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Microbial metabolites induce diverse plant physiological responses. In this study, Pseudomonas aeruginosa strain Y1 was shown to produce metabolites exhibiting a high capacity for metal chelation and moderate reducing power activity. In Phalaenopsis orchids, treatments with Y1 metabolites (Y1M) increased the contents of carbohydrates and lignin and the activity of antioxidant enzymes and phenylalanine ammonia lyase (PAL). Y1M treatments increased the tolerance to cold stress (10°C) by reducing malondialdehyde (MDA) accumulation and electrolyte leakage in a 10°C growth environment and enhanced disease resistance against bacterial soft rot caused by Erwinia chrysanthemi. Protein analyses indicated that, in response to Y1M treatment, the protein levels of antioxidant enzymes, such as catalase (CAT) and ascorbate peroxidase (APX); pathogenesis-related (PR) proteins, such as PR-2 and PR-3; and lipoxygenase 1 (LOX1) were increased in Phalaenopsis orchids. Transcriptome analyses indicated that Y1M increased transcription associated with the iron-deficient response mediated by miRNA, the regulation of reactive oxygen species (ROS) homeostasis, and Jasmonic acid (JA) biosynthesis/perception. Gene groups associated with the induced defense response, including cellular events of pattern-triggered immunity (PTI), hypersensitive response (HR), synthesis of the PR protein, and callose formation, were also increased by the Y1M treatments. Transcription factors involved in regulating the cold stress response, such as C-repeat binding factor 1 (CBF1), and cell strengthening, such as MYB26, also had increased expression. In summary, Y1M can activate cellular pathways implicated in regulating stress tolerance shared by cold stress and bacterial invasion.

The downregulation of melatonin receptor 1A (MTNR1A) is associated with a range of pathological conditions, including membranous nephropathy. Knowledge of the mechanism underlying MTNR1A expression has been limited to the transcriptional regulation level. Here, RNA interference screening in human kidney cells revealed that heterogeneous nuclear ribonucleoprotein L (hnRNPL) upregulated MTNR1A RNA post-transcriptionally. hnRNPL knockdown or overexpression led to increased or decreased levels of cyclic adenosine monophosphate-responsive element-binding protein phosphorylation, respectively. Molecular studies showed that cytoplasmic hnRNPL exerts a stabilizing effect on the MTNR1A transcript through CA-repeat elements in its coding region. Further studies revealed that the interaction between hnRNPL and MTNR1A serves to protect MNTR1A RNA degradation by the exosome component 10 protein. MTNR1A, but not hnRNPL, displays a diurnal rhythm in mouse kidneys. Enhanced levels of MTNR1A recorded at midnight correlated with robust binding activity between cytoplasmic hnRNPL and the MTNR1A transcript. Both hnRNPL and MTNR1A were decreased in the cytoplasm of tubular epithelial cells from experimental membranous nephropathy kidneys, supporting their clinical relevance. Collectively, our data identified cytoplasmic hnRNPL as a novel player in the upregulation of MTNR1A expression in renal tubular epithelial cells, and as a potential therapeutic target.

Melatonin is a hormone majorly secreted by the pineal gland and contributes to a various type of physiological functions in mammals. The melatonin production is tightly limited to the AANAT level, yet the most known molecular mechanisms underlying AANAT gene transcription is limited in the pinealocyte. Here, we find that c-Fos and cAMP-response element-binding protein (CREB) decreases and increases the AANAT transcriptional activity in renal tubular epithelial cell, respectively. Notably, c-Fos knockdown significantly upregulates melatonin levels in renal tubular cells. Functional results indicate that AANAT expression is decreased by c-Fos and resulted in enhancement of cell damage in albumin-injury cell model. We further find an inverse correlation between c-Fos and AANAT levels in renal tubular cells from experimental membranous nephropathy (MN) samples and clinical MN specimens. Our finding provides the molecular basis of c-Fos in transcriptionally downregulating expression of AANAT and melatonin, and elucidate the protective role of AANAT in preventing renal tubular cells death in albumin-injury cell model and MN progression.

Background: Few studies have studied the association between asthma and pediatric transfusion naïve thalassemia. Methods: A nationwide population-based retrospective cohort study was conducted using medical records of selected children from the 2010 Registry for Beneficiaries of the Taiwan National Health Insurance Research Database, with a follow-up period extending to the end of 2013. One thalassemia patient was matched with four control patients without thalassemia according to year of birth, sex, and the propensity score model based on comorbidities. Results: In this study, 794 patients with thalassemia and 3176 controls were included. Transfusion-naïve thalassemia children had higher rates to develop asthma (41.03 vs 36.69 per 1000 person-y; P = 0.032) than the non-thalassemia controls with an adjusted hazard ratio of 1.16 (95% confidence interval (CI) = 1.01–1.33). Boys in the thalassemia cohort had a significantly higher adjusted hazard ratio of asthma than those in the non-thalassemia cohort (adjusted hazard ratio = 1.20, 95% CI = 1.02–1.42). In thalassemic patients without atopic dermatitis, the risk of asthma was 1.25-fold higher than in the non-thalassemic ones (95% CI=1.07–1.47). Conclusions: Transfusion-naïve thalassemia children are more likely to have asthma. We need to pay more attention to it in order to diagnosis asthma earlier and to prevent asthma attacked earlier.

