Balanced (endoscopic medial and transcutaneous lateral) orbital decompression in Graves' orbitopathy.
To determine the clinical outcomes and morbidity of endoscopic medial wall combined with transcutaneous lateral orbital wall decompression in Graves' orbitopathy. A retrospective noncomparative case series of patients who underwent surgical decompression for Graves' orbitopathy at Hospital Universitario de Fuenlabrada between 2004 and 2014 was performed. We reviewed the patients' charts and analyzed before and after the decompression, the visual acuity (Snellen chart), optic nerve compression (fundoscopy and optic coherence tomography), exophthalmometry (Hertel measurement), ocular motility, diplopia, eyelid surgery needed after decompression and its possible complications. A total of 20 patients (36 orbits) were operated. The mean follow-up was 44 months (range 18-84). Vision improved dramatically in all compressive optic neuropathy cases (5 cases). Hertel measurements improved on average 3.5 mm (range 1.5-4.5). Diplopia was cured in eight patients (40%) and nine patients with severe preoperative diplopia required strabismus surgery after decompression. Eyelid surgery was further needed in 13 patients. Hyaluronic acid injection was the most used technique for the treatment of eyelid retraction (6 out of 13 patients). Only two major complications were observed: one case had a major post-operative epistaxis and another a cerebrospinal fluid leak. Both were resolved without further sequelae. These results suggest that endoscopic medial wall combined with transcutaneous lateral wall orbital decompression is an effective and safe treatment for the symptomatic dysthyroid eye disease with important proptosis or compressive optic neuropathy.


Coronary artery wall shear stress is associated with endothelial dysfunction and expansive arterial remodelling in patients with coronary artery disease.
To investigate in vivo relationships between segmental wall shear stress (WSS), endothelium-dependent vasoreactivity and arterial remodelling. Twenty-four patients with minor angiographic coronary arterial disease (≤30% stenosis severity) underwent intracoronary (IC) salbutamol provocation during intravascular ultrasound (IVUS)-upon-Doppler guidewire imaging. Macrovascular response (change in segmental lumen volume [SLV] at baseline and following IC salbutamol), plaque burden (percent atheroma volume [PAV]), remodelling indices (RI), eccentricity indices (EI) and WSS were evaluated in 179 consecutive 5 mm coronary segments. Baseline WSS was directly related to endothelium-dependent epicardial coronary vasomotion (% change SLV, coefficient 17.2, p=0.004), and inversely related to RI (coefficient -0.23, p=0.02) and EI (coefficient -10.0, p=0.001). Baseline WSS was lower in segments displaying endothelial dysfunction (defined as any change in SLV ≤0) compared with preserved function (0.66±0.33 vs. 0.71±0.22 N/m2, p=0.046). Independent of plaque burden, segments with the lowest tertile of WSS displayed less vasodilatation, or vasoconstriction, than segments with the highest tertile of WSS. Higher plaque burden segments harbouring the lowest tertiles of WSS displayed vasoconstriction, expansive arterial remodelling and greater plaque eccentricity. In patients with stable coronary syndromes and minor angiographic coronary disease, coronary segments with lower in vivo WSS values display functional and morphological features of plaque vulnerability.


Use of a wireless local area network in an orthodontic clinic.
Radiographic images and other patient records, including medical histories, demographics, and health insurance information, can now be stored digitally and accessed via patient management programs. However, digital image acquisition and diagnosis and treatment planning are independent tasks, and each is time consuming, especially when performed at different computer workstations. Networking or linking the computers in an office enhances access to imaging and treatment planning tools. Access can be further enhanced if the entire network is wireless. Thanks to wireless technology, stand-alone, desk-bound personal computers have been replaced with mobile, hand-held devices that can communicate with each other and the rest of the world via the Internet. As with any emerging technology, some issues should be kept in mind when adapting to the wireless environment. Foremost is network security. Second is the choice of mobile hardware devices that are used by the orthodontist, office staff, and patients. This article details the standards and choices in wireless technology that can be implemented in an orthodontic clinic and suggests how to select suitable mobile hardware for accessing or adding data to a preexisting network. The network security protocols discussed comply with HIPAA regulations and boost the efficiency of a modern orthodontic clinic.


Overlapping and distinct roles of the duplicated yeast transcription factors Ace2p and Swi5p.
The yeast transcription factors Ace2p and Swi5p regulate the expression of several target genes involved in mating type switching, exit from mitosis and cell wall function. We describe the analysis of 12 novel targets, some regulated by Ace2p or Swi5p alone and some by both. We show that Ace2p is the major regulator of four genes (CTS1, YHR143W, SCW11 and YER124C). Expression of all four is inhibited by Swi5p. Like Cts1p and Scw11p, the two new Ace2p targets are associated with cell wall metabolism. Yhr143p is localized to the cell wall, and deletion affects cell separation and enhances pseudohyphal growth. Deleting YER124C also affects cell separation and sensitivity to drugs targeted against the cell wall. Expression of PIR1, YPL158C and YNL046W is dependent on Swi5p alone. In contrast, expression of YBR158W, YNL078W and YOR264W is minimized when both ace2 and swi5 are disrupted. We propose that, although Ace2p and Swi5p co-operate to induce the expression of a subset of genes, some functional divergence has occurred. This results in a delay in the expression of those genes predominantly regulated by Ace2p, compared with those predominantly regulated by Swi5p.


Associations of physical activity dose and movement quality with executive functions in socioeconomically disadvantaged children aged 5-6 years.
Growing up in areas of high deprivation can negatively impact children's movement behaviours and cognitive development. Enhancing the quantity and quality of children's movement experiences is believed to enhance cognitive development. This study investigated the association of three different modes of movement assessment, movement proficiency and divergent movement ability (collectively understood as motor competence) and PA dose with executive function in a low socio-economic demographic. Demographics, motor competence, and a combination of motor competence and physical activity were hypothesized to be significantly predictor of executive functions. In this cross-sectional study, 360 children aged 5-6 years from deprived areas were assessed using three movement assessments: wrist-worn accelerometery for physical activity dose, Test of Gross Motor Development-3 for movement proficiency, and divergent movement assessment. Executive function, including inhibitory control, working memory, and cognitive flexibility, was measured using the NIH Toolbox on an iPad. Multiple linear regression models were designed to evaluate the independent and combined association of demographics, movement competence and physical activity variables with executive function. The regression analysis, with demographic factors only, explained 12% of EF variance (r2 = 0.12 95%CI 0.06-0.18). In addition to this demographics the model with divergent movement explained 19% of EF variance (r2 = 0.19 95% CI = 0.12-0.28), the model with movement proficiency explained 16% of EF variance (r2 = 0.16 95% CI = 0.08-0.26) and the model with PA dose explained 13% of EF variance (r2 = 0.13 95% CI = 0.07-0.20). In these models both divergent movement and proficiency were significant predictors, whilst physical activity variables were not. The final models, combining motor competence and physical activity variables, explained 24% and 23% of EF variance (r2 = 0.24 CI = 0.14-0.33 and r2 = 0.23 CI = 0.14-0.32). In these models, motor competence variables were significant predictors, and only vigorous physical activity and Euclidean Norm Minus One emerged as significant PA dose predictors. These findings emphasise that motor competence and physical activity variables better predict executive functions when they are combined. When considered individually both motor competence variables were significant predictors of executive function whilst physical activity variables were not. Importantly, among the two movement competence facets, divergent movement assessment exhibited the strongest association with executive function. Future interventions should consider how to facilitate both movement and cognitive development in children. Future interventions should consider both the interplay of movement quality and quantity and the importance of environments that invite children's exploratory movement behavior.


MLST Reveals a Separate and Novel Clonal Group for Acidovorax avenae Strains Causing Red Stripe in Sugarcane from Argentina.
Acidovorax spp. cause a wide range of economically important diseases in monocotyledonous and dicotyledonous plants, including sugarcane, corn, rice, oat, millet, foxtail watermelon, and orchid. In Argentina, the red stripe disease of sugarcane caused by Acidovorax avenae affects 30% of the milling stems with important economic losses. To explore the genetic diversity of this bacterium associated with red stripe in Argentina, multilocus sequence typing (MLST) was applied. This study included 15 local strains isolated from four different sugarcane planting regions and selected after random amplified polymorphic DNA analysis and reference strains of A. citrulli, A. avenae, and A. oryzae to investigate their phylogenetic relationships. MLST analysis resulted in five sequence types among the sugarcane A. avenae strains which constitute a clonal complex, meaning a common and close origin. Sugarcane strains were related to A. avenae from other hosts and distant to A. citrulli. Signals of frequent recombination in several lineages of A. avenae was detected and we observed that A. oryzae is closely related to A. avenae strains. This study provides valuable data in the field of epidemiological and evolutionary investigations of novel clone of A. avenae strains causing sugarcane red stripe. The knowledge of the genetic diversity and strain-host specificity are important to select the genotypes with the best response to the red stripe disease.


Direct and reflex cardiac bradydysrhythmias from small vagal nerve stiumaltions.
Alterations in cardiac pacemaker location, its rate of discharge, and A-V conduction patterns were induced in anesthetized adult dogs by electrical stimulation of the thoracic vagi and their small cardiac branches before and after cervical vagotomy. Electrical activity from small, contiguous bipolar silver electrodes was amplified and recorded by an optical oscillograph. The electrodes were located over the SA node, the three internodal pathways, the left atrium, and ventricular epicardium. A hoffman-type plaque electrode was placed over the A-V node to record a His bundle electrogram simultaneously with a Lead II electrocardiogram. Electrical stimulation of the intact left recurrent laryngeal nerve and its cardiac branches before and after vagotomy induced both direct and reflex effects on SA nodal cycle length. Efferent dromotropic effects on the A-V node varied from first- to third-degree heart block during stimulation of individual left recurrent cardiac branches. Stimulation of the right recurrent cardiac nerve induced atrial bradycardia with heart block above the His bundle. Stimulation of individual right vagal branches near the heart induced bradycardia, cardiac asystole, shifts in atrial pacemaker location, or activation of His pacemakers. Establishment of the His rhythm probably indicates selective inhibition of supraventricular but not of the His bundle. Asystole and His rhythms induced during stimulation of the more caudal branches of the right cardiac vagal nerves were generally reflexly mediated and were abolished by cervical vagotomy.


