Onset of Irritable Bowel Syndrome, Dyspepsia, Diarrhea, Bloating, and Constipation in Deployed Gulf War Veterans.

An estimated 694,550 United States service members were actively deployed to the Persian Gulf from 1990-1991. Many veterans who were deployed developed Persian Gulf War Syndrome along with chronic gastrointestinal symptoms after returning from the Persian Gulf. Our objective in this study was to determine the phenotypic expression of gastrointestinal symptom complexes in previously healthy veterans who had been stationed in the Persian Gulf. One hundred and four consecutive veterans (88 males, 16 females) who had previously been deployed in 1990-91 were evaluated for their bowel habits and gastrointestinal symptoms. A workup was completed to find identifiable causes of their symptoms and all veterans were asked to do a modified version of the Bowel Disease Questionnaire symptom survey. None of the veterans reported gastrointestinal symptoms before deployment. During deployment to the Persian Gulf: 22 veterans (21%) developed irritable bowel syndrome; 17 (16%) developed dyspepsia; 50 (48%) developed diarrhea; 11 (11%) developed bloating; and 4 (4%) developed constipation. The results of the current study suggest that the development of irritable bowel syndrome, dyspepsia, diarrhea, bloating, and constipation is frequently seen in deployed Gulf War Veterans and the gastrointestinal symptoms commonly persist upon returning home. These novel findings are very important for currently deployed veterans who are serving in the Middle East and are at a high risk of developing gastrointestinal disorders.

Combining Off-flow, a Nextflow-coded program, and whole genome sequencing reveals unintended genetic variation in CRISPR/Cas-edited iPSCs.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas nucleases and human induced pluripotent stem cell (iPSC) technology can reveal deep insight into the genetic and molecular bases of human biology and disease. Undesired editing outcomes, both on-target (at the edited locus) and off-target (at other genomic loci) hinder the application of CRISPR-Cas nucleases. We developed Off-flow, a Nextflow-coded bioinformatic workflow that takes a specific guide sequence and Cas protein input to call four separate off-target prediction programs (CHOPCHOP, Cas-Offinder, CRISPRitz, CRISPR-Offinder) to output a comprehensive list of predicted off-target sites. We applied it to whole genome sequencing (WGS) data to investigate the occurrence of unintended effects in human iPSCs that underwent repair or insertion of disease-related variants by homology-directed repair. Off-flow identified a 3-base-pair-substitution and a mono-allelic genomic deletion at the target loci, KCNQ2, in 2 clones. Unbiased WGS analysis further identified off-target missense variants and a mono-allelic genomic deletion at the targeted locus, GNAQ, in 10 clones. On-target substitution and deletions had escaped standard PCR and Sanger sequencing analysis, while missense variants at other genomic loci were not detected by Off-flow. We used these results to filter out iPSC clones for subsequent functional experiments. Off-flow, which we make publicly available, works for human and mouse genomes currently and can be adapted for other genomes. Off-flow and WGS analysis can improve the integrity of studies using CRISPR/Cas-edited cells and animal models.

Catechol-O-Methyltransferase Loss Drives Cell-Specific Nociceptive Signaling via the Enteric Catechol-O-Methyltransferase/microRNA-155/Tumor Necrosis Factor α Axis.