Plants have evolved diverse cellular mechanisms to maintain their fitness under stressful environments. Banana (Musa spp.) plants inoculated with a new rhizobacterial isolate, Pseudomonas aeruginosa strain Y1 (PaY1), showed improved vegetative growth, and increased levels of H2O2, glucosinolates, phenolic compounds, and lignin contents. Plants treated with PaY1 had reduced membrane peroxidation and electrolyte leakages, and exhibited higher PSII efficiencies after drought and submergence treatments. Furthermore, PaY1 treatment reduced disease infection rates in the Foc TR4 (Fusarium wilt pathogen)-inoculated plants. RNA seq results identified signaling molecules activated by PaY1, including ROS/antioxidant molecules and signaling of G protein and sphingolipids. Besides, PaY1 exerted positive effects on hormonal signaling, including auxin, ABA, and jasmonic acid (JA) in banana seedlings. Genes associated with cellular pathways of cell division and flowering control were significantly affected; up-regulated genes were also implicated in cellular pathways regulating nutrient availability. The up-regulated genes functioning in abiotic stress tolerance comprised genes encoding DETOXIFICATION-like proteins, aquaporins, autophagy-like, and MAPKK2-like. Furthermore, genes encoding proteins participating in the regulatory network of disease resistance were discovered, which included members of pathogenesis-related proteins (PRs), cell death associated proteins, proteins implicated in the MAMP-trigger immunity (MTI), and genes such as RGA2-like and ETHYLENE-RESPONSIVE TRANSCRIPTION FACTOR 1B (ERF1B) with predicted functions regulating disease resistance against Fusarium oxysporum in different plant species. The transcriptome data presented here indicated that PaY1 is a potent activator of banana genes related to hormonal signaling and cellular pathways including antioxidant defense, detoxification, and MTI, which worked collaboratively to control plant growth, abiotic and biotic stress tolerance in banana plants.

Interest in developing a rapid and robust DNA sequencing platform has surged over the past decade. Various next-/third-generation sequencing mechanisms have been employed to replace the traditional Sanger sequencing method. In sequencing by synthesis, a signal is monitored by a scanning charge-coupled device (CCD) to identify thousands to millions of incorporated dNTPs with distinctive fluorophores on a chip. Because one reaction site usually occupies dozens of pixels on a CCD detector, a bottleneck related to the bandwidth of CCD imaging limits the throughputs of the sequencing performance and causes trade-offs among speed, accuracy, read length, and the numbers of reaction sites in parallel. Thus, current research aims to align one reaction site to a few pixels by directly stacking nanophotonic layers onto a CMOS detector to minimize the size of the sequencing platforms and accelerate the processing procedures. This article reports a custom integrated optoelectronic device based on a triple-junction photodiode (TPD) CMOS sensor in conjunction with NPL integration for real-time illumination and detection of fluorescent molecules.

We present a sprayed composite thin film, comprising Cu−In-Zn−S (CIZS) particles embedded in ZnO matrix for photoelectrochemical hydrogen production from water splitting. CIZS, a photoactive semiconductor was used as a photon absorber, whereas ZnO channels as the pathway for charge transfer. It was found that the distribution of the CIZS particles had a direct impact on the photoelectrochemical (PEC) activity. A more homogeneous dispersion of smaller CIZS particles (0.56 μm) within ZnO matrix exhibited a higher photocurrent density, and 3.27 μmol/ cm2 hydrogen evolution for 5 h. Electrochemical impedance spectroscopy (EIS) was employed to analyze the charge transfer mechanism of this composite thin film. In addition, ZnO coating on top of CIZS particles also served as the adhesion and protection layers. All the PEC experiments were performed in 0.5 M K2SO4 electrolyte. No sacrificial reagents were used. The composite electrode was stable under illumination: 75.67 % of photo-activity remained after 1 h illumination at a bias of 0.2 V vs. SCE. This study demonstrates a simple and low-cost spray preparation of composite thin film consisting of particles embedded in any semiconductor matrix.

Originality/Value – Overall, our results highlight the key economic role played by top corporate managers in major business restructurings, suggesting that CEO turnover leads to both real changes in managerial actions and altered reporting incentives.

The effective and efficient treatment of diseases, such as HIV, cancer or hereditary diseases, requires accurate and precise control of the combinatorial drug-dosage and their release. Herein, we introduce a simple photosensitive poly(ethylene glycol) diacrylate (PEGDA) hydrogel based platform for high dynamic range testing of combinatorial cocktail drug screening using three chemical and two protein drug treatments for colon cancer. UV cross linked PEGDA hydrogel droplet arrays on a Teflon patterned glass substrate enable a rapid yet accurate selection and dosage assignment of the drugs. Precisely loaded cocktails of the anticancer drugs were simultaneously released in-parallel with the PEGDA hydrogel chips into 2D or 3D cultured HCT-8 colon cancer cells for combinatorial drug screening. We demonstrate the functionality of our UV gel-Drug Chips 1000 fold range of concentrations for each of the five drugs in 30 seconds to find the optimized drug cocktail using a fractional factorial control system. Our device has low drug consumption, requiring only 12 nL per screening run per droplet. In addition, our UV gel-Drug Chips were employed for find the optimized drug cocktail using a fractional search algorithm. Our cocktail drug response results for both 2D (cell viability is 7.3%) and 3D (cell viability is 10.8%) colon cancer cells were analogous to those found by conventional method (6.8 and 9.3 respectively). In contrast to conventional method, our approach is faster, more effective, less time consuming and requires a lower amounts of drug volume.

Idiopathic membranous nephropathy (MN) is an autoimmune-mediated glomerulonephritis and the most common cause of idiopathic nephrotic syndrome in adult humans. A tumor necrosis factor α (TNF-α)-mediated inflammatory response via TNF receptor 1 (TNFR1) and TNFR2 has been proposed as a pathogenic factor. In this study, we assessed the therapeutic response to blocking TNF signaling in experimental MN. Murine MN was induced experimentally by cationic bovine serum albumin (cBSA); phosphate-buffered saline was used in control mice. In MN mice, TNF was inhibited by etanercept blocking of TNFR1/TNFR2 or the preligand assembly domain fusion protein (PLAD.Fc), a small fusion protein that can preferentially block TNFR1 signaling. Disease severity and possible mechanisms were assessed by analyzing the metabolic and histopathology profiles, lymphocyte subsets, immunoglobulin production, oxidative stress, and apoptosis. cBSA-induced MN mice exhibited typical nephrotic syndrome and renal histopathology. MN mice given etanercept or PLAD.Fc did not exhibit significant reduction of proteinuria, amelioration of glomerular lesions, or attenuation of immune complex deposition. Immune cell subsets, serum immunoglobulin levels, production of reactive oxygen species, and cell apoptosis in the kidney were not altered by TNF inhibition. By contrast, MN mice receiving etanercept or PLAD.Fc exhibited significantly decreased infiltration of immune cells into the kidney. These results show that the therapeutic effects of blocking TNFR1 and/or TNFR2 signaling in experimental MN are not clinically effective. However, TNF signaling inhibition significantly attenuated renal immune cell infiltration in experimental MN.

