed using cell counting kit-8, colony formation, wound healing, and transwell assays. Apoptosis rate was examined using flow cytometry. In in vivo study, the antitumor effect of Andro (10 mg/kg) was evaluated by 5637 tumor-bearing mice, and levels of nuclear factor κ B (NF- κ B) and phosphoinositide 3-kinase/AKT related-proteins were determined by immunoblotting. RESULTS: Andro suppressed growth, migration, and infiltraion of bladder cancer cells (P⩽0.05 or P⩽0.01). Additionally, Andro induced intrinsic mitochondria-dependent apoptosis in bladder cancer cell lines. Furthermore, Andro inhibited bladder cancer growth in mice (P⩽0.01). The expression of p65, p-AKT were suppressed by Andro treatment in vitro and in vivo (P⩽0.05 or P⩽0.01). CONCLUSIONS: Andrographolide inhibits proliferation and promotes apoptosis in bladder cancer cells by interfering with NF- κ B and PI3K/AKT signaling in vitro and in vivo.

Detection and Analysis of Microplastics in Human Sputum.

Microplastic pollution is an emerging environmental problem, and little research has focused on its impact on the human body. Based on retrospective case series, the study required participants to fill out a questionnaire and provide sputum samples in order to investigate the presence of microplastics in human sputum and determine whether humans involuntarily inhale them. A total of 22 patients suffering from different respiratory diseases were recruited. We used an Agilent 8700 laser infrared imaging spectrometer and Fourier-transform infrared microscope to analyze sputum samples and evaluate microplastics in the respiratory tract. Remarkably, the size range of the method for detecting microplastics in our study is 20-500 µm. The results showed that 21 types of microplastics were identified, and polyurethane was dominant, followed by polyester, chlorinated polyethylene, and alkyd varnish, accounting for 78.36% of the total microplastics. Most of the aspirated microplastics detected are smaller than 500 µm in size (median: 75.43 µm; interquartile range: 44.67-210.64 µm). Microplastics are ubiquitous in all sputum, indicating that inhalation is a potential way for plastics to enter the human body. Additionally, the quantities of microplastic types in the respiratory tract are related to smoking, invasive examination, etc. (P < 0.05). This study sheds new light on microplastic exposure, which provides basic data for the risk assessment of microplastics to human health.

An Approach for the Synthesis of Pyrazolo[1,5-a]pyrimidines via Cu(II)-Catalyzed [3+3] Annulation of Saturated Ketones with Aminopyrazoles.

A one-step synthesis of diversely substituted pyrazolo[1,5-a]pyrimidines from saturated ketones and 3-aminopyrazoles is presented. This transformation involves the in situ formation of α,ß-unsaturated ketones via a radical process, followed by [3+3] annulation with 3-aminopyrazoles in one pot. Mechanistic studies have shown that the dual C(sp3)-H bond functionalization of inactive ketones is required for the formation of the title compounds. Notably, this dehydrogenative coupling process provides access to a host of functionalized pyrazolo[1,5-a]pyrimidines with antitumor potential from commercially available substrates.

Mechanism of As(III) removal properties of biochar-supported molybdenum-disulfide/iron-oxide system.

Sulfate (SO4•-) and hydroxyl-based (HO•) radical are considered potential agents for As(III) removal from aquatic environments. We have reported the synergistic role of SO4•- and HO• radicals for As(III) removal via facile synthesis of biochar-supported SO4•- species. MoS2-modified biochar (MoS2/BC), iron oxide-biochar (FeOx@BC), and MoS2-modified iron oxide-biochar (MoS2/FeOx@BC) were prepared and systematically characterized to understand the underlying mechanism for arsenic removal. The MoS2/FeOx@BC displayed much higher As(III) adsorption (27 mg/g) compared to MoS2/BC (7 mg/g) and FeOx@BC (12 mg/g). Effects of kinetics, As(III) concentration, temperature, and pH were also investigated. The adsorption of As(III) by MoS2/FeOx@BC followed the Freundlich adsorption isotherm and pseudo-second-order, indicating multilayer adsorption and chemisorption, respectively. The FTIR and XPS analysis confirmed the presence of Fe-O bonds and SO4 groups in the MoS2/FeOx@BC. Electron paramagnetic resonance (EPR) and radical quenching experiments have shown the generation of SO4•- radicals as predominant species in the presence of MoS2 and FeOx in MoS2/FeOx@BC via radical transfer from HO• to SO42-. The HO• and SO4•- radicals synergistically contributed to enhanced As(III) removal. It is envisaged that As(III) initially adsorbed through electrostatic interactions and partially undergoes oxidation, which is finally adsorbed to MoS2/FeOx@BC after being oxidized to As(V). The MoS2/FeOx@BC system could be considered a novel material for effective removal of As(III) from aqueous environments owing to its cost-effective synthesis and easy scalability for actual applications.

