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1.
Prostate ; 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38899404

ABSTRACT

BACKGROUND: Prebiopsy prostate-specific antigen density (PSAD) is a well-known predictor of clinically significant prostate cancer (csPCa). Since prostate-specific antigen (PSA) and prostate volume (PV) increase normally with aging, PSAD thresholds may vary. The purpose of the study was to determine if PSAD was predictive of csPCa in different age strata. METHODS: We retrospectively reviewed our institutional database for patients who underwent multiparametric magnetic resonance imaging (MRI) between January 2016 and December 2021. We included patients who had post-MRI prostate biopsies. Based on age, we divided our cohort into four subgroups (groups 1-4): <55, 55-64, 65-74, and ≥75 years old. PSAD accuracy was estimated by the area under the curve (AUC) as a predictive model for differentiating csPCa between the groups. CsPCa was defined as a Gleason Grade Group 2 or higher. Three different PSAD thresholds (0.1, 0.15, and 0.2) were tested across the groups for sensitivity, specificity, and positive predictive value (PPV) and negative predictive value (NPV). Chi-square and analysis of variance tests were used for bivariate analysis. All analys were completed using R 4.3 (R Core Team, 2023). RESULTS: Among 1913 patients, 883 (46.1%) had prostate biopsies. In groups 1, 2, 3, and 4, there were 62 (7%), 321 (36.4%), 404 (45.8%), and 96 (10.9%) patients, respectively. Median PSA was 5.6 (interquartile range 3.4-8.1), 6.2 (4.8-9), 6.8 (5.1-9.7), and 9 (5.6-13), respectively (p < 0.01). Median PV was 42.3 (30-62), 51 (36-77), 55.5 (38-85.9), and 59.3 (42-110) mL, respectively (p < 0.01). No difference was observed in median PSAD between age groups 1-4 (0.1 [0.07-0.16], 0.11 [0.08-0.18], 0.1 [0.07-0.19], and 0.1 [0.07-0.2]), respectively (p = 0.393). CsPCa was diagnosed in 241 (27.3%) patients, of which 10 (16.1%), 65 (20.2%), 121 (30%), and 45 (46.7%) were in groups 1-4, respectively (p < 0.001). For groups 1-4, the PSAD AUC for predicting csPCa was 0.75, 0.68, 0.71, and 0.74. While testing PSAD threshold of 0.15 across the different age groups (1-4), the PPV vs. NPV was 39.1 vs. 93.2, 33.6 vs. 87, 50.9 vs. 80.8, and 66.1 vs. 64.7, respectively. CONCLUSIONS: PSAD prediction model was found to be similar among different age groups. In young patients, PSAD had a high NPV but low PPV. With increasing age, the opposite trend was observed, likely due to higher disease prevalence. While PSAD thresholds may be less useful in older patients to rule out higher-grade prostate cancer, the clinical consequences of these diagnoses require a case-by-case evaluation.

2.
J Perioper Pract ; : 17504589241251697, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38785312

ABSTRACT

INTRODUCTION: This study aims to assess the feasibility and safety of same-day discharge after transurethral resection of the prostate. MATERIALS AND METHODS: Five years of records were retrospectively analysed. Length of stay categorised patients into Groups 1 (same-day discharge) and 2 (standard-length discharge). Logistic regression analysis was performed, controlling for clinicodemographic factors. Student's t-test compared continuous bladder irrigation and catheter dwell times. RESULTS: A total of 459 patients were identified between 2016 and 2021, 280 in Group 1 and 179 in Group 2, with median ages of 71.0 (interquartile range 36-92) and 72.0 (interquartile range 47-101) years (p = 0.067), respectively. Same-day discharge rates notably increased post-2018 (p = 0.025). Median prostate tissue resected in Group 2 was 7.1g (3.4-12.4g) and in Group 1 was 4.9g (2.4-10.2g; p = 0.034). While continuous bladder irrigation >1 hour was significantly lower in Group 1 than Group 2 (96.8% versus 27.4%; p = 0.0001), catheter dwell times were comparable (70.1 and 70.8 hours, respectively). Control-adjusted results showed a 40% reduction in emergency department representation odds for Group 1 compared with Group 2 (odds ratio = 0.60; 95% confidence interval = 0.37-0.99; p = 0.04). Length of stay was not significantly associated with hospital readmissions (p = 0.11). Continuous bladder irrigation for <1 hour in Group 1 was associated with a reduced emergency department representation (odds ratio = 0.43; 95% confidence interval = 0.197-0.980) but not readmission (odds ratio = 0.413; 95% confidence interval = 0.166-1.104). CONCLUSIONS: Same-day discharge post-transurethral resection of the prostate may be a viable and safe option for carefully selected patients.

