Genetic analysis carried out in population tails reveals diverse two-loci interactions as a basic factor of quantitative traits variation in rye.
Bidirectional selective genotyping carried out independently for five quantitative traits within a biparental population of recombinant inbred lines of rye has revealed dramatic changes in alleles distribution in the population tails. A given allele, predominant in the lower tail, is often neutral for reversely directed selection or associates with the upper tail following divergent selection for a related trait. Such radical changes in the alleles distribution cannot be explained by differences in genotypic values within a single locus. This paper presents the theoretical model of a genetic mechanism underlying observed responses of individual loci to divergent selection. The presented model refers to the specific interactions between alleles at two loci. Its wider application in genetic analysis will open up new possibilities for testing positions of genes in the hierarchical structure of interacting loci revealed under selection pressure.


A secondary analysis to develop a scale for measuring unemployed workers' experiences of Australian employment services.
Research consistently shows that Australian employment services are failing those they are intended to serve. Based on findings in other human service areas, a valid and reliable instrument to measure unemployed workers' experiences may provide an opportunity for improvement in this sector. To establish a basis for developing a suitable rating scale. An exploratory factor analysis combined with qualitative cross check for face validity of an existing large survey of Australian unemployed workers. Six factors appear to be important elements of service delivery: (F1) useful and competent, (F2) client-centred, (F3) receptive to feedback, (F4) trustworthy, (F5) fair, and (F6) friendly. While each of these factors have been either described explicitly or referred to implicitly in previous studies, this study is the first to attempt to combine these factors and is a precursor to establishing a valid and reliable rating scale for use by unemployed workers in evaluating their employment service providers. At a time when Australia is exploring new approaches to employment services, such a scale using a robust set of factors may allow for the improvement of employment services and thus be held accountable to a significant stakeholder group whom they aim to serve -unemployed workers.


A life-course approach to assess the relationship between social and psychological circumstances and gingival status in adolescents.
Several models have been proposed to explain the causes of periodontal diseases. None have adopted the life-course approach. To investigate the relationship between social, psychosocial and biological conditions experienced in early life and through the life course and gingival bleeding on probing. A two-phase study was carried out in Brazil. In Phase I, 652 13-year-olds were clinically examined and interviewed. In Phase II, 311 families were randomly selected for an interview to collect information on the teenager's state at birth and selected impacts in their early years of life. Clinical examination included assessment of dental caries, periodontal and dental trauma status. The data analysis used logistic regression and the models were determined using stepwise procedure. Adolescents who were born in a non-brick house, who were living in an overcrowded house at 13 years of age, those whose mother had less than 8 years of education, who were at a lower school grade for their age, those who reported high levels of paternal punishment and those who were from reconstituted families were significantly more likely to experience high levels of bleeding gums after probing. Early life and life-course experiences were important determinants of the level of gingival bleeding after probing in adolescents.