Targeting Mutated p53 Dependency in Triple-Negative Breast Cancer Cells Through CDK7 Inhibition.

BACKGROUND: Cyclin-dependent kinase 7 (CDK7) is crucial for cell cycle progression and gene expression transcriptional regulation, which are often not assessed in cancer developing process. CDK7 inhibitors have emerged as promising drugs for treating diverse cancers, including breast cancer. However, the mechanism behind its anticancer effect has not been well investigated. Here, the possible mechanism of CDK7 inhibitors for treating human triple-negative breast cancer (TNBC) has been studied. METHODS: The effects of CDK7 inhibitors on breast cancer cells have been identified by measuring cell viability (Cell Counting Kit-8) and cell proliferation and calculating colony formation. The short hairpin RNA and short interfering RNA were used for the construction of knockdown cells. To assess the expression of associated proteins, western blot was used. RESULTS: This study confirmed that, compared to hormone receptor-positive breast cancer cells, TNBC cells were more sensitive to THZ1, a novel CDK7 inhibitor. THZ1 treatment specifically downregulated mutated p53 in a dose- and time-dependent manner in TNBC cells with p53 mutation. Another CDK7 inhibitor, LDC4297, also potently interfered with the expression of mutated p53. Furthermore, endogenous CDK7 expression was positively correlated with the levels of mutated p53 in TNBC cells with p53 mutation. Downregulating mutated p53 expression significantly suppressed the proliferation of TNBC cells with p53 mutation. CONCLUSION: Our findings demonstrated that targeting CDK7 was an effective approach for the treatment of TNBC with p53 mutation.

IL-6 deficiency promotes colitis by recruiting Ly6Chi monocytes into inflamed colon tissues in a CCL2-CCR2-dependent manner.

Interleukin 6 (IL-6) is a pleiotropic cytokine that is elevated in inflammatory bowel disease. However, the role of IL-6 deficiency in colitis is not well-defined. Some IL-6 and IL-6 receptor antagonists are associated with severe gastrointestinal immune adverse effects, but the mechanisms of the effects are not clear. This study aimed to investigate the effect of IL-6 in ulcerative colitis in Il6-/- mice. Results indicated that physiological deficiency of IL-6 promoted the development of colitis. Moreover, IL-6 deficiency significantly increased the mRNA levels of monocytes chemokine Ccl2 and its receptor Ccr2 in colon tissues. Similarly, the percentage of Ly6Chigh monocytes and neutrophils were increased in the colon of Il6-/- mice. Intestinal crypts more strongly increased the migration of Il6-/- macrophages than wild-type ones. Moreover, Il6-/- macrophages promoted the migration of neutrophils. Most importantly, RS102895, an antagonist of CCR2, diminished chemotaxis of macrophages and inhibited colitis in Il6-/- mice. Collectively, these results indicate that Il6-/- macrophages migrate to inflamed colon tissues and recruit neutrophils, thereby promoting the effect of Il6-/- on colitis. This study expands our understanding on the effect of IL-6 deficiency in colitis and the development of gastrointestinal immune adverse effects.

Measurement and prognosis of frail patients undergoing transcatheter aortic valve implantation: a systematic review and meta-analysis.