3.
Biochemistry ; 63(6): 797-805, 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38420671

ABSTRACT

The sesquiterpene cyclase epi-isozizaene synthase (EIZS) from Streptomyces coelicolor catalyzes the metal-dependent conversion of farnesyl diphosphate (FPP) into the complex tricyclic product epi-isozizaene. This remarkable transformation is governed by an active site contour that serves as a template for catalysis, directing the conformations of multiple carbocation intermediates leading to the final product. Mutagenesis of residues defining the active site contour remolds its three-dimensional shape and reprograms the cyclization cascade to generate alternative cyclization products. In some cases, mutagenesis enables alternative chemistry to quench carbocation intermediates, e.g., through hydroxylation. Here, we combine structural and biochemical data from previously characterized EIZS mutants to design and prepare F95S-F198S EIZS, which converts EIZS into an α-bisabolol synthase with moderate fidelity (65% at 18 °C, 74% at 4 °C). We report the complete biochemical characterization of this double mutant as well as the 1.47 Å resolution X-ray crystal structure of its complex with three Mg2+ ions, inorganic pyrophosphate, and the benzyltriethylammonium cation, which partially mimics a carbocation intermediate. Most notably, the two mutations together create an active site contour that stabilizes the bisabolyl carbocation intermediate and positions a water molecule for the hydroxylation reaction. Structural comparison with a naturally occurring α-bisabolol synthase reveals common active site features that direct α-bisabolol generation. In showing that EIZS can be redesigned to generate a sesquiterpene alcohol product instead of a sesquiterpene hydrocarbon product, we have expanded the potential of EIZS as a platform for the development of designer cyclases that could be utilized in synthetic biology applications.


Subject(s)
Carbon-Carbon Lyases , Sesquiterpenes , Sesquiterpenes/metabolism , Monocyclic Sesquiterpenes
4.
Biochemistry ; 62(15): 2301-2313, 2023 08 01.
Article in English | MEDLINE | ID: mdl-37449555

ABSTRACT

The class I sesquiterpene cyclase epi-isozizaene synthase from Streptomyces coelicolor (EIZS) catalyzes the transformation of linear farnesyl diphosphate (FPP) into the tricyclic hydrocarbon epi-isozizaene in the biosynthesis of albaflavenone antibiotics. The active site cavity of EIZS is largely framed by four aromatic residues - F95, F96, F198, and W203 - that form a product-shaped contour, serving as a template to chaperone conformations of the flexible substrate and multiple carbocation intermediates leading to epi-isozizaene. Remolding the active site contour by mutagenesis can redirect the cyclization cascade away from epi-isozizaene biosynthesis to generate alternative sesquiterpene products. Here, we present the biochemical and structural characterization of four EIZS mutants in which aromatic residues have been substituted with polar residues (F95S, F96H, F198S, and F198T) to generate alternative cyclization products. Most notably, F95S EIZS generates a mixture of monocyclic sesquiterpene precursors of bisabolane, a D2 diesel fuel substitute. X-ray crystal structures of the characterized mutants reveal subtle changes in the active site contour showing how each aromatic residue influences the chemistry of a different carbocation intermediate in the cyclization cascade. We advance that EIZS may serve as a robust platform for the development of designer cyclases for the generation of high-value sesquiterpene products ranging from pharmaceuticals to biofuels in synthetic biology approaches.


