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Background: Previous research has underscored the correlation between Alzheimer's disease (AD) and erectile dysfunction (ED). However, due to inherent limitations of observational studies, the causative relationship remains inconclusive. Methods: Utilizing publicly available data from genome-wide association studies (GWAS) summary statistics, this study probed the potential causal association between AD and ED using univariate Mendelian randomization (MR). Further, the multivariable MR assessed the confounding effects of six cardiovascular diseases (CVDs). The primary approach employed was inverse variance weighted (IVW), supplemented by three additional methods. A series of sensitivity analyses were conducted to ensure the robustness of the results. Results: In the forward MR analysis, the IVW method revealed causal evidence of genetically predicted AD being a risk factor for ED (OR = 1.077, 95% CI 1.007∼1.152, P = 0.031). Reverse analysis did not demonstrate any causal evidence linking ED to AD (OR = 1.018, 95% CI 0.974∼1.063, P = 0.430). Multivariable MR analysis showed that after adjusting for coronary heart disease (OR = 1.082, 95% CI 0.009∼1.160, P = 0.027), myocardial infarction (OR = 1.085, 95% CI 1.012∼1.163, P = 0.022), atrial fibrillation (OR = 1.076, 95% CI 1.002∼1.154, P = 0.043), heart failure (OR = 1.103, 95% CI 1.024∼1.188, P = 0.010), ischemic stroke (OR = 1.079, 95% CI 1.009∼1.154, P = 0.027), hypertension (OR = 1.092, 95% CI 1.011∼1.180, P = 0.025), and all models (OR = 1.115, 95% CI 1.024∼1.214, P = 0.012), the causal association between AD and ED persisted. Sensitivity analyses confirmed the absence of pleiotropy, heterogeneity, and outliers, validating the robustness of our results (P > 0.05). Conclusions: This MR study consistently evidences a causal effect of genetically predicted AD on the risk of ED, independent of certain CVDs, yet offers no evidence for a reverse effect from ED. [ABSTRACT FROM AUTHOR]

Ionic liquid salts (ILs) are generally recognized as additives in perovskite precursor solutions to enhance the efficiency and stability of solar cells. However, the success of ILs incorporation as additives is highly dependent on the precursor formulation and perovskite crystallization process, posing challenges for industrial‐scale implementation. In this study, a room‐temperature spin‐coated IL, n‐butylamine acetate (BAAc), is identified as an ideal passivation agent for formamidinium lead iodide (FAPbI3) films. Compared with other passivation methods, the room‐temperature BAAc capping layer (BAAc RT) demonstrates more uniform and thorough passivation of surface defects in the FAPbI3 perovskite. Additionally, it provides better energy level alignment for hole extraction. As a result, the champion n–i–p perovskite solar cell with a BAAc capping layer exhibits a power conversion efficiency (PCE) of 24.76%, with an open‐circuit voltage (Voc) of 1.19 V, and a Voc loss of ≈330 mV. The PCE of the perovskite mini‐module with BAAc RT reaches 20.47%, showcasing the effectiveness and viability of this method for manufacturing large‐area perovskite solar cells. Moreover, the BAAc passivation layer also improves the long‐term stability of unencapsulated FAPbI3 perovskite solar cells, enabling a T80 lifetime of 3500 h when stored at 35% relative humidity at room temperature in an air atmosphere. [ABSTRACT FROM AUTHOR]

Spiro‐OMeTAD is one of the most used hole transport layers (HTLs) in high efficiency n‐i‐p perovskite solar cells (PSCs). However, due to the unsatisfactory conductivity of pristine Spiro‐OMeTAD, additives such as tert‐butylpyridine (tBP) and lithium bis (trifluoromethylsulfonyl)‐imide (LiTFSI) are required to improve its hole transportation. The hygroscopic nature of these additives inevitably deteriorates the device's stability. Here, it is shown that by adding fluorinated graphene (FG) into the Li‐TFSI and tBP doped Spiro‐OMeTAD, both efficiency and stability of the PSCs are significantly enhanced. Using the FG incorporated Spiro‐OMeTAD HTL, the power conversion efficiency (PCE) of the PSC reaches 21.92%, which is 11.8% higher than the original device. The FG not only improves the hole mobility of Spiro‐OMeTAD but also effectively reduces the amount of lithium ions in the perovskite layer and improves the hydrophobicity of the HTL. The FG incorporating cell shows better stability, maintaining 90% of initial efficiency over a 2400 h test in ambient conditions with 25% humidity. Finally, it is further demonstrated that the valence band of FG incorporated Spiro‐OMeTAD HTL has a positive effect on PSCs with a 2D interfacial layer, achieving an impressive PCE of 23.14% and a Voc of 1.226 V. [ABSTRACT FROM AUTHOR]