Sonochemical synthesis of high-performance Pd@CuNWs/MWCNTs-CH electrocatalyst by galvanic replacement toward ethanol oxidation in alkaline media.
In this paper, a fast and effective method for the palladium (Pd) wire nanostructures synthesis with the great surface area through galvanic replacement reaction utilizing copper nanowires (CuNWS) as a template by the assistance of ultrasound under room temperature condition is proposed. A multifunctional catalyst with the mentioned nanostructure, Pd@CuNWs, and multi walled carbon nanotubes (MWCNTs) and chitosan (CH) as a binder was fabricated. To investigate the morphology and bulk composition of the prepared catalyst, Field Emission Scanning Electron Microscopy (FE-SEM), Energy Dispersive X-ray Spectroscopy (EDS), X-ray Powder Diffraction (XRD), and Inductively Coupled Plasma atomic Emission Spectroscopy (ICP-AES) were utilized. Various electrochemical techniques including chronoamperometry and cyclic voltammetry were employed for the electrocatalytic activity of ethanol electrooxidation and durability in basic solution. Electrochemical catalytic activity and durability evaluation results proved that the as-synthesized Pd@CuNWs/MWCNTs-CH has a super electrocatalytic activity compared to Pd/MWCNTs and Pd/C electrocatalysts for ethanol electrooxidation. Pd@CuNWs/MWCNTs-CH catalyst demonstrated substantially enhanced performance and long-term stability for ethanol electrooxidation in the basic solution in comparison to Pd/MWCNTs and commercial Pd/C demonstrated the potential in utilizing Pd@CuNWs/MWCNTs-CH as an efficient catalyst for ethanol oxidation. Additionally, thermodynamic and kinetic evaluations revealed that the Pd@CuNWs/MWCNTs-CH catalyst has lower activation energy compared to Pd/MWCNTs and Pd/C which leads to a lower energy barrier and an excellent charge transfer rate towards ethanol oxidation. Noticeably, the Pd@CuNWs/MWCNTs-CH presented excellent catalytic activities with high peak current density which was 9.5 times more than Pd/C, and more negative onset potential in comparison to Pd/C is acquired for ethanol electrooxidation denoting synergistic effect between CuNWs/MWCNs-CH and Pd. The Pd@CuNWs/MWCNTs-CH can be considered as a valid candidate among available electrocatalysts in direct ethanol fuel cells (DEFCs).


Collagenolytic/gelatinolytic enzymes in corneal wound healing.
We have documented changes in expression of collagenolytic/gelatinolytic enzymes of the matrix metalloproteinase family (MMP) in healing or ulcerating corneal wounds of rat or rabbit. Correlation of our findings with specific changes in the extracellular matrix of the repair tissue suggests two different roles for the enzymes, MMP-2 and MMP-9. MMP-2 is expressed in undamaged corneal stroma where it may degrade the occasional collagen molecule that becomes damaged. After corneal wounding, expression of this enzyme is increased and much of it appears in the active form. These changes persist for at least seven months, suggesting that MMP-2 is involved in the prolonged process of collagen remodelling in the stromal repair tissue. MMP-9 is expressed in the epithelial layer of repair tissue with a timing suggesting it might participate in controlling resynthesis of the basement membrane. MMP-9 also appears to be involved in degradation of the epithelial basement membrane that precedes corneal ulceration.


RN-1, a potent and selective lysine-specific demethylase 1 inhibitor, increases γ-globin expression, F reticulocytes, and F cells in a sickle cell disease mouse model.
Increased levels of fetal hemoglobin are associated with decreased symptoms and increased lifespan in patients with sickle cell disease (SCD). Hydroxyurea, the only drug currently approved for SCD, is not effective in a large fraction of patients, and therefore, new agents are urgently needed. Recently it was found that lysine demethylase 1, an enzyme that removes monomethyl and dimethyl residues from the lysine 4 residue of histone H3, is a repressor of γ-globin gene expression. In this article, we have compared the ability of tranylcypromine (TCP) and a more potent TCP derivative, RN-1, to increase γ-globin expression in cultured baboon erythroid progenitor cells and in the SCD mouse model. The results indicate that the ability of RN-1 to induce F cells and γ-globin mRNA in SCD mice is similar to that of decitabine, the most powerful fetal hemoglobin-inducing drug known, and greater than that of either TCP or hydroxyurea. We conclude that RN-1 and other lysine demethylase 1 inhibitors may be promising new γ-globin-inducing agents for the treatment of SCD that warrant further studies in other preclinical models, such as nonhuman primates.