Purpose Developing a DNA dot hybridization model for diagnosing parasitic keratitis. Methods Newly designed oligonucleotide probes for detecting Acanthamoeba and microsporidia were tested with target reference strains of Acanthamoeba (n = 20) and microsporidia (n = 3), and non-target microorganisms, including bacteria (n = 20) and fungi (n = 20). These probes, which had passed the preliminary tests, were then assembled as a parasite dot hybridization (PDH) model for assessing 33 clinical samples from patients with clinically suspected Acanthamoeba and microsporidia keratitis, including eight positives for Acanthamoeba, 13 positives for microsporidia, and 12 negatives for both pathogens. Results Two probes for detecting Acanthamoeba and two for detecting microsporidia passed the tests using target and non-target strains and then were assembled in the PDH model. For clinical samples, one Acanthamoeba-positive sample (proved with pathology) was falsely negative according to the PDH assay. The sensitivity and specificity of the PDH assay for diagnosing Acanthamoeba keratitis were 87.5% and 100%, respectively, while the sensitivity and specificity for diagnosing microsporidia keratitis were 100%. The infectious agent of all clinical samples of microsporidia keratitis was identified as Vittaforma corneae with DNA sequencing, while those of Acanthamoeba keratitis were caused by four species of Acanthamoeba, with Acanthamoeba castellanii found in four samples (50%, 4/8). Conclusions The PDH model has the potential to be a molecular assay for diagnosing Acanthamoeba and microsporidia keratitis. However, a prospective clinical study might be needed before the model is adopted in routine clinical practice.

The potential probiotic properties of lactic acid bacteria (LAB) after treatment with gastrointestinal (GI) conditions were investigated. Some LAB strains that survived simulated GI treatment retained their adhesiveness and antagonism against the pathogen. Therefore pre-challenging LAB with simulated GI conditions is a suitable way for potential probiotic studies.

Membranous nephropathy (MN), a type of glomerular nephritis, is the most common cause of nephrotic syndrome in human adults. Changes in gene expression as a result of epigenetic dysregulation through long noncoding RNAs (lncRNAs) are increasingly being recognized as important factors in disease. Using an experimental MN mouse model, we identify the first dysregulated lncRNAs, Xist and NEAT1, whose levels are significantly upregulated in both tubular epithelial and glomerular cells. MN is also often characterized by glomerular podocyte injury. Treatment of a mouse podocyte cell line with lipopolysaccharides to induce injury resulted in the stable elevation of Xist, but not NEAT1 levels. In mice, the observed changes in Xist levels are specific: Xist can be effectively detected in urine, with a strong correlation to disease severity, but not serum in MN samples. We find that regulation of Xist may be controlled by post-translational modifications. H3K27me3 levels are significantly downregulated in mouse MN kidney, where chromatin immunoprecipitation experiments also showed decreased H3K27me3 at Xist promoter regions. Finally, we show that our findings in mice can be extended to human clinical samples. Urinary Xist is significantly elevated in urine samples from patients with different types of glomerular nephritis, including MN, compared to normal counterparts. Together, our results suggest that a reduction of H3K27me3 at Xist promoter regions leads to elevated levels of urinary Xist, which may be used as a biomarker to detect MN.

eTP(embedded touch panel) which provide the highly integration with notebook system design. It re-design the touch panel dimension for industry standardization, the all new design make touch panel glass utilize rate become more effective in the glass cutting process. The eTP architecture integrate the touch panel control board on the LCD PCBA; it can be solve the system control board placement issue and simplification the assembly process. eTP development the touch panel with system cover coplanar design, it provide the slim touch notebook and fluent user touch gesture.

This paper examines whether, why, and how managerial ability is associated with firms’ investment behavior. Specifically, we focus on the effect of managerial ability on extreme investment behavior. We define expansionary (contractionary) investments as investing significantly more (less) than what is expected based on the firm’s sales growth and industry membership. The baseline results reveal that more able managers are less likely to make contractionary investments, while they are more likely to make expansionary investments. We further propose and test the strategic investment hypothesis, which predicts that more able managers time the product markets and invest aggressively to ensure firms’ future competitiveness. The evidence is supportive of this hypothesis: More able managers are more (less) likely to make expansionary (contractionary) investments when the industry (1) becomes more competitive, and (2) is at the onset of R&D growth. Moreover, expansionary investments by more able managers are indeed their strategic investments, which lead to superior future abnormal returns.