Subject(s)
Alkyl and Aryl Transferases , Sesquiterpenes , Streptomyces coelicolor , Terpenes/chemistry , Cyclization , Sesquiterpenes/chemistry , Streptomyces coelicolor/genetics , Monocyclic Sesquiterpenes , Alkyl and Aryl Transferases/genetics
5.
Biochemistry ; 61(18): 2025-2035, 2022 09 20.
Article in English | MEDLINE | ID: mdl-36084241

ABSTRACT

The regiospecific prenylation of an aromatic amino acid catalyzed by a dimethylallyl-l-tryptophan synthase (DMATS) is a key step in the biosynthesis of many fungal and bacterial natural products. DMATS enzymes share a common "ABBA" fold with divergent active site contours that direct alternative C-C, C-N, and C-O bond-forming trajectories. DMATS1 from Fusarium fujikuroi catalyzes the reverse N-prenylation of l-Trp by generating an allylic carbocation from dimethylallyl diphosphate (DMAPP) that then alkylates the indole nitrogen of l-Trp. DMATS1 stands out among the greater DMATS family because it exhibits unusually broad substrate specificity: it can utilize geranyl diphosphate (GPP) or l-Tyr as an alternative prenyl donor or acceptor, respectively; it can catalyze both forward and reverse prenylation, i.e., at C1 or C3 of DMAPP; and it can catalyze C-N and C-O bond-forming reactions. Here, we report the crystal structures of DMATS1 and its complexes with l-Trp or l-Tyr and unreactive thiolodiphosphate analogues of the prenyl donors DMAPP and GPP. Structures of ternary complexes mimic Michaelis complexes with actual substrates and illuminate active site features that govern prenylation regiochemistry. Comparison with CymD, a bacterial enzyme that catalyzes the reverse N-prenylation of l-Trp with DMAPP, indicates that bacterial and fungal DMATS enzymes share a conserved reaction mechanism. However, the narrower active site contour of CymD enforces narrower substrate specificity. Structure-function relationships established for DMATS enzymes will ultimately inform protein engineering experiments that will broaden the utility of these enzymes as useful tools for synthetic biology.


Subject(s)
Biological Products , Dimethylallyltranstransferase , Tryptophan Synthase , Catalysis , Dimethylallyltranstransferase/chemistry , Fusarium , Hemiterpenes , Indoles , Neoprene , Nitrogen , Organophosphorus Compounds , Prenylation , Substrate Specificity , Tryptophan/chemistry , Tryptophan Synthase/metabolism
6.
Biochemistry ; 60(42): 3162-3172, 2021 10 26.
Article in English | MEDLINE | ID: mdl-34609847

ABSTRACT

Copalyl diphosphate (CPP) synthase from Penicillium verruculosum (PvCPS) is a bifunctional diterpene synthase with both prenyltransferase and class II cyclase activities. The prenyltransferase α domain catalyzes the condensation of C5 dimethylallyl diphosphate with three successively added C5 isopentenyl diphosphates (IPPs) to form C20 geranylgeranyl diphosphate (GGPP), which then undergoes a class II cyclization reaction at the ßγ domain interface to generate CPP. The prenyltransferase α domain mediates oligomerization to form a 648-kD (αßγ)6 hexamer. In the current study, we explore prenyltransferase structure-function relationships in this oligomeric assembly-line platform with the goal of generating alternative linear isoprenoid products. Specifically, we report steady-state enzyme kinetics, product analysis, and crystal structures of various site-specific variants of the prenyltransferase α domain. Crystal structures of the H786A, F760A, S723Y, S723F, and S723T variants have been determined at resolutions of 2.80, 3.10, 3.15, 2.65, and 2.00 Å, respectively. The substitution of S723 with bulky aromatic amino acids in the S723Y and S723F variants constricts the active site, thereby directing the formation of the shorter C15 isoprenoid, farnesyl diphosphate. While the S723T substitution only subtly alters enzyme kinetics and does not compromise GGPP biosynthesis, the crystal structure of this variant reveals a nonproductive binding mode for IPP that likely accounts for substrate inhibition at high concentrations. Finally, mutagenesis of the catalytic general acid in the class II cyclase domain, D313A, significantly compromises prenyltransferase activity. This result suggests molecular communication between the prenyltransferase and cyclase domains despite their distant connection by a flexible polypeptide linker.