OsHYPK-mediated protein N-terminal acetylation coordinates plant development and abiotic stress responses in rice.
N-terminal acetylation is one of the most common protein modifications in eukaryotes, and approximately 40% of human and plant proteomes are acetylated by ribosome-associated N-terminal acetyltransferase A (NatA) in a co-translational manner. However, the in vivo regulatory mechanism of NatA and the global impact of NatA-mediated N-terminal acetylation on protein fate remain unclear. Here, we identify Huntingtin Yeast partner K (HYPK), an evolutionarily conserved chaperone-like protein, as a positive regulator of NatA activity in rice. We found that loss of OsHYPK function leads to developmental defects in rice plant architecture but increased resistance to abiotic stresses, attributable to perturbation of the N-terminal acetylome and accelerated global protein turnover. Furthermore, we demonstrated that OsHYPK is also a substrate of NatA and that N-terminal acetylation of OsHYPK promotes its own degradation, probably through the Ac/N-degron pathway, which could be induced by abiotic stresses. Taken together, our findings suggest that the OsHYPK-NatA complex plays a critical role in coordinating plant development and stress responses by dynamically regulating NatA-mediated N-terminal acetylation and global protein turnover, which are essential for maintaining adaptive phenotypic plasticity in rice.


All-Arthroscopic Suprapectoral Biceps Tenodesis.
Biceps tenodesis is a common treatment for pathology of the long head of the biceps tendon. Several authors have described various arthroscopic and open techniques for biceps tenodesis. Open techniques have been associated with complications such as wound infection and nerve injury. Previously described arthroscopic techniques have placed the tenodesis site within the bicipital groove, which may lead to persistent pain. We describe an all-arthroscopic suprapectoral biceps tenodesis technique that places the tenodesis site distal to the bicipital groove. This technique potentially avoids the complications associated with open tenodesis surgery while still removing the biceps tendon from the bicipital groove.


Do the substance P-ergic vagus afferents in cats reinnervate the deafferented superior cervical ganglion?
By ligating specific nerves in the cat, the central processes of the nodose ganglion (NG) cells containing substance P-like immunoreactive materials were shown, immunohistochemically, to run through the cross-anastomosis made between the cranial end of the NG and the caudal end of the superior cervical ganglion (SCG), and to reach the portions cranial to the SCG without making synaptic contacts with the SCG cells.


Comparison of gadoxetic acid-enhanced magnetic resonance imaging and contrast-enhanced computed tomography with histopathological examinations for the identification of hepatocellular carcinoma: a multicenter phase III study.
Gadoxetic acid-enhanced magnetic resonance imaging (MRI) has an important role in preoperative evaluation of hepatocellular carcinoma (HCC). However, no studies have prospectively performed intraindividual comparison of gadoxetic acid-enhanced 3T MRI and multidetector-row computed tomography (MDCT) with histopathological examination for the detection of HCCs. We prospectively compared the efficacies of gadoxetic acid-enhanced MRI and multiphasic contrast-enhanced MDCT with that of histopathological examination, used as a reference standard, for the detection of HCC in surgical candidates. The study was approved by the institutional review boards at each of four centers. Patients scheduled to undergo multiphasic CT, gadoxetic acid-enhanced MRI, and liver surgery were prospectively included in this study. The diagnostic abilities of MRI and CT were evaluated and compared on the basis of sensitivity and positive predictive value for detection of and differentiation between HCCs and benign lesions. Fifty-four patients with 83 histopathologically confirmed HCCs were included in the study. Combined interpretation of the dynamic and hepatobiliary phases of gadoxetic acid-enhanced MRI showed statistically higher sensitivity for lesion detection (83 %) than did interpretation of multiphasic MDCT images (70 %; p < 0.001). The mean area under each alternative free-response receiver operating characteristics curve was significantly higher for MR images (0.927) than for CT images (0.864, p < 0.01). The sensitivity for preoperative detection of HCCs was higher for gadoxetic acid-enhanced MRI than for multiphasic MDCT imaging.