Cell alignment is a critical factor to govern cellular behavior and function for various tissue engineering applications ranging from cardiac to neural regeneration. In addition to physical geometry, strain is a crucial parameter to manipulate cellular alignment for functional tissue formation. In this paper, we introduce a simple approach to generate a range of gradient static strains without external mechanical control for the stimulation of cellular behavior within 3D biomimetic hydrogel microenvironments. A glass-supported microfluidic chip with a convex flexible polydimethylsiloxane (PDMS) membrane on the top was employed for loading the cells suspended in a prepolymer solution. Following UV crosslinking through a photomask with a concentric circular pattern, the cell-laden hydrogels were formed in a height gradient from the center (maximum) to the boundary (minimum). When the convex PDMS membrane retracted back to a flat surface, it applied compressive gradient forces on the cell-laden hydrogels. The concentric circular hydrogel patterns confined the direction of hydrogel elongation, and the compressive strain on the hydrogel therefore resulted in elongation stretch in the radial direction to guide cell alignment. NIH3T3 cells were cultured in the chip for 3 days with compressive strains that varied from ~65% (center) to ~15% (boundary) on hydrogels. We found that the hydrogel geometry dominated the cell alignment near the outside boundary, where cells aligned along the circular direction, and the compressive strain dominated the cell alignment near the center, where cells aligned radially. This study developed a new and simple approach to facilitate cellular alignment based on hydrogel geometry and strain stimulation for tissue engineering applications. This platform offers unique advantages and is significantly different than the existing approaches owing to the fact that gradient generation was accomplished in a miniature device without using an external mechanical source.

Idiopathic membranous nephropathy (MN), an autoimmune-mediated glomerulonephritis, is one of the most common causes of nephrotic syndrome in adults. Therapeutic agents for MN remain ill defined. We assessed the efficacy of melatonin therapy for MN. Experimental murine MN was induced with cationic bovine serum albumin, and the mice were immediately administered 20 mg/kg melatonin or phosphate-buffered saline subcutaneously once a day. Disease severity was verified by examining serum and urine metabolic profiles and renal histopathology. The expression of cytokines and oxidative stress markers, cell apoptosis, and the associated mechanisms were also determined. Mice treated with melatonin displayed a significant reduction in proteinuria and a marked amelioration of glomerular lesions, with attenuated immunocomplex deposition. The subpopulations of T cells were not altered, but the CD19+ B-cell subpopulation was significantly reduced in the MN mice treated with melatonin. The expression of cytokine mRNAs in splenocytes indicated that melatonin reduced the expression of proinflammatory cytokines and increased the expression of anti-inflammatory cytokines (interleukin 10). The production of reactive oxygen species and TUNEL-positive apoptotic cells in the kidney were also significantly reduced in the melatonin-treated MN mice. Melatonin also upregulated heme oxygenase 1 (HO1) and ameliorated MN. The blockade of HO1 expression with SnPP, a HO1 inhibitor, attenuated HO1 induction by melatonin and thus mitigated its renoprotective effects during MN. Our results suggest that melatonin treatment ameliorates experimental MN via multiple pathways, including by its antioxidative, antiapoptotic, and immunomodulatory effects. Melatonin should be considered a potential therapeutic intervention for MN in the future.

Increasing the hot-spot area with high enhancement ability on SERS-active particles is generally acknowledged as one of the efficient ways to significantly improve the average SERS signal of nanopa...

The integrated effect of the cholesterol and CYP46 genotypes on the risk of cognitive decline needs to be determined. Using the Cognitive Abilities Screening Instrument (CASI), 145 mentally healthy middle-aged and older adults were recruited to investigate the influence of cholesterol and CYP46 genotypes on cognitive event-related potentials (ERPs). The subjects with a high low-density lipoprotein cholesterol (LDL-C) level displayed significantly lower amplitude ERPs, although the CASI scores showed no difference. There was no association between the CYP46 genotypes, CASI scores, cholesterol levels, and measures of ERPs. No interaction between LDL-C level and CYP46 genotypes was noted. The LDL-C level is an independent predictor of low P300 amplitude. Prevention and treatment of high cholesterol may be of potential benefit in reducing cognitive impairment.

Purpose This study compares 1) progressive dental and skeletal changes, 2) postsurgical stability, and 3) treatment efficacy of patients with skeletal Class III correction with and without presurgical orthodontic treatment. Patients and Methods The study includes 53 patients who underwent orthognathic surgery (OGS) to correct skeletal Class III malocclusion. The patient grouping is based on presurgical orthodontics: surgical-first (SF) approach (n = 18) and modified-conventional (MC) approach (n = 35). This study divides the MC group into 2 groups based on whether patients underwent tooth extraction in the presurgical phase (Ext group) (n = 10) or not (Nxt group) (n = 25). Serial lateral cephalometric film measurements identify skeletal and dental changes before treatment (T1), before OGS (T2), 1 month after OGS (T3), and at completion of treatment (T4). This investigation reviews the medical charts for treatment progress and duration. Results In the presurgical phase, the Ext group showed mild retraction of the upper incisors and more proclination of the lower incisors than the Nxt group. The skeletal sagittal parameters were similar from T1 to T4 in both the SF and MC groups. In the SF group, SN/U1 decreased 6.2° after surgery and was mildly proclined at T4; in the MC group, upper incisor inclination (SN/U1) increased 1.8° from T1 to T4, being 9.4° greater than that in the SF group at T4. The lower incisor inclination (MP/L1) was similar at T4 in both groups. In the MC group, the MP/L1 was shown to be proclined 4.5° before surgery, retroclined 1.9° after surgery, and further retroclined 4.5° until T4. The relapse rate of the mandibular setback was 14.3% in the SF group and 15.7% in the MC group without significant differences. The percentage of sagittal relapse less than 2 mm was 50% in the SF group and 54% in the MC group. The ratio was greater in the MC group with a relapse between 2 and 4 mm but lesser with a relapse greater than 4 mm. The Ext group showed a 3-month longer treatment duration than the Nxt group. Conclusion The amount of skeletal correction and postsurgical relapse, as well as treatment duration, were no different in Class III OGS patients with or without presurgical orthodontic treatment. The presurgical work of lower incisor proclination returned to an inclination similar to the initial status after completing treatment. The final outcome of patients evidenced no difference in lower incisor inclination, with or without presurgical orthodontics.