Essential role of conserved arginine 160 in intramolecular electron transfer in human sulfite oxidase.
Arginine 160 in human sulfite oxidase (SO) is conserved in all SO species sequenced to date. Previous steady-state kinetic studies of the R160Q human SO mutant showed a remarkable decrease in k(cat)/K(m)(sulfite) of nearly 1000-fold, which suggests that Arg 160 in human SO makes an important contribution to the binding of sulfite near the molybdenum cofactor [Garrett, R. M., Johnson, J. L., Graf, T. N., Feigenbaum, A., Rajagopalan, K. V. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 6394-6398]. In the crystal structure of chicken SO, Arg 138, the equivalent of Arg 160 in human SO, is involved in the formation of a positively charged sulfite binding site [Kisker, C., Schindelin, H., Pacheco, A., Wehbi, W., Garnett, R. M., Rajagopalan, K. V., Enemark, J. H., Rees, D. C. (1997) Cell 91, 973-983]. To further assess the role of Arg 160 in human SO, intramolecular electron transfer (IET) rates between the reduced heme [Fe(II)] and oxidized molybdenum [Mo(VI)] centers in the wild type, R160Q, and R160K human SO forms were investigated by laser flash photolysis. In the R160Q mutant, the IET rate constant at pH 6.0 was decreased by nearly 3 orders of magnitude relative to wild type, which indicates that the positive charge of Arg 160 is essential for efficient IET in human SO. Furthermore, the IET rate constant for the R160K mutant is about one-fourth that of the wild type enzyme, which strongly indicates that it is the loss of charge of Arg 160, and not its precise location, that is responsible for the much larger decrease in IET rates in the R160Q mutant. Steady-state kinetic measurements indicate that IET is rate-limiting in the catalytic cycle of the R160Q mutant. Thus, the large decrease in the IET rate constant rationalizes the fatal impact of this mutation in patients with this genetic disorder.


Renal cell carcinoma in patients with chronic renal failure.
It has been found that patients suffering from chronic renal failure (CRF) are prone to develop acquired cystic kidney disease, which may subsequently lead to the development of renal cell carcinoma (RCC). We reviewed 250 consecutive cases of RCC diagnosed between January 1990 and June 1998 in our department and found 19 had associated CRF (7.6%). Their clinical presentation, mode and duration of dialysis, diagnostic evaluations, pathological stage and surgical outcome were reviewed. Sixteen had CRF with chronic glomerulonephritis and 3 with adult polycystic kidney disease. Three patients were on continuous ambulatory peritoneal dialysis (CAPD), 5 were on haemodialysis (HD) and 3 had renal transplant (2 on HD, 1 on CAPD previously). The remaining 8 patients were not on renal replacement therapy at the time of diagnosis. Ten patients were asymptomatic with incidental radiological findings while 9 had specific urological symptoms, most commonly haematuria. Ultrasonography (USG) and computed tomography (CT) scan were the main modalities of imaging employed. Nine out of the 10 asymptomatic patients had suspicious lesions detected incidentally by USG. All had subsequent preoperative CT scans confirming the presence of these lesions. All patients had single focus RCC except for 1 with multi-focal disease involving both kidneys. Sixteen patients had early stage (T1 or T2) and low grade (G1 or G2) RCC. The remaining 3 patients had advanced stage (T3a or T3b) and high grade (G3) tumours. Since half of the patients were asymptomatic, USG may be a useful tool in the outpatient review of patients with CRF and allow early diagnosis and surgical treatment of early stage, low-grade tumours and therefore may have better survival.


Fibrinogen Baltimore I: polymerization defect associated with a gamma 292Gly----Val (GGC----GTC) mutation.
Fibrinogen Baltimore I is one of the very first congenital abnormal fibrinogens reported over several decades ago; however, the molecular defect of this dysfibrinogen has eluded identification. In fact, several reports misidentified the functional defect of Baltimore I, which has impaired fibrin monomer polymerization. Reversed-phase high-performance liquid chromatography analysis of lysyl endopeptidase digest of the purified Baltimore I gamma-chain showed an abnormal peptide not found in the co-existing normal gamma-chain of this heterozygote. Amino acid sequencing of this peptide indicated that gamma-chain Gly292 is replaced by valine. This observation was confirmed, and the genetic defect was determined by direct nucleotide sequencing of a polymerase chain reaction product containing codon gamma 292, which is mutated: GGC----GTC. The molecular defect of Fibrinogen Baltimore I lies in a region of the gamma-chain required for fibrin polymerization, suggesting that the integrity of gamma Gly292 is critical for fibrin assembly.


Altered postural sway in patients suffering from non-specific neck pain and whiplash associated disorder - A systematic review of the literature.
Systematic literature review. To assess differences in center of pressure (COP) measures in patients suffering from non-specific neck pain (NSNP) or whiplash-associated disorder (WAD) compared to healthy controls and any relationship between changes in postural sway and the presence of pain, its intensity, previous pain duration and the perceived level of disability. Over the past 20 years, the center of pressure (COP) has been commonly used as an index of postural stability in standing. While several studies investigated COP excursions in neck pain and WAD patients and compared these to healthy individuals, no comprehensive analysis of the reported differences in postural sway pattern exists. Six online databases were systematically searched followed by a manual search of the retrieved papers. Papers comparing COP measures derived from bipedal static task conditions on a force plate of people with NSNP and WAD to those of healthy controls. Two reviewers independently screened titles and abstracts for relevance. Screening for final inclusion, data extraction and quality assessment were carried out with a third reviewer to reconcile differences. Ten papers met the inclusion criteria. Heterogeneity in study designs prevented pooling of the data and no direct comparison of data across the studies was possible. Instead, a qualitative data analysis was conducted. There was broad consensus that patients with either type of neck pain have increased COP excursions compared to healthy individuals, a difference that was more pronounced in people with WAD. An increased sway in antero-posterior direction was observed in both groups. Patients with neck pain (due to either NSNP or WAD) exhibit greater postural instability than healthy controls, signified by greater COP excursions irrespective of the COP parameter chosen. Further, the decreased postural stability in people with neck pain appears to be associated with the presence of pain and correlates with the extent of proprioceptive impairment, but appears unrelated to pain duration.


Constructing a 3-D mesh model for electrical cardiac activity simulation.
The 3-D ventricle model in this study was reconstructed from a series of MRI torso cross-section data. We used a 3-D voxel array to represent the ventricle. As in cardiac simulations proposed by previous studies, the activation sequence and body surface ECG were simulated in this model. But to reduce the amount of elements in the model, so that the amount of parameters in the model can be handled numerically, we propose another approach to simulate cardiac activity. A mesh model was constructed on the closed surface formed by epicardiac and endocardiac surfaces of the ventricle. We propose a method to simulate the activation sequence on the epicardiac and endocardiac surfaces of the mesh model. As with the uniform double layer theorem, body surface ECG can be estimated in terms of epicardiac and endocardiac surface current source. Consequently, we can also generate ECG waveforms corresponding to this mesh simulation. Both the depolarization sequence and ECG simulated by the mesh model resemble those generated by the 3-D voxel model. However, the mesh model greatly simplified the process of ECG simulation. Both the simulation of depolarization and ECG estimation were expressed in terms of clear and simple mathematical representations. Consequently, we can analytically investigate the effects of the mesh model's parameters on the cardiac activation sequence and ECG. It could be a useful tool to numerically study the relation of ECG waveforms and electrical activity of the heart.


The "Parkinsonian heart": from novel vistas to advanced therapeutic approaches in Parkinson's disease.
The present manuscript reviews novel data on the progressive involvement of different regions of the central nervous system as well as peripheral nerves in Parkinson's disease. Most of these regions are involved in the regulation of the autonomic nervous system, and their damage is concomitant with the specific loss of sympathetic cardiac axon terminals. This causes a cardiovascular dysfunction, which occurs solely in Parkinsonian patients. In order to specify the peculiarity of this cardiovascular alteration we coined the term "Parkinsonian Heart". This is characterized by a severe loss of the physiological noradrenergic innervation and a slight impairment of central autonomic control and it is often characterized by drug-induced morpho-functional alterations. In fact, the current dopamine substitution therapy could make worse such an already abnormal heart. For instance, structure-activity studies on dopamine substitutive drugs report that dopamine agonists belonging to the class of ergot derivatives may produce, with a high frequency, valvular fibrosis in Parkinsonian patients. These effects recently became a major issue and led to consider all ergot dopamine agonists as dangerous for the treatment of Parkinson's disease. In the present review we re-describe the effects of dopamine agonist within the specific context of the Parkinsonian heart. In line with this, additional factors need to be considered: 1--The lack of noradrenergic innervation which might play a significant role in the fibrogenic mechanism. 2--The ergot structure per se, which is not sufficient, but it is rather the ability to act as agonist at 5HT(2B) or alpha-noradrenergic receptors to determine the fibrotic reaction. Therefore, we suggest that binding to these receptor subtypes, joined with the lack of endogenous noradrenergic innervation, might synergize to produce the cardiac fibrosis.


Underutilization of the reports of adverse events in an Argentine hospital.
An adverse event is defined as any unintentional harm that results in temporary or permanent disability and/or prolongation of hospitalization time, or death of a patient; as a consequence of health care provided by any staff member of the health institution. The aim was to describe the adverse events that affect patient safety, reported in 2015 in a private hospital in the city of Córdoba, Argentina. We analyzed 678 events reported through the computer system on the hospital's intranet. The highest frequency of events reported corresponded to the nursing professionals (40.7% ). Problems related to drug therapy process showed the highest frequency of reports (17.7% ), followed by communication failures (11.1% ) and patient's fall (10.3% ). In the notification of the causes of the incident, 51.9% of "No answer" was observed. In the case of this hospital, this valuable tool is being underutilized. The reports should allow identifying the entire chain of events that lead to the incidents to address effective interventions in patient safety that involve all hospital staff, with greater emphasis on senior staff.