Metasurface wavefront control for high-performance user-natural augmented reality waveguide glasses.
Augmented reality (AR) devices, as smart glasses, enable users to see both the real world and virtual images simultaneously, contributing to an immersive experience in interactions and visualization. Recently, to reduce the size and weight of smart glasses, waveguides incorporating holographic optical elements in the form of advanced grating structures have been utilized to provide light-weight solutions instead of bulky helmet-type headsets. However current waveguide displays often have limited display resolution, efficiency and field-of-view, with complex multi-step fabrication processes of lower yield. In addition, current AR displays often have vergence-accommodation conflict in the augmented and virtual images, resulting in focusing-visual fatigue and eye strain. Here we report metasurface optical elements designed and experimentally implemented as a platform solution to overcome these limitations. Through careful dispersion control in the excited propagation and diffraction modes, we design and implement our high-resolution full-color prototype, via the combination of analytical-numerical simulations, nanofabrication and device measurements. With the metasurface control of the light propagation, our prototype device achieves a 1080-pixel resolution, a field-of-view more than 40°, an overall input-output efficiency more than 1%, and addresses the vergence-accommodation conflict through our focal-free implementation. Furthermore, our AR waveguide is achieved in a single metasurface-waveguide layer, aiding the scalability and process yield control.


Natural history collections document biological responses to climate change: A commentary on DeLeo et al. (2019), Effects of two centuries of global environmental variation on phenology and physiology of Arabidopsis thaliana.
Natural history collections can complement and enhance our research programs in a variety of ways. DeLeo et al. (2019) used herbarium records to study the changes in physiology and phenology in Arabidopsis thaliana (Brassicaceae) due to contemporary climate change. Here, we discuss their approach and results as well as highlight other ways in which herbarium and natural history museum records can be leveraged for future studies.The copyright holder of the image (the herbarium sheet of Arabidopsis thaliana) is the first author, Derek Denney. This article is a commentary on DeLeo et al, 26, 523-538.


Long-Term Prognosis of Acute Myocardial Infarction Associated With Metabolic Health and Obesity Status.
Emerging evidence supports the favorable cardiovascular health in nonobese subjects with healthy metabolism. However, little is known regarding the prognosis across the range of metabolic phenotypes once cardiovascular disease is established. We examined the prognosis of patients with acute myocardial infarction (AMI) stratified according to metabolic health and obesity status. This is a retrospective study on consecutive patients with AMI admitted to a tertiary hospital between 2014 and 2021. Patients were allocated into the following 4 groups based on metabolic and obesity profile: (1) metabolically healthy obese (MHO), (2) metabolically healthy nonobese (MHNO), (3) metabolically unhealthy obese (MUO), and (4) metabolically unhealthy nonobese (MUNO). Metabolic health was defined in accordance to the Biobank Standardisation and Harmonisation for Research Excellence in the European Union Healthy Obese Project. The primary outcome was all-cause mortality. The Cox regression analysis examined the independent association between mortality and metabolic phenotypes, adjusting for age, sex, AMI type, chronic kidney disease, smoking status, and left ventricular ejection fraction. Of 9958 patients, the majority (68.5%) were MUNO, followed by MUO (25.1%), MHNO (5.6%), and MHO (0.8%). MHO had the lowest mortality (7.4%), followed by MHNO (9.7%), MUO (19.2%), and MUNO (22.6%) (P < .001). Compared with MHNO, MUO (hazard ratio [HR], 1.737; 95% confidence interval [CI], 1.282-2.355; P < .001) and MUNO (HR, 1.482; 95% CI, 1.108-1.981; P = .008) had a significantly higher mortality risk but not MHO (HR, 1.390; 95% CI, 0.594-3.251; P = .447), after adjusting for confounders. The Kaplan-Meier curves showed favorable survival in the metabolically healthy and obesity groups, with the highest overall survival in the MHO, followed by MHNO, MUO, and MUNO (P < .001). Metabolically healthy and obese patients with AMI have favorable prognosis compared with metabolically unhealthy and nonobese patients. It is equally important to prioritize intensive metabolic risk factor management to weight reduction in the early phase after AMI.