The twin-arginine translocation (Tat) pathway is capable of translocating folded proteins into the periplasm of Gram-negative bacteria and thus holds great potential for the expression of recombinant proteins in Escherichia coli. Nevertheless, this promise has been hampered by the low translocation efficiency. In this study, we demonstrate that the co-expression of DmsD, a system specific cytoplasmic chaperone similar to TorD, in conjunction with the DmsA signal peptide can enhance the translocation of the GFP fusion protein by 28.2%. We further show the presence of cross-activity between DmsD and TorD for the DmsA and TorA leader-fusions. The co-expression of DmsD and TorD enhances the translocation of ssTorA-GFP fusion and ssDmsA-GFP fusion by 28.6% and 46.6%, respectively. It was also observed that the co-expression of DmsD led to a reduction in the formation of GFP inclusion bodies, whereas the co-expression of TorD primarily led to a reduction in proteolysis by the Clp system. It is concluded that DmsD and TorD enhance protein translocation via the Tat pathway by providing activity against protein aggregation and/or proteolysis.

Objective Gingivoperiosteoplasty performed at the time of lip repair of cleft patients is one kind of alveolar repair. The purpose of this retrospective study was to evaluate the effect of gingivoperiosteoplasty on facial growth of patients with complete unilateral cleft lip and palate (UCLP). Design Retrospective study. Patients Sixty-two consecutive patients with nonsyndromic complete unilateral cleft lip/palate with 5-year-olds’ record were included in this retrospective study. Interventions All the patients had received nasoalveolar molding treatment before cheiloplasty at the age of 3 to 6 months. Twenty-six patients had gingivoperiosteoplasty performed at the time of cheiloplasty and function as the GPP group. Thirty-six patients did not have gingivoperiosteoplasty at the time of cheiloplasty and function as the non-GPP group. Main Outcome Measures Cephalometry was used to evaluate the facial growth at 5 years of age in the two groups of patients. Results Gingivoperiosteoplasty had significant effects on the maxillary position (SNA), intermaxillary position (ANB), maxillary length (PMP-ANS), and maxillary alveolar length (PMP-A) at the age of 5 years. The SNA and ANB angles were larger in non-GPP group than in the GPP group by 3.0° and 2.6°, respectively. The maxillary length (PMP-ANS) and maxillary alveolar length (PMP-A) were larger in the non-GPP group than in the GPP group by 2.1 and 2.9 mm, respectively. Conclusions In patients with UCLP, the sagittal growth of the maxilla would be affected more adversely in the GPP group than in the non-GPP group at the age of 5 years.

Membranous nephropathy (MN), a type of glomerular nephritis, is one of the most common causes of nephrotic syndrome in adults. Although it is known that melatonin plays a protective role in MN, the role of melatonin receptors in the pathophysiology of MN is unclear. Using an experimental MN model and clinical MN specimens, we studied melatonin receptor expression and found that melatonin receptor 1A (MTNR1A) expression was significantly downregulated in renal tubular epithelial cells. Molecular studies showed that the transcription factor pituitary homeobox-1 (PITX1) promoted MTNR1A expression via direct binding to its promoter. Treatment of a human tubular cell line with albumin to induce injury resulted in the stable reduction in MTNR1A and PITX1 expression. PITX1 levels were significantly downregulated in tubular epithelial cells from mice MN kidneys and MN renal specimens. Knockdown of MTNR1A, PITX1, or cyclic adenosine monophosphate-responsive element-binding protein (CREB) decreased E-cadherin (CDH1) expression, but upregulated Per2 and α-smooth muscle actin (αSMA) expression. Blockade of the MTNR1A receptor with luzindole in MN mice further impaired renal function; this was accompanied by CDH1 downregulation and Per2 and αSMA upregulation. Together, our results suggest that in injured tissue, decreased PITX1 expression at the MTNR1A promoter regions leads to decreased levels of MTNR1A in renal tubular epithelial cells, which increases the future risk of MN.

Protein microarrays are emerging as an important enabling technology for the simultaneous investigation of complicated interactions among thousands of proteins. The solution-based blocking protocols commonly used in protein microarray assays often cause cross-contamination among probes and diminution of protein binding efficiency because of the spreading of blocking solution and the obstruction formed by the blocking molecules. In this paper, an alternative blocking process for protein microarray assays is proposed to obtain better performance by employing a vapor-phase deposition method to form self-assembled surface coatings using a highly fluorinated organosilane as the blocking agent on the background surfaces. Compared to conventional solution-based blocking processes, our experimental results showed that this vapor-phase process could shorten the blocking time from hours to less than 10 min, enhance the binding efficiency by up to 6 times, reduce the background noise by up to 16 times, and improve the S/N ratio by up to 64 times. This facile blocking process is compatible with current microarray assays using silica-based substrates and can be performed on many types of silane-modified surfaces.

The incidence of pulmonary nodules after cardiac transplantation is not uncommon, and prompt diagnostic procedures are necessary to minimize disease-related morbidity and mortality. We report a 56-year-old woman who was found to have bilateral pulmonary nodules four months after cardiac transplantation. The microorganism was identified with a molecular diagnostic method as Schizophyllum commune, which had not been reported in English literature as a pathogen inducing pulmonary nodules after transplantation. She remained asymptomatic during the therapeutic period and the pulmonary nodules resolved six months later.

Cystic fibrosis (CF) is the most common inherited genetic disease in Caucasian populations. Besides bacteria, many species of fungi may colonize the respiratory tract of these patients, sometimes leading to true respiratory infections. In this study, an oligonucleotide array capable of identifying 20 fungal species was developed to directly detect fungi in the sputum samples of CF patients. Species-specific oligonucleotide probes were designed from the internal transcribed spacer (ITS) regions of the rRNA operon and immobilized on a nylon membrane. The fungal ITS regions were amplified by PCR and hybridized to the array for species identification. The array was validated by testing 182 target strains (strains which we aimed to identify) and 141 nontarget strains (135 species), and a sensitivity of 100% and a specificity of 99.2% were obtained. The validated array was then used for direct detection of fungi in 57 sputum samples from 39 CF patients, and the results were compared to those obtained by culture. For 16 sputum samples, the results obtained by the array corresponded with those obtained by culture. For 33 samples, the array detected more fungal species than culture did, while the reverse was found for eight samples. The accuracy of the array for fungal detection in sputum samples was confirmed (or partially confirmed) in some samples by cloning and resequencing the amplified ITS fragments. The present array is a useful tool for both the simultaneous detection of multiple fungal species present in the sputa of CF patients and the identification of fungi isolated from these patients.