SnO2 has been universally applied as electron transporting layer (ETL) towards the fabrication of highly efficient perovskite solar cells (PSCs), owing to its unique advantages including low‐temperature solution‐processability, high optical, transmittance and good electrical conductivity. Uncoordinated Sn‐dangling bonds on SnO2 surface exist as deep traps to capture the photogenerated carriers, causing hysteresis and device instability. Fullerene derivatives, though being widely utilized as the passivator for SnO2, are highly prone to self‐aggregate due to their π‐cage structures, which hampers passivation. Herein, π‐conjugated n‐type small molecules with better film formation ability are innovatively designed, to improve passivation effectiveness. By exploring the interplay between molecular stacking of small molecules and charge transporting/recombination dynamics at the SnO2/perovskite interface, it is unveiled that a more compact molecular packing of the organic passivators yields superior interfacial characteristics, in terms of fewer trap states, lower charge recombination and higher electron transporting efficiency. An impressive PCE over 23% is achieved with the assistance of this new‐type SnO2‐passivator, which is among the highest reported value for triple‐cation perovskite systems to date. This work offers an original concept for the design and synthesis of ETL passivators towards the development of high performance and stable PSCs. [ABSTRACT FROM AUTHOR]

Cell migration is important for renal recovery from tubular cell injury. Heat shock transcription factor 1 (HSF1) is a well-studied regulatory factor that is active during acute kidney injury. HSF1 is also involved in the migration process during tumor metastasis. Therefore, we hypothesized that HSF1 may promote the recovery of renal function by affecting kidney tubular cell migration. A wound healing assay was used to examine the cell migration rate. The results demonstrated that the migration of rat kidney proximal tubular cells (RPTCs) was increased following knockdown of HSF1. In addition, the invasion ability of HSF1 knockdown RPTCs was also significantly upregulated. The present study also identified that transforming growth factor-β1 (TGF-β1) was highly expressed at the edge of the wound in control cells, and its expression was further increased upon knockdown of HSF1. Inhibition of TGF-β1 signaling prevented RPTC HSF1 knockdown cell migration, suggesting that HSF1-regulated RPTC cell migration was dependent on the TGF-β1 signaling pathway. Furthermore, phosphorylation of TGF-β1 and Smad2/3 was induced in HSF1 knockdown cells. Together, these results suggest that HSF1 may suppress RPTC migration by inhibiting the activation of the TGF-β1-Smad2/3 signaling pathway. [ABSTRACT FROM AUTHOR]

The development of machine vision demands accurate image capture under different lighting conditions, which is crucial for perceiving the environment correctly. In this paper, we present a human-eye-inspired sensor based on quasi-two-dimensional perovskite and indium gallium zinc oxide phototransistor array. The sensor exhibits a light detection limit as low as 6.1 nW/cm2 with a responsivity of 5 × 105 A/W, capable of perceiving light in visible spectrum range. It demonstrates light adaptation under both dim and illuminated conditions, enhancing the contrast between images and ambient light, while achieving a dynamic range of 162 dB. [ABSTRACT FROM AUTHOR]

OCILRP2 is a typical Type-II transmembrane protein that is selectively expressed in activated T lymphocytes, dendritic cells, and B cells and functions as a novel co-stimulator of T cell activation. However, the signaling pathways underlying OCILRP2 in T cell activation are still not completely understood. In this study, we found that the knockdown of OCILRP2 expression with shRNA or the blockage of its activity by an anti-OCILRP2 antagonist antibody reduced CD3/CD28-costimulated EL4 T cell viability and IL-2 production, inhibit Raf1, MAPK3, and MAPK8 activation, and impair NFAT and NF-κB transcriptional activities. Furthermore, immunoprecipitation results indicated that OCILRP2 could interact with the DAP12 protein, an adaptor containing an intracellular ITAM motif that can transduce signals to induce MAP kinase activation for T cell activation. Our data reveal that after binding with DAP12, OCILRP2 activates the Raf-MAP kinase pathways, resulting in T cell activation. [ABSTRACT FROM AUTHOR]