How does it "feel"? A signal detection approach to feeling generation.
Feeling, or the subjective emotional experience, is a fundamental element of the emotional reaction, yet past attempts to understand the mechanisms of feeling generation remain limited. The current study presents a signal detection theory (SDT) conceptualization of feeling generation. Accordingly, feeling, like other sensations, reflects an outcome of an inner decision regarding the emotional evidence, and, therefore, can be evaluated via 2 processes: evidence differentiation (d')-the ability to emotionally differentiate between external stimuli, given the essentially noisy evidence-and criterion (c)-the report threshold, or amount of evidence needed to have an intense reportable feeling. According to the model, feelings can be disproportionally intense (false alarms; e.g., emotional overreaction) or disproportionally weak (misses; e.g., failing to detect danger), with the criterion controlling the relative proportion of these "errors." Results from a novel task indicate that our conceptualization provides a suitable model for valence (pleasant-unpleasant) feeling generation, as reflected in superior model fit relative to plausible alternative models, nonsignificant lack of fit, and by successful experimental tests of a novel prediction regarding contextual influences and related uncertainty. Additional evidence for the external validity of the model shows that SDT parameters, especially the criterion, were meaningfully correlated with relevant emotion regulation and affective style constructs. Implications for the understanding of feeling generation, in general, and in psychopathology, in particular, are discussed. (PsycINFO Database Record


[Autoimmune encephalitis-update: roles of autoantibodies in the pathogenesis].
Autoimmune encephalitis is increasingly recognized having autoantibodies to synaptic cell surface antigens, such as anti-N-methyl-D-aspartate receptor (NMDAR) and leucine-rich glioma-inactivated protein 1 (LGI1) by neurologists as well as pediatricians and psychiatrists, because these antibodies have been detected in cases of intractable epilepsy or atypical psychosis and in some demyelinating diseases, together with typical limbic encephalitis. Each group have characteristic clinical features, however, the disease spectrum has been expanding. To understand the significance of anti-NMDAR antibodies in the pathogenesis of NMDAR encephalitis, the role of the antibody in the disease process have been evaluated. The binding of antibody is shown to dimerize NMDARs and trigger their internalization on the postsynaptic site, thereby suppressing NMDAR-mediated transmission. To evaluate the antibody-induced dysfunction of NMDARs, we tested and showed the antibodies from the patients suppress the induction of NMDAR-dependent long-term potentiation (LTP) in mouse hippocampal slices. We also tested the antibody-effects on the cognitive functions of mice and revealed the CSF from NMDAR encephalitis patients had effects on disturbing spacial memory in mice. These results firmly support the proposal that the anti-NMDAR encephalitis autoantibody is responsible for cognitive disorders accompanying in this disease.


Diffusion of macromolecules in a polymer hydrogel: from microscopic to macroscopic scales.
To gain insight into the fundamental processes determining the motion of macromolecules in polymeric matrices, the dynamical hindrance of polymeric dextran molecules diffusing as probe through a polyacrylamide hydrogel is systematically explored. Three complementary experimental methods combined with Brownian dynamics simulations are used to study a broad range of dextran molecular weights and salt concentrations. While multi-parameter fluorescence image spectroscopy (MFIS) is applied to investigate the local diffusion of single molecules on a microscopic length scale inside the hydrogel, a macroscopic transmission imaging (MTI) fluorescence technique and nuclear magnetic resonance (NMR) are used to study the collective motion of dextrans on the macroscopic scale. These fundamentally different experimental methods, probing different length scales of the system, yield long-time diffusion coefficients for the dextran molecules which agree quantitatively. The measured diffusion coefficients decay markedly with increasing molecular weight of the dextran and fall onto a master curve. The observed trends of the hindrance factors are consistent with Brownian dynamics simulations. The simulations also allow us to estimate the mean pore size for the herein investigated experimental conditions. In addition to the diffusing molecules, MFIS detects temporarily trapped molecules inside the matrix with diffusion times above 10 ms, which is also confirmed by anisotropy analysis. The fraction of bound molecules depends on the ionic strength of the solution and the charge of the dye. Using fluorescence intensity analysis, also MTI confirms the observation of the interaction of dextrans with the hydrogel. Moreover, pixelwise analysis permits to show significant heterogeneity of the gel on the microscopic scale.


Combined Surface-Enhanced Raman and Infrared Absorption Spectroscopies for Streamlined Chemical Detection of Polycyclic Aromatic Hydrocarbon-Derived Compounds.
Polycyclic aromatic hydrocarbons (PAHs) constitute a class of universally prevalent carcinogenic environmental contaminants. It is increasingly recognized, however, that PAHs derivatized with oxygen, sulfur, or nitrogen functional groups are frequently more dangerous than their unfunctionalized counterparts. This much larger family of chemicals─polycyclic aromatic compounds─PACs─is far less well characterized than PAHs. Using surface-enhanced Raman and IR Absorption spectroscopies (SERS + SEIRA) combined on a single substrate, along with density functional theoretical (DFT) calculations, we show that direct chemical detection and identification of PACs at sub-parts-per-billion concentration can be achieved. Focusing our studies on 9,10-anthraquinone, 5,12-tetracenequinone, 9-nitroanthracene, and 1-nitropyrene as model PAC contaminants, detection is made possible by incorporating a hydroxy-functionalized self-assembled monolayer that facilitates hydrogen bonding between analytes and the SERS + SEIRA substrate. 5,12-Tetracenequinone was detected at 0.3 ppb, and the limit of detection was determined to be 0.1 ppb using SEIRA alone. This approach is straightforwardly extendable to other families of analytes and will ultimately facilitate fieldable chemical detection of these dangerous yet largely overlooked environmental contaminants.


Electric Potential at the Interface of Membraneless Organelles Gauged by Graphene.
Eukaryotic cells contain membrane-bound and membrane-less organelles that are often in contact with each other. How the interface properties of membrane-less organelles regulate their interactions with membranes remains challenging to assess. Here, we employ graphene-based sensors to investigate the electrostatic properties of synapsin 1, a major synaptic phosphoprotein, either in a single phase or after undergoing phase separation to form synapsin condensates. Using these graphene-based sensors, we discover that synapsin condensates generate strong electrical responses that are otherwise absent when synapsin is present as a single phase. By introducing atomically thin dielectric barriers, we show that the electrical response originates in an electric double layer whose formation governs the interaction between synapsin condensates and graphene. Our data indicate that the interface properties of the same protein are substantially different when the protein is in a single phase versus within a biomolecular condensate, unraveling that condensates can harbor ion potential differences at their interface.


Cerebral plasticity and recovery of function after childhood prefrontal cortex damage.
Recovery of function after early brain injury depends upon both reparative and compensatory processes that are minimally understood. Using functional magnetic resonance imaging (fMRI), this study investigated the reorganization of hemispheric brain activity of a 24 year old male who suffered right prefrontal cortex damage at 7 years of age related to ruptured arteriovenous malformation. His pattern of recovery has been examined and tracked over the past 17 years and evolved from initial significant impairments in executive, spatial and attentional abilities from the brain lesion to remarkable recovery of function. High field fMRI studies were completed with experimental cognitive tasks sensitive to right prefrontal functions, including visuospatial relational reasoning, spatial working memory, go no-go, emotional face recognition, and coin calculation. RESULTS were compared to a matched control group for total hemispheric activity patterns. Analyses revealed that on fMRI activation tasks where the patient scored similar to controls, he activated a broader network of bilateral cortical regions than controls. On tasks where he scored lower than controls, there was under-activation of prefrontal cortical regions in comparison to controls. Recovery of function after prefrontal cortex damage in childhood can occur and be associated with significant functional reorganization of hemispheric activity patterns (i.e. developmental cerebral plasticity). Although not all tasks showed recovery to the same extent in this case, those tasks with the most robust recovery entailed compensatory activation of additional cortical regions on fMRI. Further studies are needed to confirm and extend these findings.


Descriptive epidemiology of cutaneous squamous cell carcinoma in Croatia.
The aim of the study was to investigate the squamous cell carcinoma (SCC) incidence in Croatia in the 2003-2005 period. The cases of SCC were retrospectively studied. Data were collected from University Department of Dermatology and Venereology, Zagreb University Hospital Center and National Cancer Registry. In the study period, there were 1,860 cases of SCC (934 men and 926 women). The crude incidence rate for the Croatian population of 100,000 was 14.6 for men and 13.4 for women. The age-standardized incidence rate (adjusted for the world standard population) was 8.9 for men and 5.2 for women. The head was almost exclusive localization of SCC in both sexes. The highest SCC incidence was recorded in Zadar County. These results will serve for the SCC trend monitoring in Croatia and Europe in the forthcoming years.


(Micro)Glia as Effectors of Cortical Volume Loss in Schizophrenia.
Contrary to the notion that neurology but not psychiatry is the domain of disorders evincing structural brain alterations, it is now clear that there are subtle but consistent neuropathological changes in schizophrenia. These range from increases in ventricular size to dystrophic changes in dendritic spines. A decrease in dendritic spine density in the prefrontal cortex (PFC) is among the most replicated of postmortem structural findings in schizophrenia. Examination of the mechanisms that account for the loss of dendritic spines has in large part focused on genes and molecules that regulate neuronal structure. But the simple question of what is the effector of spine loss, ie, where do the lost spines go, is unanswered. Recent data on glial cells suggest that microglia (MG), and perhaps astrocytes, play an important physiological role in synaptic remodeling of neurons during development. Synapses are added to the dendrites of pyramidal cells during the maturation of these neurons; excess synapses are subsequently phagocytosed by MG. In the PFC, this occurs during adolescence, when certain symptoms of schizophrenia emerge. This brief review discusses recent advances in our understanding of MG function and how these non-neuronal cells lead to structural changes in neurons in schizophrenia.


Differential regulation of multiple flagellins in Vibrio cholerae.
Vibrio cholerae, the causative agent of the human diarrheal disease cholera, is a motile bacterium with a single polar flagellum. Motility has been implicated as a virulence determinant in some animal models of cholera, but the relationship between motility and virulence has not yet been clearly defined. We have begun to define the regulatory circuitry controlling motility. We have identified five V. cholerae flagellin genes, arranged in two chromosomal loci, flaAC and flaEDB; all five genes have their own promoters. The predicted gene products have a high degree of homology to each other. A strain containing a single mutation in flaA is nonmotile and lacks a flagellum, while strains containing multiple mutations in the other four flagellin genes, including a flaCEDB strain, remain motile. Measurement of fla promoter-lacZ fusions reveals that all five flagellin promoters are transcribed at high levels in both wild-type and flaA strains. Measurement of the flagellin promoter-lacZ fusions in Salmonella typhimurium indicates that the promoter for flaA is transcribed by the sigma54 holoenzyme form of RNA polymerase while the flaE, flaD, and flaB promoters are transcribed by the sigma28 holoenzyme. These results reveal that the V. cholerae flagellum is a complex structure with multiple flagellin subunits including FlaA, which is essential for flagellar synthesis and is differentially regulated from the other flagellins.


