Taking Another Look at the Pornography Problems Due to Moral Incongruence Model: Does Gender Play a Role?

The pornography problems due to moral incongruence (PPMI) model is a premier framework for understanding problematic pornography use (PPU). However, past studies have generally examined men or entered gender as a covariate in primary analyses. Such approaches mask between-gender differences. Additionally, dysregulation constructs are also thought to be relevant to PPU, yet it is unclear the degree to which they incrementally predict PPU beyond moral incongruence constructs in non-pathological populations. We addressed these gaps by gathering a large sample of college students (n = 295 men, n = 838 women). Analyses with pornography users (n = 251 men, n = 407 women) were consistent with the PPMI model, adjusted for pornography use frequency. Findings did not change when dysregulation constructs of impulsivity and emotional resilience were added to the model. No paths significantly differed between genders. Altogether, among college student pornography users, religiosity was strongly positively correlated with moral disapproval (ß = .65 men, ß = .62 women), moral disapproval was moderately positively correlated with PPU (ß = .41 men, ß = .29 women), religiosity was initially moderately positively correlated with PPU (r = .21 men, r = .22 women), but became non-significant in the full model (ß = - .21 men, ß = - .04 women), and indirect effects of religiosity to PPU through moral disapproval were significant (indirect ß = .27 men, ß = .18 women). None of the dysregulation constructs significantly predicted PPU. The full model accounted for 23-22% of the PPU variance in men and women, respectively. Implications, future directions, and limitations are discussed.

High yield expression in Pichia pastoris of human neutrophil elastase fused to cytochrome B5.

Recombinant human neutrophil elastase (rHNE), a serine protease, was expressed in Pichia pastoris. Glycosylation sites were removed via bioengineering to prevent hyper-glycosylation (a common problem with this system) and the cDNA was codon optimized for translation in Pichia pastoris. The zymogen form of rHNE was secreted as a fusion protein with an N-terminal six histidine tag followed by the heme binding domain of Cytochrome B5 (CytB5) linked to the N-terminus of the rHNE sequence via an enteropeptidase cleavage site. The CytB5 fusion balanced the very basic rHNE (pI = 9.89) to give a colored fusion protein (pI = 6.87), purified via IMAC. Active rHNE was obtained via enteropeptidase cleavage, and purified via cation exchange chromatography, resulting in a single protein band on SDS PAGE (Mr = 25 KDa). Peptide mass fingerprinting analysis confirmed the rHNE amino acid sequence, the absence of glycosylation and the absence of an 8 amino acid C-terminal peptide as opposed to the 20 amino acids usually missing from the C-terminus of native enzyme. The yield of active rHNE was 0.41 mg/L of baffled shaker flask culture medium. Active site titration with alpha-1 antitrypsin, a potent irreversible elastase inhibitor, quantified the concentration of purified active enzyme. The Km of rHNE with methoxy-succinyl-AAPVpNA was identical with that of the native enzyme within the assay's limit of accuracy. This is the first report of full-length rHNE expression at high yields and low cost facilitating further studies on this major human neutrophil enzyme.

Shear stress regulation of miR-93 and miR-484 maturation through nucleolin.

Pulsatile shear (PS) and oscillatory shear (OS) elicit distinct mechanotransduction signals that maintain endothelial homeostasis or induce endothelial dysfunction, respectively. A subset of microRNAs (miRs) in vascular endothelial cells (ECs) are differentially regulated by PS and OS, but the regulation of the miR processing and its implications in EC biology by shear stress are poorly understood. From a systematic in silico analysis for RNA binding proteins that regulate miR processing, we found that nucleolin (NCL) is a major regulator of miR processing in response to OS and essential for the maturation of miR-93 and miR-484 that target mRNAs encoding Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS). Additionally, anti-miR-93 and anti-miR-484 restore KLF2 and eNOS expression and NO bioavailability in ECs under OS. Analysis of posttranslational modifications of NCL identified that serine 328 (S328) phosphorylation by AMP-activated protein kinase (AMPK) was a major PS-activated event. AMPK phosphorylation of NCL sequesters it in the nucleus, thereby inhibiting miR-93 and miR-484 processing and their subsequent targeting of KLF2 and eNOS mRNA. Elevated levels of miR-93 and miR-484 were found in sera collected from individuals afflicted with coronary artery disease in two cohorts. These findings provide translational relevance of the AMPK-NCL-miR-93/miR-484 axis in miRNA processing in EC health and coronary artery disease.