In order to more accurately predict an individual's health status, in clinical applications it is often important to perform analysis of high-dimensional gene expression data that varies with time. A major challenge in predicting from such temporal microarray data is that the number of biomarkers used as features is typically much larger than the number of labeled subjects. One way to address this challenge is to perform feature selection as a preprocessing step and then apply a classification method on selected features. However, traditional feature selection methods cannot handle multivariate temporal data without applying techniques that flatten temporal data into a single matrix in advance. In this study, a feature selection filter that can directly select informative features from temporal gene expression data is proposed. In our approach, we measure the distance between multivariate temporal data from two subjects. Based on this distance, we define the objective function of temporal margin based feature selection to maximize each subject's temporal margin in its own relevant subspace. The experimental results on synthetic and two real flu data sets provide evidence that our method outperforms the alternatives, which flatten the temporal data in advance. [ABSTRACT FROM AUTHOR]

Abstract: It has been reported that mesenchymal stem cells (MSCs) can transdifferentiate into Schwann cell-like cells by a series of treatments with a reducing agent, retinoic acid and a combination of trophic factors in vitro, and can transdifferentiate into myelin-forming cells to repair the demyelinated rat spinal cord in vivo. We now report that when co-cultured with dorsal root ganglion (DRG) neurons, MSCs were induced to transdifferentiate into Schwann cell-like cells that had ensheathed DRG axons. Following differentiation, MSCs underwent morphological changes similar to those of cultured Schwann cells and express GFAP and S100, the marker of Schwann cells. Moreover, 6 weeks later, MSCs wrapped their membrane around DRG axons. Further, initiation of myelination was observed in the co-cultured DRG neurons, which was determined by signals to MBP and this initiation of axon myelination by MSCs is similar to that of Schwann cells. However, electron micrographs show that no compact myelin was present in the MSCs co-cultures, whereas the Schwann cells co-cultures had formed a multilammelar myelin sheath around the axon. These indicate that the release of cytokine by DRG neurons may promote the transdifferentiation of MSCs, but is not sufficient to elicit compact myelination by transdifferentiated MSCs. These results improve our understanding in the mechanism of MSC transdifferentiation, and the mechanism underlying ensheathment and myelination by transdifferentiated MSCs. [Copyright &y& Elsevier]

Abstract: Protein antigens have been covalently linked randomly to surface proteins on immature dendritic cells (DC). This has been achieved under physiological conditions using a heterobifunctional reagent that couples antigens to free thiol groups expressed on DC surface proteins. This results in a significant increase in the amount of antigen that is bound to DC, and the antigen/membrane protein complexes that are formed are rapidly internalized. DC, loaded covalently with either β-galactosidase (β-gal) or a tumor-associated immunoglobulin (Ig) when injected into mice, induce a β-gal- or Ig-specific T cell response, and a protective anti-tumor immunity for tumors expressing either β-gal or the targeted Ig. This response is shown here to be significantly greater than that which is induced by DC that are loaded with these antigens via the conventional antigen pulse protocol. These results establish a novel, safe, and viable approach of enhancing the effectiveness of DC-based vaccination strategies for B cell lymphoma. [Copyright &y& Elsevier]

Clinical efficacy and complications of nickel-titanium memory alloy in the treatment of multiple rib fractures combined with sternal fractures was investigated. A retrospective analysis of 123 patients with multiple rib fractures combined with sternal fractures admitted to First People's Hospital of Fuzhou from January 2013 to December 2015 was performed, including study group (treated with internal fixation by the nickel-titanium memory alloy, n=68) and control group (treated with internal fixation by partial pressure bandage, n=55). Μean arterial pressure (MAP), heart rate (HR), and visual analogue pain score (VAS) of the two groups before and after treatment were compared and analyzed. No significant difference in MAP, HR and VAS scores between groups was detected before treatment (P>0.05). After treatment, MAP score of study group was significantly higher, and HR and VAS scores were significantly lower (P<0.05). Μethod of internal fixation by the nickel-titanium memory alloy, with better efficacy than the traditional method of internal fixation by partial pressure bandage and less postoperative complications in the treatment of flail chest caused by multiple rib fractures combined with sternal fractures, is worthy of clinical application and promotion. [ABSTRACT FROM AUTHOR]