Subject(s)
Alkyl and Aryl Transferases/chemistry , Multifunctional Enzymes/chemistry , Plant Proteins/chemistry , Alkyl and Aryl Transferases/genetics , Catalytic Domain/genetics , Kinetics , Multifunctional Enzymes/genetics , Plant Proteins/genetics , Protein Domains/genetics , Protein Engineering , Talaromyces/enzymology
7.
J Urol ; 201(3): 556-562, 2019 03.
Article in English | MEDLINE | ID: mdl-30316894

ABSTRACT

PURPOSE: Emergency department visits after ureteroscopy are costly and inconvenient. To better understand those at risk we aimed to identify patient demographic, medical and surgical factors associated with 30-day emergency department presentation following ureteroscopy for urolithiasis with particular attention to those with a history of a psychiatric diagnosis. MATERIALS AND METHODS: We retrospectively reviewed 1,576 cases (1,395 adults) who underwent stone related ureteroscopy during 3 years at a total of 2 hospitals. We collected patient demographics, medical history and operative details. The primary outcome was return to the emergency department within 30 days of ureteroscopy. Logistic regression was performed to examine factors associated with emergency department presentation. RESULTS: Of the patients 613 (43.9%) had a history of psychiatric diagnosis. Of those with ureteroscopy encounters 12.6% returned to the emergency department within 30 days of ureteroscopy, including 58.8% with a history of psychiatric diagnosis. On multivariable analysis variables associated with emergency department return included a history of psychiatric diagnosis (OR 1.57, p = 0.012), uninsured status (OR 2.46, p = 0.001) and a stone only in the kidney (OR 1.76, p = 0.022). Patients who returned to the emergency department had had more emergency department visits in the year prior to surgery (OR 1.40, p <0.001). On univariable analysis older patients and those with longer operative time were more frequently admitted from the emergency department (OR 1.03, p = 0.002 and OR 1.96, p = 0.03. respectively) while uninsured patients were admitted less frequently (OR 0.19, p = 0.013). No difference was noted in admissions between those with a psychiatric diagnosis and all others (60.7% vs 55.8%, p = 0.48). CONCLUSIONS: We identified factors associated with emergency department return after ureteroscopy, including a history of psychiatric diagnosis, uninsured status and emergency department visits in the year before surgery. These patients may benefit from targeted interventions to help avoid unnecessary emergency department visits.


Subject(s)
Emergency Service, Hospital/statistics & numerical data , Mental Disorders/epidemiology , Ureteroscopy/statistics & numerical data , Urolithiasis/epidemiology , Urolithiasis/surgery , Ambulatory Care/statistics & numerical data , Comorbidity , Female , Humans , Male , Medically Uninsured/statistics & numerical data , Middle Aged , Retrospective Studies , Risk Factors , Ureteroscopy/psychology
8.
J Health Commun ; 23(12): 999-1007, 2018.
Article in English | MEDLINE | ID: mdl-30346894