OBJECTIVES: Our objectives were to review the literature to identify frailty instruments in use for transcatheter aortic valve implantation (TAVI) recipients and synthesise prognostic data from these studies, in order to inform clinical management of frail patients undergoing TAVI. METHODS: We systematically reviewed the literature published in 2006 or later. We included studies of patients with aortic stenosis, diagnosed as frail, who underwent a TAVI procedure that reported mortality or clinical outcomes. We categorised the frailty instruments and reported on the prevalence of frailty in each study. We summarised the frequency of clinical outcomes and pooled outcomes from multiple studies. We explored heterogeneity and performed subgroup analysis, where possible. We also used Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to assess the overall certainty of the estimates. RESULTS: Of 49 included studies, 21 used single-dimension measures to assess frailty, 3 used administrative data-based measures, and 25 used multidimensional measures. Prevalence of frailty ranged from 5.67% to 90.07%. Albumin was the most commonly used single-dimension frailty measure and the Fried or modified Fried phenotype were the most commonly used multidimensional measures. Meta-analyses of studies that used either the Fried or modified Fried phenotype showed a 30-day mortality of 7.86% (95% CI 5.20% to 11.70%) and a 1-year mortality of 26.91% (95% CI 21.50% to 33.11%). The GRADE system suggests very low certainty of the respective estimates. CONCLUSIONS: Frailty instruments varied across studies, leading to a wide range of frailty prevalence estimates for TAVI recipients and substantial heterogeneity. The results provide clinicians, patients and healthcare administrators, with potentially useful information on the prognosis of frail patients undergoing TAVI. This review highlights the need for standardisation of frailty measurement to promote consistency. PROSPERO REGISTRATION NUMBER: CRD42018090597.

Subcutaneous Face and Neck lift: A Traditional Method With Definite Effects Among Asians.

BACKGROUND: The mainstream facelifts in Western countries always involve the superficial fascia/superficial musculoaponeurotic system treatment. Meanwhile, subcutaneous face and neck lifts are widely applied among Asians. OBJECTIVES: The authors sought to evaluate outcomes of subcutaneous face and neck lift, including patient-reported and 3-dimensional (3D) measurement outcomes, and report on details of surgical procedures. METHODS: Patients who received a subcutaneous face and neck lift from January 2017 to June 2019 were asked to complete FACE-Q scales, and facial information was collected by the Vectra 3D imaging system preoperatively and postoperatively. Volume changes in midface and possible displacement of facial landmarks were measured. The range of dissection and the amount of skin removed were recorded intraoperatively. RESULTS: In total, 119 patients (median age, 46 years, interquartile range, 40-53 years) received a subcutaneous face and neck lift. Among them, 88 patients completed pre- and postoperative FACE-Q scales. Patients' satisfaction with facial subunits improved and wrinkles were significantly relieved (P < 0.001). Nineteen patients (38 midface sides) completed 3D image data collection. Postoperatively, zygomatic volume increased, and nasolabial and lateral cheek volumes decreased (volume change of 2.2 ±â€…1.3 mL). Mouth, nose, and eye displacements were negligible postoperatively. The widths of skin removed at the middle temporal, front of the sideburns, upper helix, earlobe, and retro-auricular were 13.8 ±â€…1.9 mm, 19.6 ±â€…3.1 mm, 27.6 ±â€…3.9 mm, 16.4 ±â€…3.9 mm, and 32.2 ±â€…4.0 mm, respectively. CONCLUSIONS: The authors' subcutaneous face and neck lift was effective in relieving nasolabial sagging, improving wrinkles, and achieving facial rejuvenation.

Andrographolide sensitizes human renal carcinoma cells to TRAIL­induced apoptosis through upregulation of death receptor 4.

Tumor necrosis factor­related apoptosis­inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, with minimal toxicity to normal tissues. However, accumulating evidence suggests that certain cancer types are insensitive to TRAIL signaling. The aim of this study was to identify an effective combination regimen, which can overcome TRAIL resistance in renal cancer cell. Herein, we found that human renal carcinoma cells (RCCs) are widely resistant to TRAIL­mediated growth inhibition and subsequently identified that andrographolide (Andro), a major constituent of Andrographis paniculate, an annual herbaceous plant in the family Acanthaceae, counteracts TRAIL resistance in RCCs. Combined treatment with TRAIL and Andro suppressed cell viability as determined by MTS and proliferation as determined by EdU in a dose­dependent manner and inactivated the clonogenic and migration ability of RCCs. Andro significantly enhances TRAIL­mediated cell cycle arrest at the G2/M phase as determined by flow cytometry and senescence. Moreover, Andro restored TRAIL signaling, which in turns activated pro­apoptosis caspases as determined by immunoblot assay. The TRAIL receptor, death receptor (DR)4, but not DR5, was found to be significantly upregulated in Andro­treated RCC cells, which contributed to the role of Andro as a TRAIL sensitizer. The present study demonstrated that the combined treatment of Andro and TRAIL has potential therapeutic value against renal cancer.