Monolithic integration of perovskite materials and their optoelectronic devices with well‐developed thin‐film transistor (TFT) backplane is leading to new applications in displays and image sensors. Herein, a scalable polyimide assisted patterning approach for monolithic integration of perovskite based high‐sensitive phototransistor array on indium gallium zinc oxide (IGZO) active matrix backplane is introduced. Polyimide vias are first formed by conventional photolithography process, through which uniform perovskite films of arbitrary patterns with feature size less than 20 µm are fabricated by spin‐on‐patterning method. Using this technique, patterns of quasi 2D perovskite photoabsorbing layer are precisely deposited onto the channel area of the photosensing IGZO TFT, forming high‐performance phototransistors with responsivity and detectivity reaching 835.7 A W−1 and 5.4 × 1012 Jones, respectively. An image sensor with 8 × 8 pixels array containing both photosensing perovskite/IGZO transistors and switching IGZO transistors is demonstrated, in which the switching IGZO transistor elements on the backplane are protected by the non‐patterned region of the polyimide encapsulation layer. This whole fabrication process is compatible with TFT manufacturing process and will significantly reduce the cost needed for constructing next generation high‐resolution image sensors. [ABSTRACT FROM AUTHOR]

Cornus officinalis var. koreana Kitam (Cornus officinalis) is a commonly used Chinese herbal medicine and has a good clinical efficacy in kidney and liver diseases. Recent years, a number of studies reported the significant effects of Cornus officinalis on renal fibrosis. However, it is still unclear about the underlying specific mechanism, the bioactive ingredients, and the target gene regulatory network. Aim of the study : We investigated the impact of Cornus officinalis extract on cadmium-induced renal fibrosis, screened the bioactive ingredients of Cornus officinalis using a pharmacological sub-network analysis, and explored the regulatory effects of Cornus officinalis extracts on target gene matrix metallopeptidase 9 (MMP9). Male C57BL/6N mice were treated with single or combinatorial agents such as saline, cadmium chloride, Cornus officinalis , Isoginkgetin and FSL-1. Isoginkgetin is a compound with anti-MMP9 activity. FSL-1 can induce MMP9 expression. Masson staining and Western blot and immunohistochemistry analyses were used for assessing renal fibrosis. In addition, wound healing model was established using BUMPT (Boston university mouse proximal tubular) cells to investigate how Cornus officinalis affected cadmium-induced cell migration. The main Cornus officinalis bioactive compounds were identified by UHPLC-MS (Ultra-high-performance liquid chromatography - mass spectrometry). The MMP9 target for Cornus officinalis active ingredients were confirmed through a pharmacological sub-network analysis. Aqueous extracts of Cornus officinalis protected from renal dysfunction and kidney fibrosis induced by cadmium chloride in mice. In vitro experiments validated that Cornus officinalis extracts inhibited cell migration ability especially in cadmium chloride condition. The sub-network analysis and chemical components profiling technique revealed the active compounds of Cornus officinalis. Cellular thermal shift assay verified the binding abilities of three active components Daidzein, N-Acetyl-L-tyrosine or Swertisin with matrix metalloproteinase-9. Gelatin zymography assay revealed that the activity of MMP9 was inhibited by the three active components. We further confirmed that MMP9 was involved in the process of Cornus officinalis extracts reducing renal fibrosis. Cornus officinalis attenuated the cadmium-induced renal fibrosis was correlated with decreased expression of MMP9, collagen I, α-SMA (alpha-smooth muscle actin) and vimentin. This study demonstrated that Cornus officinalis extracts could alleviate the cadmium chloride-induced renal fibrosis by targeting MMP9, and might provide new insights into the mechanism of treating renal fibrosis by Cornus officinalis. [Display omitted] • Three natural products of Cornus officinalis extracts bind with murine MMP9 and inhibit its activity. • MMP9 was identified as main molecular target of Cornus officinalis by network pharmacological analysis. • MMP9 was involved in cadmium chloride-induced renal fibrosis. • Cornus officinalis extracts protected from renal dysfunction and kidney fibrosis through regulating MMP9. [ABSTRACT FROM AUTHOR]