ABSTRACT

Studies show significant association between cancer risk and being a firefighter. After exposure to even routine firefighting, firefighters' bunker gear often contains carcinogens that may be absorbed through contact or inhaled through off-gassing, thereby increasing cancer risk. Awareness of increased cancer risk has given rise to policies and practices focused on gear cleaning and decontamination processes to decrease risk; yet, these efforts are in their infancy and tend to be somewhat piecemeal in nature. This study presents a theory-based communication intervention tailored to the unique context of high-reliability organizations (HROs). The intervention focused on increasing postfire decontamination behaviors to reduce exposure to carcinogens among firefighters. Results of the intervention across 14 fire stations from 2 fire departments in South Florida show significant increases in attitudes, norms, and self-efficacy, decreases in perceived barriers, and increased intention to engage in decontamination processes. While the intervention was highly successful in both fire departments, there were significant differences in between organizations; attitudes perceived norms, and barriers to gear cleaning remained significantly different. This highlights the need to examine the specific context of the organization in designing interventions. In line with previous research on HROs, regression models showed that norms and self-efficacy are the strongest predictors of current behavior. However, postintervention, attitudes emerge as the strongest predictor of future behavior. The results of this study provide valuable evidence for utilizing theoretical elements in message design for interventions in HROs, and of the importance of designing communication for specific sites of intervention.


Subject(s)
Carcinogens , Decontamination/methods , Firefighters , Health Promotion/methods , Neoplasms/prevention & control , Occupational Exposure/prevention & control , Personal Protective Equipment , Adult , Female , Firefighters/education , Firefighters/psychology , Humans , Male , Middle Aged , Models, Psychological , Personal Protective Equipment/adverse effects , Personal Protective Equipment/standards , Risk Reduction Behavior , Self Efficacy , Young Adult
9.
Am J Pathol ; 188(7): 1676-1692, 2018 07.
Article in English | MEDLINE | ID: mdl-29758183

ABSTRACT

The muscle-specific ubiquitin ligase atrogin-1 (MAFbx) has been identified as a critical regulator of pathologic and physiological cardiac hypertrophy; it regulates these processes by ubiquitinating transcription factors [nuclear factor of activated T-cells and forkhead box O (FoxO) 1/3]. However, the role of atrogin-1 in regulating transcription factors in aging has not previously been described. Atrogin-1 cardiomyocyte-specific transgenic (Tg+) adult mice (α-major histocompatibility complex promoter driven) have normal cardiac function and size. Herein, we demonstrate that 18-month-old atrogin-1 Tg+ hearts exhibit significantly increased anterior wall thickness without functional impairment versus wild-type mice. Histologic analysis at 18 months revealed atrogin-1 Tg+ mice had significantly less fibrosis and significantly greater nuclei and cardiomyocyte cross-sectional analysis. Furthermore, by real-time quantitative PCR, atrogin-1 Tg+ had increased Col 6a4, 6a5, 6a6, matrix metalloproteinase 8 (Mmp8), and Mmp9 mRNA, suggesting a role for atrogin-1 in regulating collagen deposits and MMP-8 and MMP-9. Because atrogin-1 Tg+ mice exhibited significantly less collagen deposition and protein levels, enhanced Mmp8 and Mmp9 mRNA may offer one mechanism by which collagen levels are kept in check in the aged atrogin-1 Tg+ heart. In addition, atrogin-1 Tg+ hearts showed enhanced FoxO1/3 activity. The present study shows a novel link between atrogin-1-mediated regulation of FoxO1/3 activity and reduced collagen deposition and fibrosis in the aged heart. Therefore, targeting FoxO1/3 activity via the muscle-specific atrogin-1 ubiquitin ligase may offer a muscle-specific method to modulate aging-related cardiac fibrosis.


Subject(s)
Aging , Cardiomegaly/prevention & control , Cardiovascular Physiological Phenomena , Fibrosis/prevention & control , Muscle Proteins/metabolism , SKP Cullin F-Box Protein Ligases/metabolism , Animals , Cardiomegaly/etiology , Cardiomegaly/metabolism , Cross-Sectional Studies , Fibrosis/etiology , Fibrosis/metabolism , Mice , Mice, Transgenic , Muscle Proteins/genetics , SKP Cullin F-Box Protein Ligases/genetics , Signal Transduction
10.
Contemp Clin Trials ; 64: 195-200, 2018 01.
Article in English | MEDLINE | ID: mdl-29030268