BACKGROUND & AIMS: The etiology of abdominal pain in postinfectious, diarrhea-predominant irritable bowel syndrome (PI-IBS-D) is unknown, and few treatment options exist. Catechol-O-methyltransferase (COMT), an enzyme that inactivates and degrades biologically active catecholamines, plays an important role in numerous physiologic processes, including modulation of pain perception. Our objective was to determine the mechanism(s) of how decreased colonic COMT in PI-IBS-D patients contributes to the chronic abdominal pain phenotype after enteric infections. METHODS: Colon neurons, epithelial cells, and macrophages were procured with laser capture microdissection from PI-IBS-D patients to evaluate cell-specific colonic COMT, microRNA-155 (miR-155), and tumor necrosis factor (TNF) α expression levels compared to recovered patients (infection cleared: did not develop PI-IBS-D) and control individuals. COMT-/-, colon-specific COMT-/-, and miR-155-/- mice and human colonoids were used to model phenotypic expression of COMT in PI-IBS-D patients and to investigate signaling pathways linking abdominal pain. Citrobacter rodentium and trinitrobenzene sulfonic acid animal models were used to model postinflammatory changes seen in PI-IBS-D patients. RESULTS: Colonic COMT levels were significantly decreased and correlated with increased visual analog scale abdominal pain ratings in PI-IBS-D patients compared to recovered patients and control individuals. Colonic miR-155 and TNF-α were increased in PI-IBS-D patients with diminished colonic COMT. COMT-/- mice had significantly increased expression of miR-155 and TNF-α in both colon tissues and dorsal root ganglia. Introduction of cV1q antibody (anti-TNF-α) into mice reversed visceral hypersensitivity after C rodentium and trinitrobenzene sulfonic acid. CONCLUSIONS: Decreased colonic COMT in PI-IBS-D patients drives abdominal pain phenotypes via the COMT/miR-155/TNF-α axis. These important findings will allow new treatment paradigms and more targeted and personalized medicine approaches for gastrointestinal disorders after enteric infections.

Autonomic dysfunction and gastroparesis in Gulf War veterans.

Over 25% of veterans with Gulf War illness developed chronic gastrointestinal (GI) symptoms of unknown etiology after they returned from deployment to the Persian Gulf. To determine the prevalence of delayed gastric emptying and its association with autonomic dysfunction in returning Gulf War (GW) veterans with chronic GI symptoms, we prospectively studied 35 veterans who were deployed to the Persian Gulf and developed chronic nausea, vomiting, postprandial abdominal pain, and bloating during their tour of duty and 15 asymptomatic controls. All veterans underwent 5 standardized cardiovascular tests to assess autonomic function. Each test was scored from 0 (normal) to 5 (severe disease) and the mean was calculated. A composite score >1.5 was considered abnormal, with 5 representing severe autonomic dysfunction. A standardized gastric emptying test with a solid phase was performed in each veteran. A gastric retention of >50% at 100 minutes was considered abnormal. The composite autonomic score was 3.7 in veterans with GI symptoms (vs 1.3 in controls) (p<0.01). The mean solid phase retention at 100 minutes was 72.6% in the symptomatic veterans versus 24.6% in controls (p<0.001). Our results suggest that autonomic dysfunction and delayed gastric emptying are common in returning GW veterans with GI symptoms. Autonomic dysfunction was positively correlated with the severity of delayed gastric emptying and may account for the GI symptoms of nausea, vomiting, postprandial abdominal pain, and bloating. These new findings are important for an increasing number of veterans who are serving in the Persian Gulf and are at a high risk of developing GI disorders while deployed.

Geometry-informed irreversible perturbations for accelerated convergence of Langevin dynamics.

We introduce a novel geometry-informed irreversible perturbation that accelerates convergence of the Langevin algorithm for Bayesian computation. It is well documented that there exist perturbations to the Langevin dynamics that preserve its invariant measure while accelerating its convergence. Irreversible perturbations and reversible perturbations (such as Riemannian manifold Langevin dynamics (RMLD)) have separately been shown to improve the performance of Langevin samplers. We consider these two perturbations simultaneously by presenting a novel form of irreversible perturbation for RMLD that is informed by the underlying geometry. Through numerical examples, we show that this new irreversible perturbation can improve estimation performance over irreversible perturbations that do not take the geometry into account. Moreover we demonstrate that irreversible perturbations generally can be implemented in conjunction with the stochastic gradient version of the Langevin algorithm. Lastly, while continuous-time irreversible perturbations cannot impair the performance of a Langevin estimator, the situation can sometimes be more complicated when discretization is considered. To this end, we describe a discrete-time example in which irreversibility increases both the bias and variance of the resulting estimator.

Establishing Background Pathologic Changes of Valve Replacement Surgery in Sheep.