Attenuation of Oxidative Injury With Targeted Expression of NADPH Oxidase 2 Short Hairpin RNA Prevents Onset and Maintenance of Electrical Remodeling in the Canine Atrium: A Novel Gene Therapy Approach to Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal because they are not targeted to the molecular mechanisms underlying AF. Using a highly novel gene therapy approach in a canine, rapid atrial pacing model of AF, we demonstrate that NADPH oxidase 2 (NOX2) generated oxidative injury causes upregulation of a constitutively active form of acetylcholine-dependent K+ current (IKACh), called IKH; this is an important mechanism underlying not only the genesis, but also the perpetuation of electric remodeling in the intact, fibrillating atrium. METHODS: To understand the mechanism by which oxidative injury promotes the genesis and maintenance of AF, we performed targeted injection of NOX2 short hairpin RNA (followed by electroporation to facilitate gene delivery) in atria of healthy dogs followed by rapid atrial pacing. We used in vivo high-density electric mapping, isolation of atrial myocytes, whole-cell patch clamping, in vitro tachypacing of atrial myocytes, lucigenin chemiluminescence assay, immunoblotting, real-time polymerase chain reaction, immunohistochemistry, and Masson trichrome staining. RESULTS: First, we demonstrate that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through the induction of NOX2 and the generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electric remodeling in AF by upregulating IKACh by a mechanism involving frequency-dependent activation of PKCε (protein kinase C epsilon). The time to onset of nonsustained AF increased by >5-fold in NOX2 short hairpin RNA-treated dogs. Furthermore, animals treated with NOX2 short hairpin RNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, at least in part attributable to the attenuation of IKACh. Attenuated membrane translocation of PKCε appeared to be a likely molecular mechanism underlying this beneficial electrophysiological remodeling. CONCLUSIONS: NOX2 oxidative injury (1) underlies the onset, and the maintenance of electric remodeling in AF, as well, and (2) can be successfully prevented with a novel, gene-based approach. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.

A Polyp Worth Removing: A Paradigm for Measuring Colonoscopy Quality and Performance of Novel Technologies for Polyp Detection.

Leaving no significant polyp behind while avoiding risks due to unnecessary resections is a commonsense strategy to safely and effectively prevent colorectal cancer (CRC) with colonoscopy. It also alludes to polyps worth removing and, therefore, worth finding. The majority of "worthy" precancerous polyps are adenomas, which for over 2 decades, have received the most attention in performance research and metrics. Consequently, the detection rate of adenomas is currently the only validated, outcome-based measure of colonoscopy demonstrated to correlate with reduced risk of postcolonoscopy CRC. However, a third or more of postcolonoscopy CRCs originate from sessile serrated polyps (SSPs), which are notoriously difficult to find, diagnose and completely resect. Among serrated polyps, the agreement among pathologists differentiating SSPs from non-neoplastic hyperplastic polyps is moderate at best. This lack of ground truth precludes SSPs from consideration in primary metrics of colonoscopy quality or performance of novel polyp detection technologies. By instead leveraging the distinct endoscopic and clinical features of serrated polyps, including those considered important due to proximal location and larger size, clinically significant serrated polyps represent serrated polyps worth removing, enriched with subtle precancerous SSPs. With the explosion of technologies to assist polyp detection, now is the time to broaden benchmarks to include clinically significant serrated polypss alongside adenomas, a measure that is relevant both for assessing the performance of endoscopists, and for assessing new polyp detection technologies.

Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase.

Human neutrophil elastase (HNE) is a uniquely destructive serine protease with the ability to unleash a wave of proteolytic activity by destroying the inhibitors of other proteases. Although this phenomenon forms an important part of the innate immune response to invading pathogens, it is responsible for the collateral host tissue damage observed in chronic conditions such as chronic obstructive pulmonary disease (COPD), and in more acute disorders such as the lung injuries associated with COVID-19 infection. Previously, a combinatorially selected activity-based probe revealed an unexpected substrate preference for oxidised methionine, which suggests a link to oxidative pathogen clearance by neutrophils. Here we use oxidised model substrates and inhibitors to confirm this observation and to show that neutrophil elastase is specifically selective for the di-oxygenated methionine sulfone rather than the mono-oxygenated methionine sulfoxide. We also posit a critical role for ordered solvent in the mechanism of HNE discrimination between the two oxidised forms methionine residue. Preference for the sulfone form of oxidised methionine is especially significant. While both host and pathogens have the ability to reduce methionine sulfoxide back to methionine, a biological pathway to reduce methionine sulfone is not known. Taken together, these data suggest that the oxidative activity of neutrophils may create rapidly cleaved elastase "super substrates" that directly damage tissue, while initiating a cycle of neutrophil oxidation that increases elastase tissue damage and further neutrophil recruitment.

Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity.

Toll-like receptors 7 and 8 (TLR7/8) agonists are potent immunostimulants that are attracting considerable interest as vaccine adjuvants. We recently reported the synthesis of a new series of 2-O-butyl-8-oxoadenines substituted at the 9-position with various linkers and N-heterocycles, and showed that TLR7/8 selectivity, potency and cytokine induction could be modulated by varying the alkyl linker length and the N-heterocyclic ring. In the present study, we further optimized the oxoadenine scaffold by investigating the effect of different substituents at the 2-position of the oxoadenine on TLR7/8 potency/selectivity, cytokine induction and DC maturation in human PBMCs. The results show that introducing a 1-(S)-methylbutoxy group at the 2-position of the oxoadenine significantly increased potency for TLR7/8 activity, cytokine induction and DC maturation.

The Variation in the Standard Entropies of Aqueous Tripositive Lanthanide Ions.

Previous published entropies of solid lanthanide trichloride hydrates are reviewed and revised by taking account of the Kramers degeneracy of ground states with half-integral values of J. The revised values necessitate corrections to the standard entropies of the aqueous tripositive lanthanide ions which display an irregular variation with both atomic number and ionic radius. These irregularities can be smoothed out by taking account of contributions from the electronic or magnetic entropy, from structural changes in the coordination that have been revealed by EXAFS and XANES measurements and X-ray crystallography, and from an increasing intrusion of eight coordination across the series. When these contributions are removed, the entropies of the aqueous ions refer to a hypothetical nine-coordinate state in trigonal triprismatic coordination. Within experimental error, they then vary uniformly across the lanthanide series and there is a good linear correlation with the reciprocal of the metal-oxygen distance in the nine-coordinate aqua complexes.

Dedicated MRI in the emergency department to expedite diagnostic management of hip fracture.

PURPOSE: To determine the effect on time to diagnosis of making MRI imaging for hip fractures available directly in the emergency department (ED). METHODS: We conducted a retrospective observational study of patients with MRI imaging of the hip for suspected occult fracture, comparing time to diagnosis and time to disposition of populations imaged in the year preceding and the year following installation of an MRI scanner in the ED. RESULTS: Time to diagnosis of hip fractures was 709 min before installation of a dedicated ED MRI scanner and 280 min after, a 60% reduction. Including the MRI in the diagnostic workup did not increase ED throughput time, and we were able to save 48% of the patients who had an ED-based MRI from an admission to the hospital. CONCLUSION: Implementation of an MRI scanner for dedicated emergency department use enables faster hip fracture diagnosis and surgical consultation, or definitive disposition without increasing ED throughput time.

Bowel preparation for colonoscopy: what is best and necessary for quality?

PURPOSE OF REVIEW: Colonoscopy is recognizably, the best colon cancer prevention test, provided the quality of the preparation is adequate for detection of precancerous polyps but also allowing for accurate identification of margins, thereby facilitating complete endoscopic resection. As there are many aspects effecting colon prep outcomes, it is timely to review new standards for optimizing outcomes, including product selection based on patient demographics. RECENT FINDINGS: New national guidelines have set a minimum quality threshold for adequacy and also defined a split day delivery for oral options as the "standard of care". Several new prep options have been recently released and these data are discussed. SUMMARY: Optimizing the quality of colon preps has major implications for clinical practice. Clinicians must recognize new targets for standard of care, providing the best approach for each individual patient, considering variable factors which may otherwise compromise success.

Response of photosynthesis, growth and water relations of a savannah-adapted tree and grass grown across high to low CO2.