Association mapping (i.e., linkage disequilibrium mapping) is a powerful tool for positional cloning of disease genes. We propose a kernel-based association test (KBAT), which is a composite function of “P-values of single-locus association tests” and “kernel weights related to intermarker distances and/or linkage disequilibria.” The KBAT is a general form of some current test statistics. This method can be applied to the study of candidate genes and can scan each chromosome using a moving average procedure. We evaluated the performance of the KBAT through simulation studies that considered evolutionary parameters, disease models, sample sizes, kernel functions, test statistics, window attributes, empirical P-value estimations, and genetic/physical maps. The results showed that the KBAT had a well-controlled false positive rate and high power compared to existing methods. In addition, the KBAT was also applied to analyze a genomewide data set from the Collaborative Study on the Genetics of Alcoholism. Important genes associated with alcoholism dependence were identified. In summary, the merits of the KBAT are multifold: the KBAT is robust against the inclusion of nuisance markers, is invariant to the map scale, and accommodates different types of genomic data, study designs, and study purposes. The proposed methods are packaged in the user-friendly software, KBAT, available at http://www.stat.sinica.edu.tw/hsinchou/genetics/association/KBAT.htm.

Cardiovascular disease is still a major healthcare concern as it continues to be the leading cause of death in developed countries. Recent advancement in bioengineering technologies to generate micro- and nanoscale materials as biotransporters and therapeutics has led to a variety of new approaches to treat cardiovascular diseases. Although these strategies are still in their initial stage of research, developing effective alternate therapies to treat life-threatening diseases such as myocardial infarction and atherosclerosis can potentially improve patient outcomes and long-term economic costs imposed on the healthcare system. Over the last decade, a wide array of materials with tunable biophysical and chemical properties has been developed to successfully deliver therapeutic agents such as nucleic acids, proteins, and small molecules, and even stem cells in combination with nanomaterials for advanced cardiovascular treatments. This mainly includes polymeric nanoparticles and nanohybrid materials, microparticles, carbon nanotubes, graphene oxide, liposomes, microgels, nanofibers, and nanoscaffolds. In addition, these materials also find application as multifunctional theranostic nanoagents which combine in vivo diagnostic properties along with therapeutic capabilities. This chapter discusses the emerging therapeutic delivery systems for biomedical research and highlights the recent developments in this highly interdisciplinary field along with examples of strategies that hold promise for the future of cardiovascular medicine.

We reports an approach to fabricate dual-faced polystyrene beads (DFPSBs) with tri-functions of tumor cell recognition, drug delivery, and real-time Raman sensing. Onestep oxygen-plasma treatment process was used to etch commercially available fluorescent polystyrene beads into a corrugated upper hemisphere and simultaneously change the entire surface with carboxylic groups. After depositing gold onto the corrugated hemisphere for surface enhanced Raman scattering (SERS) while leaving the other smooth and clean hemisphere for fluorescence detection, the DFPSBs are formed with dual-surfaces of plasmonic gold semishells on the top and fluorescent carboxylated polystyrene at the bottom. Sulfo-NHS-SS-biotin disulfide linkers and anti-CD44 antibodies can be modified and added onto the top gold surfaces and the bottom carboxyl groups through Au-S and peptide bonds, respectively. Then, the surface-modified DFPSB suspension can be employed to target overexpressive glycoproteins (CD44) on the surfaces of cancer cells and release their loads via the cleavage of disulfide bonds in the cytoplasm environment. These anti-CD44-modified DFPSBs exhibit a 12-fold cancer targeting ability on HeLa cells when compared to a normal chondrocyte cell.

Prior research suggests that firms in bilateral relationships have incentives to use accounting information to enhance stakeholders’ assessment of the firms’ reputation for fulfilling implicit claims. Using a database of firms’ major customers, we provide evidence that principal customers influence discretionary management earnings forecast disclosures. We find that firms with greater dependence on major customers are more likely to issue earnings forecasts, especially in environments where implicit claims with customers and resulting relationship-specific investments are significant. Further, we find that dependence on major customers is associated with more timely and frequent forecasts, but only when relationship-specific investments are more important. However, when relationship-specific investments are less important, the dependence on major customers is associated with more optimistically-biased forecasts. Overall, our results suggest that the decisions managers make about earnings forecasts are affected by the dependence on major customers.

The Surface Enhanced Raman Scattering (SERS) bacteria sensing chip was usually developed by wet-etching [1] or template-molding [2] approach to obtain an enhancement factor of 101−3. However, these processes may not be available for the template and difficult to integrate with other complicated fabrication designs. Therefore, in this project, we propose an easy integrated approach to develop high sensitive surface enhanced Raman scattering (SERS) with an enhancement factor of 105−6 via a metal-coated polystyrene array for quick detection of the specific bacteria in food. In the experimental results, it is detectable of less than five bacteria per laser spot (∼3 μm in diameter) on the silver-coated corrugated polystyrene bead array. The goal of this project is also to develop a disposable and room temperature fabricated SERS sensors for future integration.