PURPOSE: Sheep are the standard preclinical model for assessing safety of novel replacement heart valves, yet the anatomic and pathologic effects of invasive surgery, including those involving cardiopulmonary bypass (CPB), are unknown. Thus, we aimed to determine the gross, hematologic and biochemical effects of sham mitral and aortic replacement valve procedures in sheep to establish a useful control for evaluation of novel replacement valves. METHODS: Six control sheep were examined without any surgical intervention. Six sham mitral valve replacements (MVR) and six sham aortic valve replacements (AVR) were performed on 12 sheep. Complete blood counts and serum biochemistry were performed throughout the study. Sheep were sacrificed with a necropsy performed at 90 days. RESULTS: Renal infarcts (RIs) were the most frequently observed lesion, averaging 4.7 in control sheep, 2.5 with MVR and 5.8 with AVR. The number of infarcts strongly correlated with total estimated area of infarcted kidney (r = .84, p < .01). Additional cardiac interventions were significantly correlated with increased numbers of RIs (r = .85, p < .01). There was no correlation between number of RIs and time on CPB, or between AVR and MVR procedures. CONCLUSION: The sheep model for AVR and MVR requires invasive surgery and CPB, which are associated with background anatomic and pathologic changes, especially in cases with additional surgical cardiac interventions. These findings serve as a critical control for future evaluation and development of novel replacement valves in order to distinguish device-related safety issues from expected outcomes of the surgical procedure and normal background changes in sheep.

Long-Term Results of Diaphragmatic Hernia Repair After Left Ventricular Assist Device Explantation.

BACKGROUND: Diaphragmatic hernias after explantation of a left ventricular assist device (LVAD) at the time of heart transplantation are uncommon, but they can cause morbidity. This study presents midterm to long-term results of diaphragmatic hernia repair in these patients. METHODS: A retrospective chart review was performed on a prospectively collected database of all patients who underwent sequential LVAD explantation and heart transplantation at the University of Minnesota (Minneapolis, MN) since 1995. All patients who had a diaphragmatic hernia were included in the study. Patients' demographics, perioperative morbidity, and long-term results were recorded. RESULTS: From January 1995 to June 2018, 712 LVADs were placed, and subsequently 293 hearts were transplanted. The incidence of diaphragmatic hernia after heart transplantation was 7.1% (n = 21), with a median time from transplantation to diagnosis of 23 months (interquartile range [IQR], 9 to 39 months). Four patients did not undergo operative repair, and 1 patient was excluded for insufficient data. Sixteen patients underwent diaphragmatic hernia repair (male, 13; female, 3). Thirteen patients underwent laparoscopic repair with mesh, and 3 patients had open repair. Two patients presented with strangulated hernias requiring laparotomy and bowel resection. Median follow-up time was 53 months (IQR, 12 to 141 months) for the entire cohort. One recurrence was noted (6.2%), in a patient with laparoscopic repair. CONCLUSIONS: Diaphragmatic hernia repair after sequential LVAD explantation and orthotopic heart transplantation is feasible and appears to be safe. When this hernia is diagnosed, patients should be referred for surgical evaluation.

Driving force dependence of inner-sphere electron transfer for the reduction of CO2 on a gold electrode.

The kinetics of the inner-sphere electron transfer reaction between a gold electrode and CO2 was measured as a function of the applied potential in an aqueous environment. Extraction of the electron transfer rate constant requires deconvolution of the current associated with CO2 reduction from the competing hydrogen evolution reaction and mass transport. Analysis of the inner-sphere electron transfer reaction reveals a driving force dependence of the rate constant that has similar characteristics to that of a Marcus-Hush-Levich outer-sphere electron transfer model. Consideration of simple assumptions for CO2 adsorption on the electrode surface allows for the evaluation of a CO2,ads/CO2 •- ads standard potential of ∼-0.75 ± 0.05 V vs Standard Hydrogen Electrode (SHE) and a reorganization energy on the order of 0.75 ± 0.10 eV. This standard potential is considerably lower than that observed for CO2 reduction on planar metal electrodes (∼>-1.4 V vs SHE for >10 mA/cm2), thus indicating that CO2 reduction occurs at a significant overpotential and thus provides an imperative for the design of better CO2 reduction electrocatalysts.