ABSTRACT

Surgical-site infections (SSIs) account for 20% of all healthcare-associated infections, are the most common nosocomial infection among surgical patients, and are a focus of quality improvement initiatives. Despite implementation of many quality care measures (e.g. prophylactic antibiotics), SSIs remain a significant cause of morbidity, mortality, and economic burden, particularly in the field of neurosurgery. Topical vancomycin is increasingly utilized in instrumented spinal and cardiothoracic procedures, where it has been shown to reduce the risk of SSIs. However, a randomized controlled trial assessing its efficacy in the general neurosurgical population has yet to be done. The principle aim of "Topical Vancomycin for Neurosurgery Wound Prophylaxis" (NCT02284126) is to determine whether prophylactic, topical vancomycin reduces the risk of SSIs in the adult neurosurgical population. This prospective, multicenter, patient-blinded, randomized controlled trial will enroll patients to receive the standard of care plus topical vancomycin, or the standard of care alone. The primary endpoint of this study is a SSI by postoperative day (POD) 30. Patients must be over 18years of age. Patients are excluded for renal insufficiency, vancomycin allergy, and some ineligible procedures. Univariate analysis and logistic regression will determine the effect of topical vancomycin on SSIs at 30days. A randomized controlled trial is needed to determine the efficacy of this treatment. Results of this trial are expected to directly influence the standard of care and prevention of SSIs in neurosurgical patients.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Antibiotic Prophylaxis/methods , Neurosurgical Procedures/methods , Surgical Wound Infection/prevention & control , Vancomycin/administration & dosage , Humans , Logistic Models , Prospective Studies , Research Design , Risk Factors , Single-Blind Method
11.
Nat Commun ; 8: 15770, 2017 06 08.
Article in English | MEDLINE | ID: mdl-28593993

ABSTRACT

Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research.


Subject(s)
Carcinoma, Renal Cell/genetics , Genes, myc , Kidney Neoplasms/genetics , Von Hippel-Lindau Tumor Suppressor Protein/genetics , ADP-Ribosylation Factors/genetics , ADP-Ribosylation Factors/metabolism , Animals , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Expression Regulation, Neoplastic , Humans , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Mice, Knockout , Mice, Transgenic , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Xenograft Model Antitumor Assays
12.
Proc Natl Acad Sci U S A ; 114(28): 7216-7221, 2017 07 11.
Article in English | MEDLINE | ID: mdl-28652367

ABSTRACT

Halide perovskites are promising semiconductor materials for solution-processed optoelectronic devices. Their strong ionic bonding nature results in highly dynamic crystal lattices, inherently allowing rapid ion exchange at the solid-vapor and solid-liquid interface. Here, we show that the anion-exchange chemistry can be precisely controlled in single-crystalline halide perovskite nanomaterials when combined with nanofabrication techniques. We demonstrate spatially resolved multicolor CsPbX3 (X = Cl, Br, I, or alloy of two halides) nanowire heterojunctions with a pixel size down to 500 nm with the photoluminescence tunable over the entire visible spectrum. In addition, the heterojunctions show distinct electronic states across the interface, as revealed by Kelvin probe force microscopy. These perovskite heterojunctions represent key building blocks for high-resolution multicolor displays beyond current state-of-the-art technology as well as high-density diode/transistor arrays.