DTI-based radiomics signature for the detection of early diabetic kidney damage.

OBJECTIVE: To explore whether a radiomics signature based on diffusion tensor imaging (DTI) can detect early kidney damage in diabetic patients. MATERIALS AND METHODS: Twenty-eight healthy volunteers (group A) and thirty type 2 diabetic patients (group B) with micro-normoalbuminuria, a urinary albumin-to-creatinine ratio (ACR) < 30 mg/g and an estimated glomerular filtration rate (eGFR) of 60-120 mL/(min 1.73 m2) were recruited. Kidney DTI was performed using 1.5T magnetic resonance imaging (MRI).The radiologist manually drew regions of interest (ROI) on the fractional anisotropy (FA) map of the right kidney ROI including the cortex and medulla. The texture features of the ROIs were extracted using MaZda software. The Fisher coefficient, mutual information (MI), and probability of classification error and average correlation coefficient (POE + ACC) methods were used to select the texture features. The most valuable texture features were further selected by the least absolute shrinkage and selection operator (LASSO) algorithm. A LASSO regression model based on the radiomics signature was established. The diagnostic performance of the model for detecting early diabetic kidney changes was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). Empower (R), R, and MedCalc15.8 software were used for statistical analysis RESULTS: A total of 279 texture features were extracted from ROI of the kidney, and 30 most valuable texture features were selected from groups A and B using MaZda software. After LASSO-logistic regression, a diagnostic model of diabetic kidney damage based on texture features was established. Model discrimination evaluation: AUC = 0.882 (0.770 ± 0.952). Model calibration evaluation: Hosmer-Lemeshow X2 = 5.3611, P = 0.7184, P > 0.05, the model has good calibration. CONCLUSION: The texture features based on DTI could play a promising role in detecting early diabetic kidney damage.

Quantitative Proteome Landscape of the NCI-60 Cancer Cell Lines.

Here we describe a proteomic data resource for the NCI-60 cell lines generated by pressure cycling technology and SWATH mass spectrometry. We developed the DIA-expert software to curate and visualize the SWATH data, leading to reproducible detection of over 3,100 SwissProt proteotypic proteins and systematic quantification of pathway activities. Stoichiometric relationships of interacting proteins for DNA replication, repair, the chromatin remodeling NuRD complex, ß-catenin, RNA metabolism, and prefoldins are more evident than that at the mRNA level. The data are available in CellMiner (discover.nci.nih.gov/cellminercdb and discover.nci.nih.gov/cellminer), allowing casual users to test hypotheses and perform integrative, cross-database analyses of multi-omic drug response correlations for over 20,000 drugs. We demonstrate the value of proteome data in predicting drug response for over 240 clinically relevant chemotherapeutic and targeted therapies. In summary, we present a novel proteome resource for the NCI-60, together with relevant software tools, and demonstrate the benefit of proteome analyses.

A second open reading frame in human enterovirus determines viral replication in intestinal epithelial cells.

Human enteroviruses (HEVs) of the family Picornaviridae, which comprises non-enveloped RNA viruses, are ubiquitous worldwide. The majority of EV proteins are derived from viral polyproteins encoded by a single open reading frame (ORF). Here, we characterize a second ORF in HEVs that is crucial for viral intestinal infection. Disruption of ORF2p expression decreases the replication capacity of EV-A71 in human intestinal epithelial cells (IECs). Ectopic expression of ORF2p proteins derived from diverse enteric enteroviruses sensitizes intestinal cells to the replication of ORF2p-defective EV-A71 and respiratory enterovirus EV-D68. We show that the highly conserved WIGHPV domain of ORF2p is important for ORF2p-dependent viral intestinal infection. ORF2p expression is required for EV-A71 particle release from IECs and can support productive EV-D68 infection in IECs by facilitating virus release. Our results indicate that ORF2p is a determining factor for enteric enterovirus replication in IECs.