Interplay of Homogeneous Reactions, Mass Transport, and Kinetics in Determining Selectivity of the Reduction of CO2 on Gold Electrodes.

Gold electrocatalysts have been a research focus due to their ability to reduce CO2 into CO, a feedstock for further conversion. Many methods have been employed to modulate CO2 reduction (CDR) vs hydrogen evolution reaction (HER) selectivity on gold electrodes such as nano-/mesostructuring and crystal faceting control. Herein we show that gold surfaces with very different morphologies (planar, leaves, and wires) lead to similar bell-shaped CO faradaic efficiency as a function of applied potential. At low overpotential (E > -0.85 V vs standard hydrogen electrode (SHE)), HER is dominant via a potential quasi-independent rate that we attribute to a rate limiting process of surface dissociation of competent proton donors. As overpotential is increased, CO faradaic efficiency reaches a maximal value (near 90%) because CO production is controlled by an electron transfer rate that increases with potential, whereas HER remains almost potential independent. At high overpotential (E < -1.2 V vs SHE), CO faradaic efficiency decreases due to the concurrent rise of HER via bicarbonate direct reduction and leveling off of CDR as CO2 replenishment at the catalyst surface is limited by mass transport and homogeneous coupled reactions. Importantly, the analysis shows that recent attempts to overcome mass transport limitations with gas diffusion electrodes confront low carbon mass balance owing to the prominence of homogeneous reactions coupled to CDR. The comprehensive kinetics analysis of the factors defining CDR vs HER on gold electrodes developed here provides an activation-driving force relationship over a large potential window and informs on the design of conditions to achieve desirable high current densities for CO2 to CO conversion while maintaining high selectivity.

Preclinical Assessment of Cardiac Valve Substitutes: Current Status and Considerations for Engineered Tissue Heart Valves.

Tissue engineered heart valve (TEHV) technology may overcome deficiencies of existing available heart valve substitutes. The pathway by which TEHVs will undergo development and regulatory approval has several challenges. In this communication, we review: (1) the regulatory framework for regulation of medical devices in general and substitute heart valves in particular; (2) the special challenges of preclinical testing using animal models for TEHV, emphasizing the International Standards Organization (ISO) guidelines in document 5840; and (3) considerations that suggest a translational roadmap to move TEHV forward from pre-clinical to clinical studies and clinical implementation.

Electrochemical Deposition of Conformal and Functional Layers on High Aspect Ratio Silicon Micro/Nanowires.

Development of new synthetic methods for the modification of nanostructures has accelerated materials design advances to furnish complex architectures. Structures based on one-dimensional (1D) silicon (Si) structures synthesized using top-down and bottom-up methods are especially prominent for diverse applications in chemistry, physics, and medicine. Yet further elaboration of these structures with distinct metal-based and polymeric materials, which could open up new opportunities, has been difficult. We present a general electrochemical method for the deposition of conformal layers of various materials onto high aspect ratio Si micro- and nanowire arrays. The electrochemical deposition of a library of coaxial layers comprising metals, metal oxides, and organic/inorganic semiconductors demonstrate the materials generality of the synthesis technique. Depositions may be performed on wire arrays with varying diameter (70 nm to 4 µm), pitch (5 µ to 15 µ), aspect ratio (4:1 to 75:1), shape (cylindrical, conical, hourglass), resistivity (0.001-0.01 to 1-10 ohm/cm2), and substrate orientation. Anisotropic physical etching of wires with one or more coaxial shells yields 1D structures with exposed tips that can be further site-specifically modified by an electrochemical deposition approach. The electrochemical deposition methodology described herein features a wafer-scale synthesis platform for the preparation of multifunctional nanoscale devices based on a 1D Si substrate.

Suppression of epileptic seizures via Anderson localization.

Here we show that brain seizures can be effectively suppressed through random modulation of the brain medium. We use an established mesoscale cortical model in the form of a system of coupled stochastic partial differential equations. We show that by temporal and spatial randomization of parameters governing the firing rates of the excitatory and inhibitory neuron populations, seizure waves can be significantly suppressed. We find that the attenuation is the most effective when applied to the mean threshold potential. The proposed technique can serve as a non-invasive paradigm to mitigate epileptic seizures without knowing the location of the epileptic foci.