Accumulation of neurofilament proteins in the regenerating facial nerve.
In order to compare the extent of axonal regeneration in two surgical nerve repair procedures, we measured the levels of the neurofilament (NF) proteins in the regenerating facial nerve of adult New Zealand rabbits. The animals were operated on bilaterally, with a chamber model placed on one side and a cable graft model inserted on the contralateral side. Normal nerve from unoperated animals or nerve removed during nerve repair surgery served as controls. Using immunoblot techniques and densitometric measurement, we examined specific changes in the individual NF [High (H), Medium (M), and Low (L) molecular weight (MW)] in the regenerating nerve at 3 and 7 weeks postoperation time. Linearity of the densitometric system was established by separation of serial dilutions of known NF on the gel, and blotting for immunostaining. The amount of all 3 NF's decreased during the regeneration process compared to normal nerve, but there were differences between the two procedures. The NFH in the distal segment of the chamber repaired nerve at 7 weeks was 60-70% of the preoperative state, which correlated with a previous morphological study of axona) caliber during regeneration. At 3 weeks, NF content was lower in the distal segment of the chamber than in the distal cable graft. By 7 weeks, NF content was similar in proximal and distal segments of both models. Thus, although initial regeneration is slower in the chamber model, the eventual outcome is similar in both chamber and graft.


Chronic myelogenous leukemia in a great horned owl (Bubo virginianus).
A free-ranging adult female great horned owl (Bubo virginianus) was presented to the Wildlife Medical Clinic at the University of Illinois after being observed with anorexia and decreased activity. A severe leukocytosis (212 400 cells/microl), primarily comprised of mature heterophils, was found at presentation. Results of various diagnostic tests including radiographs, Chlamydophila serologic testing, measurement of Aspergillus antibody and antigen titers, plasma protein electrophoresis, fecal culture and acid-fast staining, coelioscopy, endoscopy, tracheoscopy, exploratory coelomotomy, nuclear scintigraphy, tissue cultures, bone marrow biopsy, and histopathology revealed no underlying cause for the persistent leukocytosis. No response to treatment with antibiotics or antifungal agents was observed, although a transient, significant decrease in the leukocyte count (6200 cells/microl) was observed after treatment with fenbendazole. A presumptive diagnosis of chronic myelogenous leukemia was made based on 3 factors: disease duration of greater than 3 months, a lack of identifiable foci of inflammation, and a lack of response to conventional therapy. The diagnosis was confirmed based on postmortem examination and testing 177 days after initial presentation.


Stool chemistries in patients with unexplained diarrhea.
In approaching the differential diagnosis of unexplained diarrheal disorders, separation of osmotic and secretory causes is important. The osmotic gap between measured stool osmolality and osmolality calculated from stool sodium and potassium concentrations is low in secretory diarrhea and high in osmotic diarrhea. Cholera, villous adenoma and bile salts are among the causes of secretory diarrhea. Causes of osmotic diarrhea include monosaccharidase deficiency, disaccharidase deficiency, excessive use of sugar-free gum and excessive ingestion of magnesium antacids.


Synthesis, one- and two-photon photophysical and excited-state properties, and sensing application of a new phosphorescent dinuclear cationic iridium(III) complex.
A new phosphorescent dinuclear cationic iridium(III) complex (Ir1) with a donor-acceptor-π-bridge-acceptor-donor (D-A-π-A-D)-conjugated oligomer (L1) as a N^N ligand and a triarylboron compound as a C^N ligand has been synthesized. The photophysical and excited-state properties of Ir1 and L1 were investigated by UV/Vis absorption spectroscopy, photoluminescence spectroscopy, and molecular-orbital calculations, and they were compared with those of the mononuclear iridium(III) complex [Ir(Bpq)(2)(bpy)](+)PF(6)(-) (Ir0). Compared with Ir0, complex Ir1 shows a more-intense optical-absorption capability, especially in the visible-light region. For example, complex Ir1 shows an intense absorption band that is centered at λ=448 nm with a molar extinction coefficient (ε) of about 10(4) , which is rarely observed for iridium(III) complexes. Complex Ir1 displays highly efficient orange-red phosphorescent emission with an emission wavelength of 606 nm and a quantum efficiency of 0.13 at room temperature. We also investigated the two-photon-absorption properties of complexes Ir0, Ir1, and L1. The free ligand (L1) has a relatively small two-photon absorption cross-section (δ(max) =195 GM), but, when complexed with iridium(III) to afford dinuclear complex Ir1, it exhibits a higher two-photon-absorption cross-section than ligand L1 in the near-infrared region and an intense two-photon-excited phosphorescent emission. The maximum two-photon-absorption cross-section of Ir1 is 481 GM, which is also significantly larger than that of Ir0. In addition, because the strong B-F interaction between the dimesitylboryl groups and F(-) ions interrupts the extended π-conjugation, complex Ir1 can be used as an excellent one- and two-photon-excited "ON-OFF" phosphorescent probe for F(-) ions.


The relative importance of tailpipe and non-tailpipe emissions on the oxidative potential of ambient particles in Los Angeles, CA.
This study examines the associations between the oxidative potential of ambient PM2.5 and PM0.18, measured by means of the dithiothreitol (DTT) assay, and their chemical constituents and modeled sources. Particulate matter (PM) samples were collected from 2012-2013 in Central Los Angeles (LA) and 2013-2014 in Anaheim, California, USA. Detailed chemical analyses of the PM samples, including carbonaceous species, inorganic elements and water-soluble ions, were conducted. Univariate analysis indicated a high correlation (R > 0.60) between the DTT activity and the concentrations of carbonaceous species at both sites. The strongest correlations were observed between DTT and organic tracers of primary vehicle tailpipe emissions including polycyclic aromatic hydrocarbons (PAHs) and hopanes as well as EC, with higher correlations for PM0.18versus PM2.5 components. Moreover, metals and trace elements (e.g., Ba, Cu, Fe, Mn, Pb and Sb) in both size ranges were also associated with DTT activity. Multiple linear regression (MLR) analysis was performed on DTT activity and PM sources identified by a Molecular Marker-Chemical Mass Balance (MM-CMB) model (i.e. major carbonaceous sources: vehicle tailpipe emissions, wood smoke, primary biogenic and secondary organic carbon) together with other typical sources of ambient PM (i.e. crustal material, vehicular abrasion, secondary ions and sea salt). Overall, our findings illustrate the relative importance of different traffic sources on the oxidative potential of ambient PM. Despite major reductions of tailpipe emissions, the lack of similar reductions (and possibly an increase) in non-tailpipe emissions makes them an important source of traffic-related PM in Los Angeles and their increasing role in the overall PM toxicity raises concerns for public health.


T follicular regulatory cells in the regulation of B cell responses.
High affinity antibodies result from interactions between B cells and T follicular helper (Tfh) cells in germinal centers (GCs). Recent studies have identified an effector subset of T regulatory cells termed T follicular regulatory (Tfr) cells that specifically controls GC responses by suppressing Tfh and B cells. The discovery of Tfr cells has shed new light on pathways regulating humoral immunity that enable potent and specific responses to pathogens while restricting autoimmunity. Here, we review the current understanding of the cellular and molecular mechanisms underlying the differentiation and function of Tfr cells. In this context we discuss recent insights into the role of Tfh cells in disease, how this knowledge may be translated therapeutically, and important areas of further research.


Improvement in Validity and Reliability of Airway Assessment Using Ultrasonography by Novice Personnel: A Learning Cohort Study.
To assess improvements in the validity and reliability of novices' skills in performing ultrasonography for airway assessment. A learning cohort study was conducted with 20 anesthesiology residents and 10 volunteers in the Department of Anesthesiology, Faculty of Medicine, Prince of Songkla University. The four parameters of airway assessment were soft tissue thickness at the level of 1) hyoid bone (STT-HY), 2) true vocal cords (STT-VC), 3) thyroid isthmus (STT-TI), and 4) suprasternal notch (STT-SN). The magnitude of discrepancies between the residents' and experienced anesthesiologists' measurements was evaluated over the sequence of measurements in the 10 volunteers. The mean ultrasonic measurements of STT-HY by the experienced anesthesiologists and residents were significantly different (11.09 ± 3.14 mm vs 8.53 ± 3.02 mm, respectively; P = 0.008), whereas measurements of STT-VC, STT-TI, and STT-SN were not (7.18 ± 1.70 vs 7.14 ± 1.93, P = 0.32; 7.81 ± 2.14 vs 7.73 ± 2.19, P = 0.62; and 11.32 ± 3.33 vs 10.30 ± 3.02, P = 0.35, respectively). The mean discrepancy between the residents' and experienced anesthesiologists' measurements was close to zero throughout the sequence of measurements of STT-TI and STT-VC. However, the residents' measurements of STT-HY and STT-SN were considerably lower than those of anesthesiologists. The range of discrepancies between residents and experienced anesthesiologists in each sequential measurement was wide for all measurements, particularly for the measurement values of STT-HY, and the standard deviation of the discrepancies did not decrease over the sequence of measurements. Over the sequence of measurements for airway assessment in 10 volunteers by 20 residents in this learning trial, we found no evidence of improvement in measurement accuracy. Discrepancies between the residents' and anesthesiologists' measurements and the variability in discrepancy across residents were greatest in the measurement of STT-HY.


Recommendations and practices for holistic chronic obstructive pulmonary disease (COPD) assessment and optimal referral patterns in emergency department presentations: a scoping review protocol.
Chronic obstructive pulmonary disease (COPD) is a common respiratory condition that causes persistent respiratory symptoms and decline in lung function over many years. This chronic disease significantly affects health-related quality of life and is known to contribute to frequent emergency department (ED) presentations. Multidimensional management of these patients, including interconnecting health disciplinarians will allow holistic care provision in the ED. The purpose of this scoping review is to synthesise current evidence on holistic management and assessment, and referral practices stemming from acute COPD presentation in the ED. Specifically, to determine: (1) What are the known causal factors associated with COPD ED presentations and (2) Is there an identified connection with appropriate healthcare professional assessment within ED presentations and reported referral pathways? The iterative stages of the Arskey and O'Malley, and Levac advanced scoping review framework informs this review. Using published and unpublished studies in English, a three-tiered search strategy will be applied. After duplicates are removed, screen 1 (title and abstract) and screen 2 (full-text) will be conducted by two independent reviewers to determine eligibility of articles. Disputes will be settled through discussion or by using a third reviewer. A data collection tool developed by the authors will inform the data extraction process. Schematic tabular format of results with a narrative summary will depict how the results link with the scoping review objectives. Categorisation of results will be narrowed down as key conceptual findings and will align with the strategic intent of this review. Ethics approval was not required for this study. A multidisciplinary team of authors will participate in dissemination activities (publications, reports, conference presentations, framework development).