BACKGROUND AND AIMS: By the year 2100, atmospheric CO2 concentration ([CO2]a) could reach 800 ppm, having risen from ~200 ppm since the Neogene, beginning ~24 Myr ago. Changing [CO2]a affects plant carbon-water balance, with implications for growth, drought tolerance and vegetation shifts. The evolution of C4 photosynthesis improved plant hydraulic function under low [CO2]a and preluded the establishment of savannahs, characterized by rapid transitions between open C4-dominated grassland with scattered trees and closed forest. Understanding directional vegetation trends in response to environmental change will require modelling. But models are often parameterized with characteristics observed in plants under current climatic conditions, necessitating experimental quantification of the mechanistic underpinnings of plant acclimation to [CO2]a. METHODS: We measured growth, photosynthesis and plant-water relations, within wetting-drying cycles, of a C3 tree (Vachellia karroo, an acacia) and a C4 grass (Eragrostis curvula) grown at 200, 400 or 800 ppm [CO2]a. We investigated the mechanistic linkages between trait responses to [CO2]a under moderate soil drying, and photosynthetic characteristics. KEY RESULTS: For V. karroo, higher [CO2]a increased assimilation, foliar carbon:nitrogen, biomass and leaf starch, but decreased stomatal conductance and root starch. For Eragrostis, higher [CO2]a decreased C:N, did not affect assimilation, biomass or starch, and markedly decreased stomatal conductance. Together, this meant that C4 advantages in efficient water-use over the tree were maintained with rising [CO2]a. CONCLUSIONS: Acacia and Eragrostis acclimated differently to [CO2]a, with implications for their respective responses to water limitation and environmental change. Our findings question the carbon-centric focus on factors limiting assimilation with changing [CO2]a, how they are predicted and their role in determining productivity. We emphasize the continuing importance of water-conserving strategies in the assimilation response of savannah plants to rising [CO2]a.

The Gestation and Growth of the Periodic Table.

The development of ideas of chemical periodicity from Lavoisier to Mendeleyev's first periodic table of 1869 is surveyed. Although his first periodic table contained a number of errors and weaknesses, his remarkable predictions of the properties of several then unknown elements, together with his capacity to adapt the table to new discoveries, slowly led to its general acceptance. The theory of atomic structure slowly developed to a point where it could rationalise the structure of the table which had, however, been established solely on the basis of experimental observations. Chemistry has played the central role, up to and including the final modification of Seaborg to introduce the actinides - although this had been foreseen by Alfred Werner! Finally we discuss the many physical forms in which the table has been presented.

Colorectal Cancer Screening: Recommendations for Physicians and Patients From the U.S. Multi-Society Task Force on Colorectal Cancer.

This document updates the colorectal cancer (CRC) screening recommendations of the U.S. Multi-Society Task Force of Colorectal Cancer (MSTF), which represents the American College of Gastroenterology, the American Gastroenterological Association, and The American Society for Gastrointestinal Endoscopy. CRC screening tests are ranked in 3 tiers based on performance features, costs, and practical considerations. The first-tier tests are colonoscopy every 10 years and annual fecal immunochemical test (FIT). Colonoscopy and FIT are recommended as the cornerstones of screening regardless of how screening is offered. Thus, in a sequential approach based on colonoscopy offered first, FIT should be offered to patients who decline colonoscopy. Colonoscopy and FIT are recommended as tests of choice when multiple options are presented as alternatives. A risk-stratified approach is also appropriate, with FIT screening in populations with an estimated low prevalence of advanced neoplasia and colonoscopy screening in high prevalence populations. The second-tier tests include CT colonography every 5 years, the FIT-fecal DNA test every 3 years, and flexible sigmoidoscopy every 5 to 10 years. These tests are appropriate screening tests, but each has disadvantages relative to the tier 1 tests. Because of limited evidence and current obstacles to use, capsule colonoscopy every 5 years is a third-tier test. We suggest that the Septin9 serum assay (Epigenomics, Seattle, Wash) not be used for screening. Screening should begin at age 50 years in average-risk persons, except in African Americans in whom limited evidence supports screening at 45 years. CRC incidence is rising in persons under age 50, and thorough diagnostic evaluation of young persons with suspected colorectal bleeding is recommended. Discontinuation of screening should be considered when persons up to date with screening, who have prior negative screening (particularly colonoscopy), reach age 75 or have <10 years of life expectancy. Persons without prior screening should be considered for screening up to age 85, depending on age and comorbidities. Persons with a family history of CRC or a documented advanced adenoma in a first-degree relative age <60 years or 2 first-degree relatives with these findings at any age are recommended to undergo screening by colonoscopy every 5 years, beginning 10 years before the age at diagnosis of the youngest affected relative or age 40, whichever is earlier. Persons with a single first-degree relative diagnosed at ≥60 years with CRC or an advanced adenoma can be offered average-risk screening options beginning at age 40 years.

Recommendations on Fecal Immunochemical Testing to Screen for Colorectal Neoplasia: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

The use of the fecal occult blood test (FOBT) for colorectal cancer (CRC) screening is supported by randomized trials demonstrating effectiveness in cancer prevention and widely recommended by guidelines for this purpose. The fecal immunochemical test (FIT), as a direct measure of human hemoglobin in stool has a number of advantages relative to conventional FOBT and is increasingly used relative to that test. This review summarizes current evidence for FIT in colorectal neoplasia detection and the comparative effectiveness of FIT relative to other commonly used CRC screening modalities. Based on evidence, guidance statements on FIT application were developed and quality metrics for program implementation proposed.

Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease.

Increased detection of Barrett's esophagus-associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial.

BACKGROUND AND AIMS: Wide-area transepithelial sampling (WATS) with computer-assisted 3-dimensional analysis is a sampling technique that combines abrasive brushing of the Barrett's esophagus (BE) mucosa followed by neural network analysis to highlight abnormal-appearing cells. METHODS: We performed a randomized trial of referred BE patients undergoing surveillance at 16 medical centers. Subjects received either biopsy sampling followed by WATS or WATS followed by biopsy sampling. The primary outcome was rate of detection of high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) using WATS in conjunction with biopsy sampling compared with biopsy sampling alone using standard histopathologic criteria. Secondary aims included evaluating neoplasia detection rates based on the procedure order (WATS vs biopsy sampling first), of each procedure separately, and the additional time required for WATS. RESULTS: One hundred sixty patients (mean age, 63.4 years; 76% men; 95% white) completed the trial. The median circumferential and maximal BE extents were 1.0 cm (interquartile range: .0-5.0) and 4.0 cm (interquartile range, 2.0-8.0), respectively. The diagnostic yield for biopsy sampling alone was as follows: HGD/EAC, 7 (4.4%); low-grade dysplasia (LGD), 28 (17.5%); nondysplastic BE (NDBE), 106 (66.25%); and no BE, 19 (11.9%). The addition of WATS to biopsy sampling yielded an additional 23 cases of HGD/EAC (absolute increase, 14.4%; 95% confidence interval, 7.5%-21.2%). Among these 23 patients, 11 were classified by biopsy sampling as NDBE and 12 as LGD/indefinite for dysplasia (IND); 14 received biopsy sampling first and 9 WATS first (not significant) and most (n = 21; 91.7%) had a prior dysplasia history. WATS added an average of 4.5 minutes to the procedure. CONCLUSION: Results of this multicenter, prospective, randomized trial demonstrate that the use of WATS in a referral BE population increases the detection of HGD/EAC. (Clinical trial registration number: NCT03008980.).

Diastereoselective Syntheses of ( E)-α-Trialkylsilyl α,ß-Unsaturated Esters, α-Silane-Substituted Conjugated Silyl Ketene Acetals, and α,γ-Substituted Allylsilanes.

The vicinal functionalization of propiolate esters via a catalytic carbocupration/silicon group migration sequence has been further investigated to include the syntheses of a wide variety of ß-alkyl- and ß-aryl-substituted ( E)-α-silyl α,ß-unsaturated esters. The ester substrates were transformed into their ß,γ-unsaturated isomers by means of an LDA-mediated γ-deprotonation, extended silyl ketene acetal formation, and final α-protonation sequence. The silyl ketene acetal intermediates were also isolated, and their stereochemistries were established by NOE. The isolation of the intermediate extended silyl ketene acetals afforded further understanding of the lithium-extended dienolate structure and furnished additional support for Snieckus's proposed cyclic eight-membered transition state in the deprotonation of ( Z)-α,ß-unsaturated carbonyls with metallodialkylamides.

The Effects of Sleep on the Commensal Microbiota: Eyes Wide Open?

Sleep dysfunction is an epidemic, the implications of which have a profound impact on a variety of gastrointestinal disease. Recent data suggests a relationship between sleep dysfunction and intestinal dysbiosis, a known proinflammatory driver. This article evaluates the interplay between sleep dysfunction and gastrointestinal health and disease, with a focus on the impact of circadian rhythm disruption on the commensal microbiota.

Wake-up Call to Clinicians: The Impact of Sleep Dysfunction on Gastrointestinal Health and Disease.

Sleep dysfunction is an epidemic affecting a large portion of the adult population. Recent studies have linked sleep dysfunction with an upregulation of proinflammatory cytokines (eg, tumor necrosis factor-α, interleukin-1 and interleukin-6), the implications of which can have a profound impact on a variety of gastrointestinal disease. In particular, sleep dysfunction seems to accelerate disease states characterized by inflammation (eg, gastroesophageal reflux disease, irritable bowel syndrome and functional dyspepsia, chronic liver disease, inflammatory bowel disease, and colorectal cancer). This article evaluates the complex interplay between sleep dysfunction and gastrointestinal health and disease.