The electron transport layer (ETL) has an important influence on the power conversion efficiency (PCE) and stability of n‐i‐p planar perovskite solar cells (PSCs). This paper presents an N‐type semiconductor material, (CH3)2Sn(COOH)2 (abbreviated as CSCO) that is synthesized and prepared for the first time as an ETL for n‐i‐p planar PSCs, which leads to a high PCE of 22.21% after KCl treatment, one of the highest PCEs of n‐i‐p planar PSCs to date. Further analysis reveals that the high PCE is attributed to the excellent conductivity of CSCO because of its more delocalized electron cloud distribution due to its unique −O=C−O− group, and to the defect passivation of the Cs0.05(FA0.85MA0.15)0.95Pb(I0.85Br0.15)3 (denoted as CsFAMA) perovskite through the interaction between the O (Sn) atoms of CSCO and the Pb (halogen) atoms of CsFAMA at CSCO/CsFAMA interface, while the traditional ETL materials such as SnO2 film lack this function. In addition to the high PCE, the optimal PSCs using CSCO as ETL show remarkable stability, retaining over 83% of its initial PCE without encapsulation after 130 days of storage in ambient conditions (≈25 °C at ≈40% humidity), much better than the traditional SnO2‐based n‐i‐p PSCs. [ABSTRACT FROM AUTHOR]

[Display omitted] • An optimal cadmium-induced acute kidney injury mouse model was established. • Tim-3 deficiency enhanced cadmium nephrotoxicity. • The NF-κB inhibitor TPCA-1 alleviated cadmium nephrotoxicity in Tim-3 KO mice. • Tim-3 deficiency promoted cadmium-induced mitochondrial Bax translocation. • TPCA-1 decreased the mitochondrial Bax translocation in Tim3 KO mice. Kidney is the target organ of serious cadmium injury. Kidney damage caused by cadmium exposure is greatly influenced by the inflammatory response and mitochondrial damage. T cell immunoglobulin domain and mucin domain 3 (Tim-3) is an essential protein that functions as a negative immunological checkpoint to regulate inflammatory responses. Mice were given cadmium treatments at various dosages (0, 1.5, 3, 4.5 mg/kg) and times (0, 3, 5, 7 days) to assess the effects of cadmium on kidney damage. We found that the optimal way to induce kidney injury in mice was to inject 4.5 mg/kg of cadmium intraperitoneally for five days. It is interesting that giving mice 4.5 mg/kg of cadmium intravenously for seven days drastically lowered their survival rate. After cadmium exposure, Tim-3 knockout mice exhibited higher blood concentrations of urea nitrogen and creatinine compared to control mice. Tim-3 impacted the expression of oxidative stress-associated genes such as UDP glucuronosyltransferase family 1 member A9 (Ugt1a9), oxidative stress-induced growth inhibitor 2 (Osgin2), and S100 calcium binding protein A8 (S100a8), according to RNA-seq and real-time RT-PCR data. Tim-3 deficiency also resulted in activated nuclear factor-kappa B (NF-κB) signaling pathway. The NF-κB inhibitor 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) significantly alleviated cell apoptosis, oxidative stress response, and renal tubule inflammation in Tim-3 knockout mice exposed to cadmium. Furthermore, cadmium caused obvious B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) translocation from cytoplasm to mitochondria, which can be inhibited by TPCA-1. In conclusion, Tim-3 prevented mitochondrial damage and NF-κB signaling activation, hence providing protection against cadmium nephrotoxicity. [ABSTRACT FROM AUTHOR]