13.
Am J Pathol ; 186(8): 1989-2007, 2016 08.
Article in English | MEDLINE | ID: mdl-27321750

ABSTRACT

The Bcl2-associated anthanogene (BAG) 3 protein is a member of the BAG family of cochaperones, which supports multiple critical cellular processes, including critical structural roles supporting desmin and interactions with heat shock proteins and ubiquitin ligases intimately involved in protein quality control. The missense mutation P209L in exon 3 results in a primarily cardiac phenotype leading to skeletal muscle and cardiac complications. At least 10 other Bag3 mutations have been reported, nine resulting in a dilated cardiomyopathy for which no specific therapy is available. We generated αMHC-human Bag3 P209L transgenic mice and characterized the progressive cardiac phenotype in vivo to investigate its utility in modeling human disease, understand the underlying molecular mechanisms, and identify potential therapeutic targets. We identified a progressive heart failure by echocardiography and Doppler analysis and the presence of pre-amyloid oligomers at 1 year. Paralleling the pathogenesis of neurodegenerative diseases (eg, Parkinson disease), pre-amyloid oligomers-associated alterations in cardiac mitochondrial dynamics, haploinsufficiency of wild-type BAG3, and activation of p38 signaling were identified. Unexpectedly, increased numbers of activated cardiac fibroblasts were identified in Bag3 P209L Tg+ hearts without increased fibrosis. Together, these findings point to a previously undescribed therapeutic target that may have application to mutation-induced myofibrillar myopathies as well as other common causes of heart failure that commonly harbor misfolded proteins.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Apoptosis Regulatory Proteins/genetics , Disease Models, Animal , Heart Failure/genetics , Heart Failure/physiopathology , Myocytes, Cardiac/pathology , Animals , Blotting, Western , Echocardiography , Fluorescent Antibody Technique , Haploinsufficiency , Heart Failure/pathology , Humans , In Situ Nick-End Labeling , MAP Kinase Signaling System , Mice , Mice, Transgenic , Mitochondria/pathology , Mutation, Missense , Real-Time Polymerase Chain Reaction
14.
J Am Chem Soc ; 138(23): 7236-9, 2016 06 15.
Article in English | MEDLINE | ID: mdl-27213511

ABSTRACT

Here, we demonstrate the successful synthesis of brightly emitting colloidal cesium lead halide (CsPbX3, X = Cl, Br, I) nanowires (NWs) with uniform diameters and tunable compositions. By using highly monodisperse CsPbBr3 NWs as templates, the NW composition can be independently controlled through anion-exchange reactions. CsPbX3 alloy NWs with a wide range of alloy compositions can be achieved with well-preserved morphology and crystal structure. The NWs are highly luminescent with photoluminescence quantum yields (PLQY) ranging from 20% to 80%. The bright photoluminescence can be tuned over nearly the entire visible spectrum. The high PLQYs together with charge transport measurements exemplify the efficient alloying of the anionic sublattice in a one-dimensional CsPbX3 system. The wires increased functionality in the form of fast photoresponse rates and the low defect density suggest CsPbX3 NWs as prospective materials for optoelectronic applications.

15.
ACS Nano ; 10(5): 5525-35, 2016 05 24.
Article in English | MEDLINE | ID: mdl-27124203

ABSTRACT

Photoelectrochemical (PEC) water splitting into hydrogen and oxygen is a promising strategy to absorb solar energy and directly convert it into a dense storage medium in the form of chemical bonds. The continual development and improvement of individual components of PEC systems is critical toward increasing the solar to fuel efficiency of prototype devices. Within this context, we describe a study on the growth of wurtzite indium phosphide (InP) nanowire (NW) arrays on silicon substrates and their subsequent implementation as light-absorbing photocathodes in PEC cells. The high onset potential (0.6 V vs the reversible hydrogen electrode) and photocurrent (18 mA/cm(2)) of the InP photocathodes render them as promising building blocks for high performance PEC cells. As a proof of concept for overall system integration, InP photocathodes were combined with a nanoporous bismuth vanadate (BiVO4) photoanode to generate an unassisted solar water splitting efficiency of 0.5%.