We report in this article a simple route for synthesizing small-sized silver/gold core–shell (Ag/Au) on multi-walled carbon nanotube (MWCNT) surfaces via galvanic replacement of Ag nanoparticles (Ag NPs). The Raman response of MWCNT decorated with Ag/Au was investigated under surface-enhanced Raman scattering. A relatively weak Raman signal enhancement of the tube was observed due to the large interparticle distance between neighboring small-sized nanostructures. Ag/Au gives better enhancing capability than the starting Ag because of the synergistic effect between the localized electric field of the Ag core, and the Au shell separated with a hollow space formed during the galvanic replacement reaction. Furthermore, the Ag/Au was removed from the CNT surfaces via sonication with 1-octanethiol (OT), releasing unreplaced Ag NPs and Au nanobowls (Au NBs) with 1.3 and 7.6 nm of mean diameter sizes, respectively. The production of these fine-sized nanocomposites (Au/Ag NCs) allowed us to investigate their luminescent property. Interestingly, the separated Au/Ag NCs (i.e., the mixture of Au NBs and unreplaced Ag NPs) exhibit fluorescence behavior that may be useful for single-molecule detection. Our technique provides the synthesis of smallest dimension of Au NBs so far simply achieved by wet-chemical process using MWCNTs as templates.

Many of SERS nanoparticles took advantage of the surface roughness for the significant improvement of their Raman sensing ability. Nevertheless, few papers analyzed the characteristics of surface roughness nanostructures that contribute to the SERS. Thus, this paper investigates the characteristics of the corrugated polystyrene bead (PSB) array etched by a series of oxygen plasma etching time for giving a criterion to fabricate appropriate SERS-active nanoparticles. Three factors were considered in this paper: (1) the effect of plasma coupling among neighboring particles, (2) the vertical surface roughness of nanocorrugations, and (3) the pitch size, the lateral surface roughness, of nanocorrugations. By the analysis of SEM and AFM images, those factors were quantifiable. The correlation coefficient between each factor and SERS Raman enhancement was also investigated to verify that the pitch size of nanocorrugations (ranging from ∼6 nm to ∼12 nm on the surface of PSBs) dominates the SERS enhancement. Therefore, the maximum improvement of Raman intensity that derives from surface roughness treatment is 12 times compared to smooth surface. Moreover, it has a high enhancement factor of ∼106.

This paper reports the study on spontaneous and fast motion for a microliter water droplet on nanotextured glass capillary surfaces with a wide range of curvature gradients. The surface is highly related to the surface tension gradient that is mainly formed by three distinct driving forces, including surface hydrophilicity gradents, chemically patterned nanotexture, and curvature gradient capillaries. In the experiments, the droplet velocity shows a dependency to the droplet position on the conical capillary curvature surface and moves toward the more wettable part of the gradient. The speed of the droplet on the oxygen plasma treated nanotextured glass capillary is up to 238.5 mm/s with more than two times of that, 101.7 mm/s, on the untreated surface. Therefore, we can conclude that a gradual variation of wettability property governs the droplet motion.

Idiopathic membranous nephropathy (MN), an autoimmune-mediated glomerulonephritis, is one of the most common causes of nephrotic syndrome in adults. Therapeutic agents for MN remain ill defined. We assessed the efficacy of melatonin therapy for MN. Experimental murine MN was induced with cationic bovine serum albumin, and the mice were immediately administered 20 mg/kg melatonin or phosphate-buffered saline subcutaneously once a day. Disease severity was verified by examining serum and urine metabolic profiles and renal histopathology. The expression of cytokines and oxidative stress markers, cell apoptosis, and the associated mechanisms were also determined. Mice treated with melatonin displayed a significant reduction in proteinuria and a marked amelioration of glomerular lesions, with attenuated immunocomplex deposition. The subpopulations of T cells were not altered, but the CD19(+) B-cell subpopulation was significantly reduced in the MN mice treated with melatonin. The expression of cytokine mRNAs in splenocytes indicated that melatonin reduced the expression of proinflammatory cytokines and increased the expression of anti-inflammatory cytokines (interleukin 10). The production of reactive oxygen species and TUNEL-positive apoptotic cells in the kidney were also significantly reduced in the melatonin-treated MN mice. Melatonin also upregulated heme oxygenase 1 (HO1) and ameliorated MN. The blockade of HO1 expression with SnPP, a HO1 inhibitor, attenuated HO1 induction by melatonin and thus mitigated its renoprotective effects during MN. Our results suggest that melatonin treatment ameliorates experimental MN via multiple pathways, including by its antioxidative, antiapoptotic, and immunomodulatory effects. Melatonin should be considered a potential therapeutic intervention for MN in the future.

We investigate the impact of CEO turnover in connection with corporate restructurings on subsequent performance improvement and accounting quality. Although operational restructurings are credited with performance improvements, prior studies suggest companies potentially manipulate restructuring charges to mask true economic performance. We document significant improvements in post-restructuring investment efficiency and operating performance with no differentiation between firms that experience pre-restructuring CEO turnovers and those that do not. However, continuing managers are more likely to display opportunistic behavior, suggesting their performance improvements are less consistent with real economic changes than pre-restructuring turnover firms. This difference in accounting quality is also more pronounced for firms with outside replacements. Overall, our findings suggest that the threat of managerial termination can effectively induce managers to undertake appropriate actions and commit to higher reporting quality in poorly performing firms.

This study examines the relation between labor union strength and conditional accounting conservatism. Prior research suggests that strong labor unions restrict management from substituting high risk investments for low risk investments. Conceptually, conditional accounting conservatism also serves to restrict this type of asset substitution. Thus, union strength and conservatism might act as substitutes. However, it is plausible that labor unions induce greater information asymmetry, which increases shareholder demand for conservatism, and that managers seeking a bargaining advantage with unions have incentives to supply conservatism. This implies a complementary relation between union strength and conservatism. To determine which of these relations hold, we use Basu’s (1997) asymmetric timeliness framework. We find that stronger unions are associated with lower levels of conservatism, even after controlling for abnormal bid-ask spread, size, book-to-market ratio, leverage, and litigation risk. Results are also robust to a battery of sensitivity tests, including controlling for endogeneity, alternative measurement horizons, CEO ownership, and unconditional conservatism. Overall, we provide evidence about the impact of a key stakeholder, namely labor unions, on an important property of earnings.