To improve the power conversion efficiency (PCE) and stability of inverted perovskite solar cells (PSCs) prepared in humid air (RH = 55%), a new zinc oxide (ZnO):TIPD composite film is inserted between PCBM layer and Ag electrode for the first time. Compared to the single PCBM layer, the formed PCBM/ZnO:TIPD electron transport layer (ETL) has better coverage on the perovskite layer and more effective charge extraction ability from the perovskite layer. The insertion of ZnO:TIPD film effectively suppress the charge recombination at perovskite/ETL interface. Besides, the PCBM/ZnO:TIPD layer has better ability to prevent moisture from penetrating into the perovskite layer than single PCBM film. For these reasons, the PCE and stability of the PSCs with the PCBM/ZnO:TIPD are significantly improved compared to the PSCs with single PCBM (or ZnO:TIPD) layer. The highest efficiency of the cell with PCBM/ZnO:TIPD ETL reaches (13.7 ± 0.4)% in ambient atmosphere, which is 1.20 times that of the PSCs with PCBM only. • The ZnO:TIPD composite film are fabricated for the first time. • The effect of the ZnO:TIPD film on charge separation and extraction is studied. • The efficiency and stability of the perovskite solar cells are significantly improved. [ABSTRACT FROM AUTHOR]

HSF1-mediated heat shock response is activated in most tumors and plays important roles in regulating tumor homeostasis. However, the signals underlying HSF1 activation is still not completely understood. In this paper, we find that glucose, the dominant tumor energy supplement, participates in regulating HSF1's activation in HCC cell lines. The immunoblotting results indicate that the phosphorylation of HSF1/S326, a hallmark of HSF1 activation, varies between the HCC cell lines (e.g., SMMC7721, HapG2, plc/prf5, and Chang-liver). Glucose, but not 2D-glucose, can induce the phosphorylation of HSF1 at S326 and upregulate the expression of HSF1's downstream alpha B-crystallin and Hsp70 as well as the none-heat shock proteins CSK2 and RBM23 in two tested hepatocellular carcinoma cell lines (prl/prf5 and SMMC7721). Rapamycin, an inhibitor of mTOR, can suppress the glucose-induced phosphorylation of HSF1/S326 and the expression of alpha B-crystallin. Knockdown of HSF1 with shRNA enhances the glucose-depletion-mediated inhibition of plc/prf5 cell proliferation. Our data reveal that HSF1 can be activated by glucose-mTOR pathway, providing an alternative pathway for targeting HSF1 in tumor therapy. [ABSTRACT FROM AUTHOR]

The interplay between Hsf4 and Hsf1 plays an important role in the regulation of lens homeostasis. However, the mechanism of the intermolecular association involved is still unclear. In this paper, we find that reconstitution of Hsf4b into Hsf4 −/− lens epithelial (mLEC/Hsf4 −/− ) cells can simultaneously downregulate Hsp70 expression and upregulate the expression of small heat shock proteins Hsp25 and αB-crystallin at both RNA and protein levels. ChIP assay results indicate Hsf4b, which binds to the promoters of Hsp90α, Hsp70.3, Hsp25 and αB-crystallin but not Hsp70.1, can inhibit Hsf1 binding to Hsp70.3 promoter and the heat shock mediated Hsp70 promoter activity by reducing Hsf1 protein expression. Hsf4b N-terminal hydrophobic region can interact with Hsf1 N-terminal hydrophobic region. Their interaction impairs Hsf1's intramolecular interaction between the N- and C-terminal hydrophobic regions, leading to Hsf1's cytosolic retention and protein degradation. Both lysosome inhibitors (chloroquine, pepstatin A plus E64d) and proteasome inhibitor MG132 can inhibit Hsf4-mediated Hsf1 protein degradation, but MG132 can induce Hsf1 activation as well. Upregulation of Hsf4b can significantly inhibit cisplatin and staurosporine induced lens epithelial cell apoptosis through direct upregulation of Hsp25 and αB-crystallin expression. Taken together, our results imply that upregulation of Hsf4b modulates the expression pattern of heat shock proteins in lens tissue by either directly binding to their promoters or promoting Hsf1 protein degradation. Moreover, upregulation of Hsf4b protects lens cell survival by upregulating anti-apoptotic pathways. These studies reveal a novel regulatory mechanism between Hsf1 and Hsf4b in modulating lens epithelial cell homeostasis. [ABSTRACT FROM AUTHOR]