Fasciola hepatica Infection Risk for Adult Household Members Living with Children with Fascioliasis in Cusco, Peru.
Fasciola hepatica is highly prevalent in the highlands of Peru. School-age children have the greatest risk of infection. Mass treatment of at-risk populations has been proposed to control the infection and prevent complications. However, the decreasing effectiveness of triclabendazole raises concerns regarding this strategy. Previous studies reported aggregation of Fasciola infection among family members. This study aimed to determine the risk of fascioliasis among household members living with Fasciola-infected children identified through school-based testing. We conducted a cross-sectional study including adult members of households where children with and without fascioliasis were identified. Demographic, epidemiological, and socioeconomic information was collected. One blood sample was drawn to test for Fasciola antibodies, and three stool samples were collected for microscopy for Fasciola ova. We tested 326 adults from 213 households. Of these adult subjects, chronic fascioliasis (24 of 326, 7.4%) was the most common helminth infection. Thirty-nine subjects (12.7%) tested positive for Fasciola antibodies. Combining microscopy and serum antibody tests, 13.2% (43 of 326) had evidence of Fasciola infection. One third (104 of 326, 31.9%) of the participants lived with at least one child infected with Fasciola hepatica. Adults with fascioliasis were four times more likely to live with an infected child. Poverty and diet were associated with increased risk of Fasciola infection. Adults with fascioliasis were significantly more likely to live with Fasciola-infected children.


Macrophage migration inhibitory factor and interleukin-8 produced by gastric epithelial cells during Helicobacter pylori exposure induce expression and activation of the epidermal growth factor receptor.
While a link between Helicobacter pylori exposure and gastric cancer has been established, the underlying mechanisms remain unclear. H. pylori induces a chronic inflammatory response in infected individuals. A link between chronic inflammation and carcinogenesis has long been suggested but never elucidated. Epidermal growth factor receptor (EGFR) signaling plays an important role in both proinflammatory and procarcinogenic mechanisms and is upregulated on gastric epithelial cells (GECs) during H. pylori exposure. The aim of this study was to examine the effects of two important proinflammatory cytokines released during H. pylori infection, macrophage migration inhibitory factor (MIF) and interleukin-8 (IL-8), on the expression and transactivation of EGFR and on the proliferation of GECs during H. pylori exposure. The expression of EGFR by GECs was increased by exposure to either H. pylori, recombinant MIF, or recombinant IL-8. However, cag pathogenicity island knockout strains of H. pylori had very little effect on expression. MIF and IL-8 also induced phosphorylation of EGFR, signaling events, and proliferation during H. pylori exposure, all of which were decreased when they were neutralized by these cytokines or were blocked from their receptors. The overall role of EGFR in these responses to H. pylori exposure was assessed by knocking down EGFR expression by small interfering RNA.


Activation of Glycolysis by MCM10 Increases Stemness and Paclitaxel Resistance in Gastric Cancer Cells.
Chemotherapy is an essential avenue for curing malignancies; however, tumor cells acquire resistance to chemotherapeutic agents, eventually leading to chemotherapy failure. At present, paclitaxel (PTX) resistance seriously hinders the therapeutic efficacy of gastric cancer (GC). Investigating the molecular mechanism of PTX resistance in GC is critical. This study attempted to delineate the impact of MCM10 on GC resistance to PTX and its mechanism in GC. The expression of minichromosome maintenance complex component 10 (MCM10) in GC tissues, its enrichment pathways, and its correlation with glycolysis marker genes and stemness index (mRNAsi) were analyzed in a bioinformatics effort. Real-time quantitative polymerase chain reaction was used to assay the expression of MCM10 in cells. Cell counting kit-8 (CCK-8) was used to analyze cell viability and calculate the 50% inhibitor concentration (IC50) value. Western blot was used to measure the expression of MCM10, Hexokinase 2 (HK2) and stemness-related factors in cells. Sphere-forming assay was performed to study cell sphere-forming ability. Seahorse XF 96 was utilized to measure cell extracellular acidification and oxygen consumption rates. The content of glycolysisrelated products was tested with corresponding kits. MCM10 was significantly upregulated in GC and enriched in the glycolysis pathway, and it was positively correlated with both glycolysis-related genes and stemness index. High expression of MCM10 increased sphere-forming ability of drug-resistant cells and GC resistance to PTX. The stimulation of PTX resistance and drug-resistant cell stemness in GC by high MCM10 expression was mediated by the glycolysis pathway. MCM10 was upregulated in GC and drove stemness and PTX resistance in GC cells by activating glycolysis. These findings generated new insights into the development of PTX resistance in GC, implicating that targeting MCM10 may be a novel approach to improve GC sensitivity to PTX chemotherapy.


Viral haemorrhagic septicaemia virus (VHSV Id) infections are detected more consistently using syndromic vs. active surveillance.
The eradication of viral haemorrhagic septicaemia virus (VHSV Id) from Finnish brackish-water rainbow trout Oncorhynchus mykiss farms located in the restriction zone in the Province of Åland, Baltic Sea, failed several times in the 2000s. The official surveillance programme was often unable to find VHSV-positive populations, leading to the misbelief in the fish farming industry that virus eradication could be achieved. The ability of 3 other surveillance programmes to detect infected fish populations was compared with the official programme. One programme involved syndromic surveillance based on the observation of clinical disease signs by fish farmers, while 2 programmes comprised active surveillance similar to the official programme, but included increased sampling frequencies and 2 additional tests. The syndromic surveillance concentrated on sending in samples for analysis when any sign of a possible infectious disease at water temperatures below 15°C was noticed. This programme clearly outperformed active surveillance. A real-time reverse transcriptase-polymerase chain reaction method proved to be at least as sensitive as virus isolation in cell culture in detecting acute VHSV infections. An ELISA method was used to test fish serum for antibodies against VHSV. The ELISA method may be a useful tool in VHSV eradication for screening populations during the follow-up period, before declaring an area free of infection.


Sympathetic innervation of human mesenteric artery and vein.
Innervation of blood vessels shows inter-species variability. There are few studies on the innervation of human vessels; thus, healthy mesenteric vessels were studied to identify the expression of immunomarkers and the morphology of sympathetic innervation as the basis for a study of mesenteric vessels in inflammatory bowel disease. Electron microscopy studies examined the relationships of nerves to smooth muscle cells. In veins, nerves were distributed throughout the medial smooth muscle coat, often in close apposition (50 nm) to smooth muscle cells. In arteries, nerves were located at the adventitial-medial border, few closer than 2,000 nm to smooth muscle cells, often with interposing connective tissue and Schwann cell processes. There was a significantly greater nerve density in veins than in arteries (227 vs. 41 mm(2); p = 0.03). Immunohistochemical studies revealed the presence of sympathetic and sensory-motor nerves in arteries and veins. It is suggested that in humans with an upright stance, the mesenteric venous system plays a particularly important role in controlling mesenteric capacitance, which is reflected by their dense innervation. It is speculated that transmitters released from perivascular nerves supplying the human mesenteric arteries may play a long-term (trophic) role in addition to short-term signalling roles.


Degeneration of cholinergic basal forebrain nuclei after focally evoked status epilepticus.
Status epilepticus (SE) of limbic onset might cause degenerative phenomena in different brain structures, and may be associated with chronic cognitive and EEG effects. In the present study SE was evoked focally by microinfusing picomolar doses of cyclothiazide+bicuculline into the anterior extent of the piriform cortex (APC) in rats, the so-called area tempestas, an approach which allows to evaluate selectively the effects of seizure spreading through the natural anatomical circuitries up to secondary generalization. In the brain of rats submitted to SE we analyzed neuronal density, occurrence of degenerative phenomena (by Fluoro-Jade B-FJB- staining) and expression of heat shock protein-70 (HSP-70) in the piriform cortex, the hippocampus and ventromedial thalamus. We further analyzed in detail, the loss of cholinergic neurons, and the presence of FJB- and HSP-70 positive neurons in basal forebrain cholinergic areas, i.e. the medial septal nucleus (MSN, Ch1), the diagonal band of Broca (DBB, Ch2 and Ch3) and the Nucleus basalis of Meynert (NBM, Ch4). In fact, these nuclei are strictly connected with limbic structures, and play a key pivotal role in different cognitive functions and vigilance. Although recent studies begun to investigate these nuclei in experimental epilepsy and in persons with epilepsy, conflicting results were obtained so far. We showed that after severe and long-lasting, focally induced limbic SE there is a significant cell loss within all of the abovementioned cholinergic nuclei ipsi- and contra-laterally to the infusion site. In parallel, these nuclei show also FJB and heat shock protein-70 expression. Those effects vary depending on the single nucleus assessed and on the severity of the SE seizure score. We also showed the occurrence of cell loss and degenerative phenomena in limbic cortex, hippocampus and limbic thalamic areas. These novel findings show direct evidence of SE-induced neuronal damage which is solely due to seizure activity ruling out potential confounding effects produced by systemic pro-convulsant neurotoxins. A damage to basal forebrain cholinergic nuclei, which may underlie cognitive alterations, is documented for the first time in a model of SE triggered focally.