Electronic and Morphological Studies of Conjugated Polymers Incorporating a Disk-Shaped Polycyclic Aromatic Hydrocarbon Unit.

As more research findings have shown the correlation between ordering in organic semiconductor thin films and device performance, it is becoming more essential to exercise control of the ordering through structural tuning. Many recent studies have focused on the influence of side chain engineering on polymer packing orientation in thin films. However, the impact of the size and conformation of aromatic surfaces on thin film ordering has not been investigated in great detail. Here we introduce a disk-shaped polycyclic aromatic hydrocarbon building block with a large π surface, namely, thienoazacoronenes (TACs), as a donor monomer for conjugated polymers. A series of medium bandgap conjugated polymers have been synthesized by copolymerizing TAC with electron donating monomers of varying size. The incorporation of the TAC unit in such semiconducting polymers allows a systematic investigation, both experimentally and theoretically, of the relationships between polymer conformation, electronic structure, thin film morphology, and charge transport properties. Field effect transistors based on these polymers have shown good hole mobilities and photoresponses, proving that TAC is a promising building block for high performance optoelectronic materials.

A divergent route to core- and peripherally functionalized diazacoronenes that act as colorimetric and fluorescence proton sensors.

Combining core annulation and peripheral group modification, we have demonstrated a divergent synthesis of a family of highly functionalized coronene derivatives from a readily accessible dichlorodiazaperylene intermediate. Various reactions, such as aromatic nucleophilic substitution, Kumada coupling and Suzuki coupling proceed effectively on α-positions of the pyridine sites, giving rise to alkoxy, thioalkyl, alkyl or aryl substituted polycyclic aromatic hydrocarbons. In addition to peripheral group modulation, the aromatic core structures can be altered by annulation with thiophene or benzene ring systems. Corresponding single crystal X-ray diffraction and optical studies indicate that the heteroatom linkages not only impact the solid state packing, but also significantly influence the optoelectronic properties. Moreover, these azacoronene derivatives display significant acid-induced spectroscopic changes, suggesting their great potential as colorimetric and fluorescence proton sensors.

New form of an old natural dye: bay-annulated indigo (BAI) as an excellent electron accepting unit for high performance organic semiconductors.

A novel electron acceptor was synthesized from one-step functionalization of the readily available indigo dye. The resulting bay-annulated indigo (BAI) was utilized for the preparation of a series of novel donor-acceptor small molecules and polymers. As revealed experimentally and by theoretical calculations, substituted BAIs have stronger electron accepting characteristics when compared to several premier electron deficient building blocks. As a result, the donor-acceptor materials incorporating BAI acceptor possess low-lying LUMO energy levels and small HOMO-LUMO gaps. In situ grazing incidence wide-angle X-ray scattering studies of the thin films of BAI donor-acceptor polymers indicated improved crystallinity upon thermal treatment. Field effect transistors based on these polymers show excellent ambipolar transporting behavior, with the hole and electron mobilities reaching 1.5 and 0.41 cm(2) V(-1) s(-1), respectively, affirming BAI as a potent electron accepting unit for high performance organic electronic materials.

Solution-processable donor-acceptor polymers with modular electronic properties and very narrow bandgaps.

Bridgehead imine-substituted cyclopentadithiophene structural units, in combination with highly electronegative acceptors that exhibit progressively delocalized π-systems, afford donor-acceptor (DA) conjugated polymers with broad absorption profiles that span technologically relevant wavelength (λ) ranges from 0.7 < λ < 3.2 µm. A joint theoretical and experimental study demonstrates that the presence of the cross-conjugated substituent at the donor bridgehead position results in the capability to fine-tune structural and electronic properties so as to achieve very narrow optical bandgaps (Eg (opt) < 0.5 eV). This strategy affords modular DA copolymers with broad- and long-wavelength light absorption in the infrared and materials with some of the narrowest bandgaps reported to date.