16.
Proc Natl Acad Sci U S A ; 113(8): 1993-8, 2016 Feb 23.
Article in English | MEDLINE | ID: mdl-26862172

ABSTRACT

The rapidly growing field of nanoscale lasers can be advanced through the discovery of new, tunable light sources. The emission wavelength tunability demonstrated in perovskite materials is an attractive property for nanoscale lasers. Whereas organic-inorganic lead halide perovskite materials are known for their instability, cesium lead halides offer a robust alternative without sacrificing emission tunability or ease of synthesis. Here, we report the low-temperature, solution-phase growth of cesium lead halide nanowires exhibiting low-threshold lasing and high stability. The as-grown nanowires are single crystalline with well-formed facets, and act as high-quality laser cavities. The nanowires display excellent stability while stored and handled under ambient conditions over the course of weeks. Upon optical excitation, Fabry-Pérot lasing occurs in CsPbBr3 nanowires with an onset of 5 µJ cm(-2) with the nanowire cavity displaying a maximum quality factor of 1,009 ± 5. Lasing under constant, pulsed excitation can be maintained for over 1 h, the equivalent of 10(9) excitation cycles, and lasing persists upon exposure to ambient atmosphere. Wavelength tunability in the green and blue regions of the spectrum in conjunction with excellent stability makes these nanowire lasers attractive for device fabrication.

17.
ACS Nano ; 10(2): 2600-6, 2016 Feb 23.
Article in English | MEDLINE | ID: mdl-26820809

ABSTRACT

Copper nanowire (Cu NW) based transparent conductors are promising candidates to replace ITO (indium-tin-oxide) owing to the high electrical conductivity and low-cost of copper. However, the relatively low performance and poor stability of Cu NWs under ambient conditions limit the practical application of these devices. Here, we report a solution-based approach to wrap graphene oxide (GO) nanosheets on the surface of ultrathin copper nanowires. By mild thermal annealing, GO can be reduced and high quality Cu r-GO core-shell NWs can be obtained. High performance transparent conducting films were fabricated with these ultrathin core-shell nanowires and excellent optical and electric performance was achieved. The core-shell NW structure enables the production of highly stable conducting films (over 200 days stored in air), which have comparable performance to ITO and silver NW thin films (sheet resistance ∼28 Ω/sq, haze ∼2% at transmittance of ∼90%).

18.
Urol Nurs ; 36(6): 283-8, 2016.
Article in English | MEDLINE | ID: mdl-29240349

ABSTRACT

This article presents findings of a quality improvement (QI) project using the DMAIC (define, measure, analyze, improve, and control) model designed to decrease the rate of emergency department (ED) visits and nurse advice line calls after ureteroscopic stone surgery. Results indicated that nurse-initiated follow- up phone calls can decrease ED visits.


Subject(s)
Aftercare , Kidney Calculi/surgery , Nephrology Nursing , Pain, Postoperative/nursing , Surgical Wound Infection/nursing , Telephone , Ureteral Calculi/surgery , Ureteroscopy , Urinary Tract Infections/nursing , Emergency Service, Hospital/statistics & numerical data , Female , Humans , Male , Quality Improvement
19.
J Am Chem Soc ; 137(51): 16008-11, 2015 Dec 30.
Article in English | MEDLINE | ID: mdl-26669631

ABSTRACT

Anisotropic colloidal quasi-two-dimensional nanoplates (NPLs) hold great promise as functional materials due to their combination of low dimensional optoelectronic properties and versatility through colloidal synthesis. Recently, lead-halide perovskites have emerged as important optoelectronic materials with excellent efficiencies in photovoltaic and light-emitting applications. Here we report the synthesis of quantum confined all inorganic cesium lead halide nanoplates in the perovskite crystal structure that are also highly luminescent (PLQY 84%). The controllable self-assembly of nanoplates either into stacked columnar phases or crystallographic-oriented thin-sheet structures is demonstrated. The broad accessible emission range, high native quantum yields, and ease of self-assembly make perovskite NPLs an ideal platform for fundamental optoelectronic studies and the investigation of future devices.

20.
Nat Genet ; 47(10): 1168-78, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26343385

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical.


Subject(s)
Adenocarcinoma/pathology , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/pathology , Stromal Cells/pathology , Adenocarcinoma/genetics , Animals , Carcinoma, Pancreatic Ductal/genetics , Female , Gene Expression , Genetic Heterogeneity , Heterografts , Humans , Male , Pancreatic Neoplasms/genetics
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