Outcome after proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis.
During the course of their disease, about 30% of patients with ulcerative colitis (UC) will undergo proctocolectomy with ileal pouch-anal anastomosis (IPAA). We evaluated the outcome of IPAA in a Belgian referral center. Clinical charts were reviewed for pre- and postoperative disease course, functional outcome, and complications in all patients with UC (n = 182) and indeterminate colitis (n = 2) who underwent IPAA in 1990-2004. Follow-up data were available in 173 out of 184 patients (67 female, median age at proctocolectomy 39.0 years). Median functional Oresland score 1 year after IPAA was 3 (range 0-11). Early postoperative complications were seen in 27% of patients. After a median (interquartile range) follow-up of 6.5 (3.4-9.9) years, 35% of patients developed septic and/or obstructive complications. Forty-six percent of patients developed at least 1 episode of pouchitis. Risk factors for pouchitis were the presence of extraintestinal manifestations (odds ratio [OR] 1.92 (1.23-3.01), P = 0.004) and younger age at proctocolectomy (P = 0.004). Chronic pouchitis was present in 33 patients and associated with extraintestinal manifestations (OR 2.93 (1.13-7.62), P = 0.027), backwash ileitis (OR 9.28 (1.71-50.49), P = 0.010), and length of follow-up (P = 0.004). Pouch failure occurred in 5% of patients. Although proctocolectomy with IPAA surgery has a good functional outcome, postoperative complications, especially pouchitis, remain considerable in patients with UC.


Tailoring Fibre Structure Enabled by X-ray Analytics for Targeted Biomedical Applications.
The rising interest in designing fibres via spinning techniques combining the properties of various polymeric materials into advanced functionalised materials is directed towards targeted biomedical applications such as drug delivery, wearable sensors or tissue engineering. Understanding how these functional polymers exhibit multiscale structures ranging from the molecular level to nano-, micro-and millimetre scale is a key prerequisite for their challenging applications that can be addressed by a non-destructive X-ray based analytical approach. X-ray multimodalities combining X-ray imaging, scattering and diffraction allow the study of morphology, molecular structure, and the analysis of nano-domain size and shape, crystallinity and preferential orientation in 3D arrangements. The incorporation of X-ray analytics in the design process of polymeric fibers via their nanostructure under non-ambient conditions (i.e. temperature, mechanical load, humidity…) allows for efficient optimization of the fabrication process as well as quality control along the product lifetime under operating environmental conditions. Here, we demonstrate the successful collaboration between the laboratory of Biomimetic Textiles and Membranes and the Center of X-ray Analytics at Empa for the design, characterisation and optimisation of advanced functionalised polymeric fibrous material systems.


Why Are There So Few Ethics Consults in Children's Hospitals?
In most children's hospitals, there are very few ethics consultations, even though there are many ethically complex cases. We hypothesize that the reason for this may be that hospitals develop different mechanisms to address ethical issues and that many of these mechanisms are closer in spirit to the goals of the pioneers of clinical ethics than is the mechanism of a formal ethics consultation. To show how this is true, we first review the history of collaboration between philosophers and physicians about clinical dilemmas. Then, as a case-study, we describe the different venues that have developed at one children's hospital to address ethical issues. At our hospital, there are nine different venues in which ethical issues are regularly and explicitly addressed. They are (1) ethics committee meetings, (2) Nursing Ethics Forum, (3) ethics Brown Bag workshops, (4) PICU ethics rounds, (5) Grand Rounds, (6) NICU Comprehensive Care Rounds, (7) Palliative Care Team (PaCT) case conferences, (8) multidisciplinary consults in Fetal Health Center, and (9) ethics consultations. In our hospital, ethics consults account for only a tiny percentage of ethics discussions. We suspect that most hospitals have multiple and varied venues for ethics discussions. We hope this case study will stimulate research in other hospitals analyzing the various ways in which ethicists and ethics committees can build an ethical environment in hospitals. Such research might suggest that ethicists need to develop a different set of "core competencies" than the ones that are needed to do ethics consultations. Instead, they should focus on their skills in creating multiple "moral spaces" in which regular and ongoing discussion of ethical issues would take place. A successful ethicist would empower everyone in the hospital to speak up about the values that they believe are central to respectful, collaborative practice and patient care. Such a role is closer to what the first hospital philosophers set out to do than in the role of the typical hospital ethics consultant today.


Effect of two different preparations of platelet-rich plasma on synoviocytes.
To analyse the modifications induced by two different platelet-rich plasma (PRP) preparations on osteoarthritis (OA) synoviocytes, by documenting changes in gene expression of factors involved in joint physiopathology. OA synoviocytes were cultured for 7 days in medium with different concentrations of either P-PRP (a pure platelet concentrate without leucocytes but with a limited number of platelets), L-PRP (a higher platelet concentrate containing leucocytes) or platelet-poor plasma (PPP). Gene expression of interleukin (IL)-1beta, IL-6, IL-8/CXCL8, tumour necrosis factor alpha, IL-10, IL-4, IL-13, metalloproteinase-13, tissue inhibitor of metalloproteinase (TIMP)-1, (TIMP)-3, (TIMP)-4, vascular endothelial growth factor, transforming growth factor beta1, fibroblast growth factor (FGF)-2, hepatocyte growth factor (HGF), hyaluronic acid (HA) synthases (HAS)-1, (HAS)-2, and (HAS)-3 was analysed by RT-PCR. HA production was determined in culture supernatants by ELISA. IL-1β, IL-8 and FGF-2 were significantly induced by L-PRP compared to both P-PRP and PPP; HGF was down-modulated by L-PRP versus both P-PRP and PPP, and an inverse dose-response influence was shown for all preparations. Expression level of TIMP-4 was lower in the presence of L-PRP compared with P-PRP. HA production and HAS gene expression did not seem to be modulated by PRP. L-PRP is able to sustain the up-regulation of proinflammatory factors, (IL-1beta, IL-8 and FGF-2), together with a down-modulation of HGF and TIMP-4 expression, two factors that have been recognized as anti-catabolic mediators in cartilage, thus supporting the need to further optimize the PRP preparations to be applied in clinical practice.


Orbitofrontal and limbic signatures of empathic concern and intentional harm in the behavioral variant frontotemporal dementia.
Perceiving and evaluating intentional harms in an interpersonal context engages both cognitive and emotional domains. This process involves inference of intentions, moral judgment, and, crucially, empathy towards others' suffering. This latter skill is notably impaired in behavioral variant frontotemporal dementia (bvFTD). However, the relationship between regional brain atrophy in bvFTD and deficits in the above-mentioned abilities is not well understood. The present study investigated how gray matter (GM) atrophy in bvFTD patients correlates with the perception and evaluation of harmful actions (attribution of intentionality, evaluation of harmful behavior, empathic concern, and moral judgment). First, we compared the behavioral performance of 26 bvFTD patients and 23 healthy controls on an experimental task (ET) indexing intentionality, empathy, and moral cognition during evaluation of harmful actions. Second, we compared GM volume in patients and controls using voxel-based morphometry (VBM). Third, we examined brain regions where atrophy might be associated with specific impairments in the patient group. Finally, we explored whether the patients' deficits in intentionality comprehension and empathic concern could be partially explained by regional GM atrophy or impairments in other relevant factors, such as executive functions (EFs). In bvFTD patients, atrophy of limbic structures (amygdala and anterior paracingulate cortex--APC) was related to impairments in intentionality comprehension, while atrophy of the orbitofrontal cortex (OFC) was associated with empathic concern deficits. Intentionality comprehension impairments were predicted by EFs and orbitofrontal atrophy predicted deficits in empathic concern. Thus, although the perception and evaluation of harmful actions are variously compromised in bvFTD, deficits in empathic concern may be central to this syndrome as they are associated with one of the earliest atrophied region. More generally, our results shed light on social cognition deficits in bvFTD and may have important clinical implications.


[Anxiety and anxiolysis: on the need for differentiated characterization of anxiety from the experimental and biopsychological viewpoint].
Characterization and operationalization of anxiety point to the problem of the homogenity of the construct "anxiety". Results of experimental studies show that one and the same increase in subjective anxiety can be related to systematically different autonomic-physiological processes. Accordingly, (1) an unspecific increase in ANS-arousal is not, as usually assumed, a basic characteristic of anxiety and (2) indicators of experienced anxiety, which often have a key-role in inferring a state of anxiety, do not allow a sufficient differentiation of this state. The integration of the results in experimentally based biopsychological theories of emotion and the application to the preoperative situation underline the necessity of a more differentiated characterization of anxiety, also and especially with regard to possibilities of a pharmacological anxiolysis.


Chromatin structure along the ribosomal DNA of Dictyostelium. Regional differences and changes accompanying cell differentiation.
The ribosomal genes of Dictyostelium discoideum are extrachromosomal palindromic DNA molecules situated in the nucleolus. Each molecule comprises ribosomal RNA coding regions and non-transcribed spacer regions. We used both biochemical and electron microscopic approaches to investigate the structure of transcribing and non-transcribing chromatin. Nucleoli from exponentially growing cells were digested with micrococcal nuclease, and the resulting DNA fragments were separated by gel electrophoresis and transferred to DBM paper. They were hybridized with cloned EcoRI fragments derived from different parts of the ribosomal gene. Probes of the coding region showed a smear, while probes of the non-transcribed regions gave pronounced banding patterns more complex than typical nucleosome repeats, but not due solely to sequence-specific cutting by micrococcal nuclease. The DNA of the coding region was digested more quickly than that of the non-transcribed ones. When nucleoli were digested with restriction enzymes, sites within the coding region were accessible and sites in the non-transcribed region were protected. The structure of ribosomal chromatin in differentiating cells, in which the rate of ribosomal RNA synthesis is reduced, was examined using essentially the same methods. The coding region, probed by hybridization to micrococcal digests, then showed a typical DNA repeat pattern indicating that this region had become condensed into nucleosomes, and its accessibility to restriction enzymes was very much reduced. On electron micrographs of lysed nucleoli from exponentially growing cells, two types of chromatin were observed, one with a beaded nucleosomal appearance, the other with putative RNA polymerase molecules attached to fibres indistinguishable from free DNA adsorbed to the same grid. The combined results suggest that whereas regions that are not transcribed are packaged with proteins that protect them from nuclease digestion, actively transcribing ribosomal genes are associated with few macromolecular constituents apart from those required for transcription and its regulation.