Aims: The asymptomatic nature of early-stage esophageal squamous cell carcinoma (ESCC) results in late presentation and consequent dismal prognosis This study characterized 14-3-3σ protein expression in the multi-stage development of ESCC and determined its correlation with clinical features and prognosis. Materials and Methods: Western blot was used to examine 14-3-3σ protein expression in normal esophageal epithelium (NEE), low grade intraepithelial neoplasia (LGIN), high grade intraepithelial neoplasia (HGIN), ESCC of TNM I to IV stage and various esophageal epithelial cell lines with different biological behavior. Immunohistochemistry was used to estimate 14-3-3σ protein in 110 biopsy samples of NEE, LGIN or HGIN and in 168 ESCC samples all of whom had follow-up data. Support vector machine (SVM) was used to develop a classifier for prognosis. Results: 14-3-3σ decreased progressively from NEE to LGIN, to HGIN, and to ESCC. Chemoresistant sub-lines of EC9706/PTX and EC9706/CDDP showed high expression of 14-3-3σ protein compared with non-chemoresistant ESCC cell lines and immortalized NEC. Furthermore, the downregulation of 14-3-3σ correlated significantly with histological grade (P = 0.000) and worse prognosis (P = 0.004). Multivariate Cox regression analysis indicated that 14-3-3σ protein (P = 0.016) and T stage (P = 0.000) were independent prognostic factors for ESCC. The SVM ESCC classifier comprising sex, age, T stage, histological grade, lymph node metastasis, clinical stage and 14-3-3σ, distinguished significantly lower- and higher-risk ESCC patients (91.67% vs. 3.62%, P = 0.000). Conclusions: Downregulation of 14-3-3σ arises early in the development of ESCC and predicts poor survival, suggesting that 14-3-3σ may be a biomarker for early detection of high-risk subjects and diagnosis of ESCC. Our seven-feature SVM classifier for ESCC prognosis may help to inform clinical decisions and tailor individual therapy. [ABSTRACT FROM AUTHOR]

Abstract: Hsf4b, a key regulator of postnatal lens development, is subjected to posttranslational modifications including phosphorylation. However, the phosphorylation sites in Hsf4b and their biological effects on the transcription activity of Hsf4b are poorly understood. Here we examined 17 potential phosphorylation residues in Hsf4b with alanine-scanning assays and found that a T472A mutation diminished Hsf4b-mediated expression of Hsp25 and αB-crystallin. In contrast, the phosphomimetic mutation of T472D enhanced their expression. Further investigation demonstrated that Hsf4b could interact with nuclear-transporter importin β-1 and Hsc70 via amino acids 246–320 and 320–493, respectively. T472A mutation reduced Hsf4b's interaction with importin β-1, while enhancing its interaction with Hsc70, resulting in Hsf4b cytosolic re-localization, protein instability and transcription activity attenuation. At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphorylation of Hsf4b at T472 by protein kinases such as MEK6 regulates Hsf4b interaction with the importin β-1-Hsc70 complex, resulting in blockade of its nuclear translocation and transcriptional activity of Hsf4b. [Copyright &y& Elsevier]

Abstract: 16S rRNA methylase-mediated high-level resistance to aminoglycosides has been reported recently in clinical isolates of Gram-negative bacilli from several countries. Twenty-one (6.2%, 21/337) of 337 isolates of Klebsiella pneumoniae from a teaching hospital in Wenzhou, China, were positive for 16S rRNA methylase genes (3 for armA, 13 for rmtB, 5 for both armA and rmtB) and highly resistant to gentamicin, amikacin, and tobramycin (MICs, ≥256 μg/mL). Nineteen of 21 isolates harboring 16S rRNA methyalse genes were extended-spectrum β-lactamase (ESBL) producers. The plasmids harboring 16S rRNA methylase genes from 14 of 21 donors were transferred into the recipients, Escherichia coli J53. The armA and the rmtB usually coexisted with ESBL genes in the same isolate in clinical isolates and cotransferred with ESBL genes on a self-transmissible conjugative plasmid to the recipients. Among 5 isolates harboring both armA and rmtB, the armA genes were located on the chromosomes, and the rmtB genes were located on the plasmids, as determined by Southern hybridization. The result of pulsed-field gel electrophoresis showed that horizontal gene transfer and clonal spread were responsible for the dissemination of the rmtB and the armA genes. 16S rRNA methylase-producing isolates of Klebsiella pneumoniae were commonly identified in the Chinese teaching hospital with coexistence of rmtB and armA genes in the same isolate. [Copyright &y& Elsevier]