This paper describes a Self-Aligned Wet (SAW) cell suitable for direct-cell or bacteria incubation and observation in a wet environment inside a transmission electron microscope. This SAW cell is fabricated by a bulk-micromachining process and composed of two structurally complementary counterparts (an out-frame and an in-frame), where each contain a silicon nitride film based observation window. The in- and out-frames can be self-aligned via a mechanism of surface tension from a bio-sample droplet without the aid of positioning stages. The liquid chamber is enclosed between two silicon nitride membranes that are thin enough to allow high energy electrons to penetrate while also sustaining the pressure difference between the TEM vacuum and the vapor pressure within the liquid chamber. A large field of view (150 μm × 150 μm) in a SAW cell is favored and formed from a larger sized observation window in the out-frame, which is fabricated using a unique circular membrane formation process. In this paper, we introduce a novel design to circumvent the challenges of charging/heating problems in silicon nitride that arise from interactions with an electron beam. This paper also demonstrates TEM observations of D. Radiodurans growth in a liquid environment within a thicker chamber (20 μm) within a SAW cell.

The integrated effect of the cholesterol and CYP46 genotypes on the risk of cognitive decline needs to be determined. Using the Cognitive Abilities Screening Instrument (CASI), 145 mentally healthy middle-aged and older adults were recruited to investigate the influence of cholesterol and CYP46 genotypes on cognitive event-related potentials (ERPs). The subjects with a high low-density lipoprotein cholesterol (LDL-C) level displayed significantly lower amplitude ERPs, although the CASI scores showed no difference. There was no association between the CYP46 genotypes, CASI scores, cholesterol levels, and measures of ERPs. No interaction between LDL-C level and CYP46 genotypes was noted. The LDL-C level is an independent predictor of low P300 amplitude. Prevention and treatment of high cholesterol may be of potential benefit in reducing cognitive impairment.

This paper reports the employment of carboxyl groups on polystyrene beads surface to generate high aspect ratio (HSR) nano-extrutions by plasma etching for enhancing SERS signal. We investigate the detail mechanism of the surface corrugation formation on PSBs and propose a novel method to produce HSR surface nano-extrutions on carboxyl-rich PSBs surface. By understanding the mechanism of the surface corrugation formation, we can control the HSR. Therefore, a 4-fold Raman signal enhancement was achieved when compared to the result by previous method, using oxygen plasma to generate corrugation surface on PSBs without carboxyl groups.

Background Therapeutic agents for membranous nephropathy (MN) remain ill-defined. Haeme oxygenase (HO)-1 is considered to play a protective role in various disorders. Here, we assessed the efficacy of HO-1 induction therapy for MN. Methods MN was induced in BALB/c mice with intravenous injections of cationic bovine serum albumin. Three groups of mice were administered 100 micromol/kg Cobalt protoporphyrin (CoPP, a potent HO-1 inducer), Tin protoporphyrin (SnPP, a potent HO-1 inhibitor) or phosphate-buffered saline via intra-peritoneal injections once a week starting from the induction of MN. Disease severity was verified by serum and urine metabolic profiles and by renal histopathology. Cytokine profiles, immunoglobulin production, the expression of oxidative stress markers (thiobarbituric acid reactive substances, TBARS) and apoptosis, as measured by TUNEL, were also determined. Results Mice treated with CoPP displayed a significant reduction in proteinuria and a marked amelioration of glomerular lesions, accompanied by attenuated immune-complex deposition. The production of immunoglobulins in MN mice treated with CoPP was significantly reduced compared with that of mice in the other two groups. TBARS in the serum and kidneys, as well as apoptosis, were also significantly reduced in CoPP-treated mice. Cytokine mRNA expression in the renal cortex indicated that CoPP not only decreased the expression of proinflammatory cytokines, but also increased the expression of anti-inflammatory cytokines (interleukin-10). Conclusions HO-1 induction therapy may ameliorate experimental MN via multiple pathways, including anti-oxidative, anti-apoptotic and immunomodulatory effects. HO-1 inducing regimens should be considered as a potential therapeutic intervention in MN in the future.

Background: Autism is a neurodevelopmental disorder with a strong genetic component. Previous studies have mapped the disease to chromosome 7q, where the homeobox transcription factor ENGRAILED 2 (EN2) gene is located. EN2 is specifically involved in patterning the region that gives rise to the cerebellum. In the present work, we carried out a case-control study to determine whether 2 intronic single-nucleotide polymorphisms (SNPs) of EN2 are a susceptibility to autism in a Han Chinese population. Method: We enrolled 184 cases of DSM-IV-TR diagnosed autistic disorder, 225 controls of unrelated healthy volunteers and 409 randomly selected controls from the community who lives in the adjacent geographical regions for this study. Two SNPs (rs1861972, rs1861973) at the EN2 gene that have been reported to be associated with autism underwent analysis among our studied cohorts. Both the UNPHASE and PHASE statistical programs were utilized for evaluating the association of EN2 SNPs with autism based on allelic and genotypic frequencies and haplotype compositions accompanied with the goodness-of-fit method of the χ2 test. The gender difference was also investigated by using 2-side Fisher’s exact test treated as a covariate in logistic regression analysis. Results and Conclusion: Both the allelic and genotypic distributions of the 2 polymorphisms were concordant with Hardy-Weinberg equilibrium. Significant differences were found for cases versus community and overall controls. By using the UNPHASE and PHASE programs, the 2-marker haplotype A-C of EN2 was identified to have a protective effect for autism, indicating that the ethnic difference might confound the EN2 association with autism. Therefore, more EN2 gene association studies of Han Chinese populations are warranted to confirm this finding.