Marital quality and diabetes: results from the Health and Retirement Study.
Poor marital quality is associated with many different indicators of poor health, including immunologic and metabolic responses that have relevance for distal disease outcomes such as diabetes. We conducted this study to evaluate whether poor marital quality was associated with the prevalence of diabetes in a population-based sample of Americans over the age of 50. Participants were married adults from the 2006 (N = 3,898) and 2008 (N = 3,452) waves of the Health and Retirement Study. Participants completed an interview and a self-report questionnaire, and current use of diabetes medication and glycosylated hemoglobin obtained from blood spot samples were used to index diabetes status. Marital quality was assessed with items regarding perceived frequency of positive and negative exchanges with partner. Decreasing frequency of positive exchanges and increasing frequency of negative exchanges with one's spouse were associated with higher prevalence of diabetes among men, but not women at both waves; gender significantly moderated the associations between partner exchanges and diabetes status for the 2006 data. The association between frequency of partner exchanges and diabetes status generally remained significant in men after accounting for demographic characteristics and other risk factors (obesity, hypertension, low physical activity). Poor marital quality as operationalized by rates of positive and negative partner exchanges was associated with increased prevalence of diabetes in men. These results are consistent with prior work on marriage and health, and suggest that poor marital quality may be a unique risk factor for diabetes.


Management of Brain Metastases: A Review of Novel Therapies.
Brain metastases (BMs) represent the most common intracranial tumors in adults, and most commonly originate from lung, followed by breast, melanoma, kidney, and colorectal cancer. Management of BM is individualized based on the size and number of brain metastases, the extent of extracranial disease, the primary tumor subtype, neurological symptoms, and prior lines of therapy. Until recently, treatment strategies were limited to local therapies, like surgical resection and radiotherapy, the latter in the form of whole-brain radiotherapy or stereotactic radiosurgery. The next generation of local strategies includes laser interstitial thermal therapy, magnetic hyperthermic therapy, post-resection brachytherapy, and focused ultrasound. New targeted therapies and immunotherapies with documented intracranial activity have transformed clinical outcomes. Novel systemic therapies with intracranial utility include new anaplastic lymphoma kinase inhibitors like brigatinib and ensartinib; selective "rearranged during transfection" inhibitors like selpercatinib and pralsetinib; B-raf proto-oncogene inhibitors like encorafenib and vemurafenib; Kirsten rat sarcoma viral oncogene inhibitors like sotorasib and adagrasib; ROS1 gene rearrangement (ROS1) inhibitors, anti-neurotrophic tyrosine receptor kinase agents like larotrectinib and entrectinib; anti-human epidermal growth factor receptor 2/epidermal growth factor receptor exon 20 agent like poziotinib; and antibody-drug conjugates like trastuzumab-emtansine and trastuzumab-deruxtecan. This review highlights the modern multidisciplinary management of BM, emphasizing the integration of systemic and local therapies.


Nanostructuring of sensors determines the efficiency of biomolecular capture.
The detection of biologically important molecules such as proteins and nucleic acids is of high and growing interest in the diagnosis of diseases from cancer to infectious and cardiovascular disease. The use of nanostructures to enhance sensitivity in biomolecular detection has now been reported in a broad range of assays. Here we provide direct evidence that the display of nucleic acid probe molecules on a nanostructured surface dramatically enhances hybridization efficiency compared to the case of the same probe molecules tethered on a smoother surface. Another factor expected to influence hybridization is the density of the probe monolayer. Remarkably, we find herein that the effect of nanostructuring dominates over probe density: the benefits of a high degree of nanostructuring can more than overcome the influence of dense probe packing. The results obtained herein give guidance to the development of high-performance biosensors for medical and environmental applications.


Rhodobacter capsulatus magnesium chelatase subunit BchH contains an oxygen sensitive iron-sulfur cluster.
Magnesium chelatase is the first unique enzyme of the bacteriochlorophyll biosynthetic pathway. It consists of three subunits (BchI, BchD, and BchH). Amino acid sequence analysis of the Rhodobacter capsulatus BchH revealed a novel cysteine motif (393CX2CX3CX14C) that was found in only six other proteobacteria (CX2CX3CX11-14C). The cysteine motif is likely to coordinate an unprecedented [Fe-S] cluster. Purified BchH demonstrated absorbance in the 460 nm region. This absorbance was abolished in BchH proteins with alanine substitutions at positions Cys396 and Cys414. These modified proteins were also EPR silent. In contrast, wild type BchH protein in the reduced state showed EPR signals resembling those of a [4Fe-4S] cluster with rhombic symmetry and g values at 1.90, 1.93, and 2.09, superimposed with a [3Fe-4S] cluster centered at g = 2.02. The [3Fe-4S] signal was observed independently of the [4Fe-4S] signal under oxidizing conditions. Mg-chelatase activity assays showed that the cluster is not catalytic. We suggest that the [4Fe-4S] and [3Fe-4S] signals originate from a single coordination site on the monomeric BchH protein and that the [4Fe-4S] cluster is sensitive to oxidation. It is speculated that the cluster participates in the switching between aerobic and anaerobic life of the proteobacteria.


Changing the face of diabetic care with haptoglobin genotype selection and vitamin e.
Research over the past 10 years in our laboratory has led to two major findings. The first is that haptoglobin (Hp) genotype can predict the risk of developing vascular complications in individuals with diabetes mellitus (DM), and the second, more far-reaching discovery, is that vitamin E treatment can significantly reduce vascular complications in individuals with DM and the Hp 2-2 genotype. The former finding has been well documented in numerous studies which included over 50,000 patients of diverse geographical and ethnic backgrounds. The latter discovery is more recent and less well accepted by the medical community due to confounding reports over the past 30 years regarding the efficacy of vitamin E treatment for vascular disease. We propose that the benefit of vitamin E treatment was not obvious in earlier studies due to the absence of any genetic basis for patient selection. Our studies dividing DM individuals into vitamin E treatment subgroups based on Hp genotype show a clear benefit for individuals of the Hp 2-2 genotype, while patients carrying the other two Hp genotypes are not affected or may be adversely affected by receiving vitamin E. These findings may explain the overall lack of benefit seen in previous vitamin E studies and emphasize the importance of carefully selecting which patients should receive vitamin E therapy. The pharmacogenomic paradigm discussed in this review potentially could result in a dramatic improvement in the health of millions of individuals worldwide using a treatment that is both accessible and affordable to all.


Filovirus VP24 Proteins Differentially Regulate RIG-I and MDA5-Dependent Type I and III Interferon Promoter Activation.
Filovirus family consists of highly pathogenic viruses that have caused fatal outbreaks especially in many African countries. Previously, research focus has been on Ebola, Sudan and Marburg viruses leaving other filoviruses less well studied. Filoviruses, in general, pose a significant global threat since they are highly virulent and potentially transmissible between humans causing sporadic infections and local or widespread epidemics. Filoviruses have the ability to downregulate innate immunity, and especially viral protein 24 (VP24), VP35 and VP40 have variably been shown to interfere with interferon (IFN) gene expression and signaling. Here we systematically analyzed the ability of VP24 proteins of nine filovirus family members to interfere with retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA5) induced IFN-β and IFN-λ1 promoter activation. All VP24 proteins were localized both in the cell cytoplasm and nucleus in variable amounts. VP24 proteins of Zaire and Sudan ebolaviruses, Lloviu, Taï Forest, Reston, Marburg and Bundibugyo viruses (EBOV, SUDV, LLOV, TAFV, RESTV, MARV and BDBV, respectively) were found to inhibit both RIG-I and MDA5 stimulated IFN-β and IFN-λ1 promoter activation. The inhibition takes place downstream of interferon regulatory factor 3 phosphorylation suggesting the inhibition to occur in the nucleus. VP24 proteins of Mengla (MLAV) or Bombali viruses (BOMV) did not inhibit IFN-β or IFN-λ1 promoter activation. Six ebolavirus VP24s and Lloviu VP24 bound tightly, whereas MARV and MLAV VP24s bound weakly, to importin α5, the subtype that regulates the nuclear import of STAT complexes. MARV and MLAV VP24 binding to importin α5 was very weak. Our data provides new information on the innate immune inhibitory mechanisms of filovirus VP24 proteins, which may contribute to the pathogenesis of filovirus infections.


[The etiology of salmonellosis].
Dynamic changes in the etiologic structure of salmonelloses on the territory of the town resulted in alteration of the predominant Salmonella strains. Many-year studies of the etiologic structure of salmonelloses in humans and animals and of serologic variants of Salmonella strains isolated from the environment helped establish the regularities that characterize the ecology of these agents.


The relationship of salivary and cord blood cortisol in preterm infants.
Recent studies reveal that salivary cortisol measurements accurately reflect blood cortisol levels in older children and adults; yet, the relationship between the two values in premature infants has not been established. This study explores the use of salivary cortisol as an accurate measure of adrenal steroid concentrations in premature infants to provide a reliable and less invasive tool for investigating hormonal stress response. Premature infants (n=51) were recruited, with saliva and blood collected immediately after birth, and cortisol levels measured by radioimmunoassay. A linear relationship emerged between cord plasma and salivary cortisol values in the 102 paired samples [(salivary cortisol) = 0.546 +/- 0.192 x (plasma cortisol), r = 0.481 and p = 0.0003]. Findings demonstrated that salivary and plasma cortisol levels were correlated in premature infants. This information will be useful in future studies that assess use of salivary cortisol to evaluate neonatal stress axis function.


Physiological dissection revealed that both uptake and assimilation are the major components regulating different growth responses of two tobacco cultivars to nitrogen nutrition.
K326 and HD represent major tobacco cultivars in China, which required large N fertiliser input but at different application rates. To understand primary components affecting tobacco N use physiology, we adopted these two varieties as valuable genetic material to assess their growth response to N nutrition. We established a hydroponic culture system to grow plants supplied with different N regimes. Plant biomass, N, ammonium, nitrate, arginine, GS and NR activity, N transfer and use efficiency as well as root uptake were examined. Our data revealed the preference of K326 and HD to utilise nitrate or ammonium nitrate but not ammonium alone, with 2 mm N supply probably sufficient and economical to achieve good biomass production at the vegetative stage. Moreover, both varieties were very sensitive to ammonium, perhaps due to lack of or abnormal signalling related to nitrate and/or arginine rather than impairment of N acquisition and initial assimilation; this was supported by measurements of the plant content of N, ammonium and activities of GS and NR. Notably, short-term 15 N root influx studies identified differential uptake kinetics of K326 and HD, with distinct affinities and transport rates for ammonium and nitrate. The data suggest that the growth adaptation of K326 or HD to higher or lower N may be ascribed to different competences for effective N uptake/translocation and assimilation. Thus, our work provides valuable information to prompt deeper investigation of the molecular basis controlling plant N use efficiency.


COBIOTECH's role in biotechnology worldwide.
Curious or skeptical friends often ask, "What and why is COBIOTECH? What is it doing?" After serving as president during its formative first years, I attempt here to provide information for the curious and allay concerns of the skeptics about COBIOTECH's emerging role in biotechnology internationally.


Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk.
Recent genome-wide association (GWA) studies have identified several unsuspected genes associated with type 2 diabetes (T2D) with previously unknown functions. In this investigation, we have examined the role of 9 most significant SNPs reported in GWA studies: [peroxisome proliferator-activated receptor gamma 2 (PPARG2; rs 1801282); insulin-like growth factor two binding protein 2 (IGF2BP2; rs 4402960); cyclin-dependent kinase 5, a regulatory subunit-associated protein1-like 1 (CDK5; rs7754840); a zinc transporter and member of solute carrier family 30 (SLC30A8; rs13266634); a variant found near cyclin-dependent kinase inhibitor 2A (CDKN2A; rs10811661); hematopoietically expressed homeobox (HHEX; rs 1111875); transcription factor-7-like 2 (TCF7L2; rs 10885409); potassium inwardly rectifying channel subfamily J member 11(KCNJ11; rs 5219); and fat mass obesity-associated gene (FTO; rs 9939609)]. We genotyped these SNPs in a case-control sample of 918 individuals consisting of 532 T2D cases and 386 normal glucose tolerant (NGT) subjects of an Asian Sikh community from North India. We tested the association between T2D and each SNP using unconditional logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on body mass index (BMI), waist to hip ratio (WHR), fasting insulin, and glucose and lipid levels using multiple linear regression analysis. Four of the nine SNPs revealed a significant association with T2D; PPARG2 (Pro12Ala) [odds ratio (OR) 0.12; 95% confidence interval (CI) (0.03-0.52); p = 0.005], IGF2BP2 [OR 1.37; 95% CI (1.04-1.82); p = 0.027], TCF7L2 [OR 1.64; 95% CI (1.20-2.24); p = 0.001] and FTO [OR 1.46; 95% CI (1.11-1.93); p = 0.007] after adjusting for age, sex and BMI. Multiple linear regression analysis revealed significant association of two of nine investigated loci with diabetes-related quantitative traits. The 'C' (risk) allele of CDK5 (rs 7754840) was significantly associated with decreased HDL-cholesterol levels in both NGT (p = 0.005) and combined (NGT and T2D) (0.005) groups. The less common 'C' (risk) allele of TCF7L2 (rs 10885409) was associated with increased LDL-cholesterol (p = 0.010) in NGT and total and LDL-cholesterol levels (p = 0.008; p = 0.003, respectively) in combined cohort. To our knowledge, this is first study reporting the role of some recently emerged loci with T2D in a high risk population of Asian Indian origin. Further investigations are warranted to understand the pathway-based functional implications of these important loci in T2D pathophysiology in different ethnicities.


Epitaxial growth of dual-color-emitting organic heterostructures via binary solvent synergism driven sequential crystallization.
The controlled construction of organic heterostructured architectures derived from molecules with similar nucleation thresholds and concentrations has been rare and remains a great challenge. Herein, we report a sequential epitaxial growth to synthesize dual-color-emitting organic heterostructures with 9,10-bis(phenylethynyl)anthracene (BPEA) microwire trunks and tris-(8-hydroxyquinoline)aluminium (Alq3) microstructure branches by an anti-solvent induced sequential crystallization strategy. During the epitaxial growth process, the hydrogen-bonding interactions of the anti-solvent and solvent cause a large change in the solubility and crystallization rate of BPEA and Alq3 molecules in the mixed system, which facilitates sequential crystallization of organic molecule pairs with similar nucleation thresholds and concentrations into desired heterostructures by manipulating the synergism of anti-solvents and solvents. The Förster resonant energy transfer process in heterostructures could be modulated by varying the structure of heterostructures, such as the shape, amount and angles of the branches. The present synthesis strategy provides a unique insight into the detailed formation mechanism of complex organic heterostructures, further guiding the construction of more functional heterostructure materials.


Resveratrol (trans-3,5,4'-trihydroxystilbene) induces silent mating type information regulation-1 and down-regulates nuclear transcription factor-kappaB activation to abrogate dextran sulfate sodium-induced colitis.
Inflammatory bowel disease is a chronic, relapsing, and tissue-destructive disease. Resveratrol (3,4,5-trihydroxy-trans-stilbene), a naturally occurring polyphenol that exhibits beneficial pleiotropic health effects, is recognized as one of the most promising natural molecules in the prevention and treatment of chronic inflammatory disease and autoimmune disorders. In the present study, we investigated the effect of resveratrol on dextran sodium sulfate (DSS)-induced colitis in mice and found that it effectively attenuated overall clinical scores as well as various pathological markers of colitis. Resveratrol reversed the colitis-associated decrease in body weight and increased levels of serum amyloid A, tumor necrosis factor-alpha, interleukin (IL-6), and IL-1beta. After resveratrol treatment, the percentage of CD4(+) T cells in mesenteric lymph nodes (MLN) of colitis mice was restored to normal levels, and there was a decrease in these cells in the colon lamina propria (LP). Likewise, the percentages of macrophages in MLN and the LP of mice with colitis were decreased after resveratrol treatment. Resveratrol also suppressed cyclooxygenase-2 (COX-2) expression induced in DSS-exposed mice. Colitis was associated with a decrease in silent mating type information regulation-1 (SIRT1) gene expression and an increase in p-inhibitory kappaB expression and nuclear transcription factor-kappaB (NF-kappaB) activation. Resveratrol treatment of mice with colitis significantly reversed these changes. This study demonstrates for the first time that SIRT1 is involved in colitis, functioning as an inverse regulator of NF-kappaB activation and inflammation. Furthermore, our results indicate that resveratrol may protect against colitis through up-regulation of SIRT1 in immune cells in the colon.


The RsmA RNA-Binding Proteins in Pseudomonas syringae Exhibit Distinct and Overlapping Roles in Modulating Virulence and Survival Under Different Nutritional Conditions.
The post-transcriptional regulator RsmA globally controls gene expression in bacteria. Previous studies showed that RsmA2 and RsmA3 played critical roles in regulating type III secretion system (T3SS), motility, syringafactin, and alginate productions in Pseudomonas syringae pv. tomato strain DC3000 (PstDC3000). In this study, we investigated global gene expression profiles of the wild-type PstDC3000, the rsmA3 mutant, and the rsmA2/A3 double mutant in the hrp-inducing minimum medium (HMM) and King's B (KB) medium. By comparing the rsmA2/A3 and rsmA3 mutants to PstDC3000, a total of 1358 and 1074 differentially expressed genes (DEGs) in HMM, and 870 and 1463 DEGs in KB were uncovered, respectively. When comparing the rsmA2/A3 mutant with the rsmA3 mutant, 277 and 741 DEGs in HMM and KB, respectively, were revealed. Transcriptomic analysis revealed that the rsmY, rsmZ, and rsmX1-5 non-coding small RNAs (ncsRNAs) were positively affected by RsmA2 and RsmA3, while RsmA3 positively regulates the expression of the rsmA2 gene and negatively regulates both rsmA1 and rsmA5 gene expression. Comparative transcriptomic analysis showed that RsmA2 and RsmA3 synergistically influenced the expression of genes involved in T3SS and alginate biosynthesis in HMM and chemotaxis in KB. RsmA2 and RsmA3 inversely affected genes involved in syringafactin production in HMM and ribosomal protein biosynthesis in KB. In addition, RsmA2 played a major role in influencing genes involved in sarcosine and thiamine biosynthesis in HMM and in mannitol and phosphate metabolism in KB. On the other hand, genes involved in fatty acid metabolism, cellulose biosynthesis, signal transduction, and stress responses were mainly impacted by RsmA3 in both HMM and KB; whereas RsmA3 played a major role in controlling genes involved in c-di-GMP, phosphate metabolism, chemotaxis, and capsular polysaccharide in HMM. Furthermore, regulation of syringafactin production and oxidative stress by RsmA2 and RsmA3 was experimentally verified. Our results suggested the potential interplay among the RsmA proteins, which exhibit distinct and overlapping roles in modulating virulence and survival in P. syringae under different nutritional conditions.


Antisense-based RNA therapy of factor V deficiency: in vitro and ex vivo rescue of a F5 deep-intronic splicing mutation.
Antisense molecules are emerging as a powerful tool to correct splicing defects. Recently, we identified a homozygous deep-intronic mutation (F5 c.1296+268A>G) activating a cryptic donor splice site in a patient with severe coagulation factor V (FV) deficiency and life-threatening bleeding episodes. Here, we assessed the ability of 2 mutation-specific antisense molecules (a morpholino oligonucleotide [MO] and an engineered U7 small nuclear RNA [snRNA]) to correct this splicing defect. COS-1 and HepG2 cells transfected with a F5 minigene construct containing the patient's mutation expressed aberrant messenger RNA (mRNA) in excess of normal mRNA. Treatment with mutation-specific antisense MO (1-5 µM) or a construct expressing antisense U7snRNA (0.25-2 µg) dose-dependently increased the relative amount of correctly spliced mRNA by 1 to 2 orders of magnitude, whereas control MO and U7snRNA were ineffective. Patient-derived megakaryocytes obtained by differentiation of circulating progenitor cells did not express FV, but became positive for FV at immunofluorescence staining after administration of antisense MO or U7snRNA. However, treatment adversely affected cell viability, mainly because of the transfection reagents used to deliver the antisense molecules. Our data provide in vitro and ex vivo proof of principle for the efficacy of RNA therapy in severe FV deficiency, but additional cytotoxicity studies are warranted.


Different sample preparation and detection methods for normal and lung cancer urinary proteome analysis.
The urinary proteome is known to be a valuable field of study related to human physiological functions because many components in urine provide an alternative to blood plasma as a potential source of disease biomarkers useful in clinical diagnosis and therapeutic application. Due to the variability and complexity of urine, sample preparation is very important for decreasing the dynamic range of components and isolating specific urinary proteins prior to analysis. We discuss many useful sample preparation methods in this chapter, including those of lung cancer urine samples. In addition, protein detection methods are also crucial in visualizing protein profiles and for quantification of protein content in urine samples from both normal donor and lung cancer patients. This chapter also provides alternative choices of urine sample preparation and detection methods for selective use in urinary proteome analysis and for identifying urinary protein markers in lung cancer and other diseases.