A Case of Electrical Right-Ventricular Infarction in the Absence of Clinical Right-Ventricular Failure.
In the setting of acute coronary syndrome, right-ventricular (RV) infarction, which has significant clinical implications, can occur in conjunction with inferior left-ventricular (LV) infarction. In rare cases, RV infarction is isolated. We describe a case of isolated RV infarction identified based on previously described electrocardiogram findings in the absence of hemodynamic or imaging evidence of RV dysfunction. This case highlights the fact that RV transmural ischemia can exist in the absence of the clinical syndrome associated with RV infarction, which we hypothesize is related to the proportion of RV myocardium involved in the infarct, or conversely, the amount of myocardium protected through various mechanisms.


Evaluation of the impact of SO₂ and NO₂ emissions on the ambient air-quality in the Çan-Bayramiç region of northwest Turkey during 2007-2008.
The characterization and assessment of air-quality in this region are essential steps for the implementation of the "Clean Air Action Plan" as this is set by the Turkish Regulation on Ambient Air-Quality Assessment and Management. This study area intends to shed a light on use of modeling tools as an alternative method for the assessment of local atmospheric pollution and the determination of the importance of local emissions. This modeling approach can be also used for the consistent geographic representation of air-quality concentration as well as for assessing the future air-quality condition after the implementation of emission reduction measures in a certain area. With this article we evaluate the impact of sulfur dioxide and nitrogen dioxide emissions on the ambient air-quality in the Çan-Bayramiç region of Turkey. The emission rates of sulfur dioxide and nitrogen dioxide were calculated by using the CALPUFF model. The concentration of these pollutants had also been monitored at ten air-quality locations during 2007-2008 in the research area. The measured data were also utilized for testing the model performance. Results showed that the air-quality in this important rural region of Turkey can be evaluated effectively by using the current numerical modeling system.


Vitamin D3 binding activity during leukemic cell differentiation.
In this paper we report that differentiation of the human promyelocytic leukemia cell line, HL60, along the myelocytic pathway, induced by retinoic acid (RA), or monocytic pathway, induced by phorbol-myristate acetate (PMA) and gamma interferon (IFN), was accompanied by a significant decline in 1,25-dihydroxycholecalciferol (1,25(OH)2D3) binding (control: 30.3 +/- 3.0 fM/10(6) cells; RA treated: 6.8 + 2.5 fM/10(6) cells; PMA treated: 12.3 +/- 6.7 fM/10(6) cells and IFN treated: 16.0 +/- 5.0 fM/10(6) cells). When differentiation and proliferation were uncoupled, by incubation with IFN or by inhibition of proliferation by cell density saturation, 1,25(OH)2D3 binding was better related to differentiation than to proliferation. Additionally we have compared 1,25(OH)2D3 binding levels in blasts from acute lymphocytic leukemia (ALL) patients (25.4 +/- 18.1 fM/10(6) cells) and normal, mature lymphocytes (10.6 +/- 2.1 fM/10(6) cells). Receptor binding was significantly higher (p < 0.05) in the immature blasts. Our data suggest that 1,25(OH)2D3 receptor levels could be considered a marker of functional immaturity, in these cells.


Cleaning the dose falloff with low modulation in SBRT lung plans.
Purpose.This dosimetric study is intended to lower the modulation factor in lung SBRT plans generated in the Eclipse TPS that could replace highly modulated plans that are prone to the interplay effect.Materials and methods.Twenty clinical lung SBRT plans with high modulation factors (≥4) were replanned in Varian Eclipse TPS version 15.5 utilizing 2 mm craniocaudal and 1 mm axial block margins followed by light optimization in order to reduce modulation. A unique plan optimization methodology, which utilizes a novel shell structure (OptiForR50) for R50%optimization in addition to five consecutive concentric 5 mm shells, was utilized to control dose falloff according to RTOG 0813 and 0915 recommendations. The prescription varied from 34-54 Gy in 1-4 fractions, and the dose objectives were PTV D95%= Rx, PTV Dmax< 140% of Rx, and minimizing the modulation factor. Plan evaluation metrics included modulation factor, CIRTOG, homogeneity index (HI), R50%, D2cm, V105%, and lung V8-12.8Gy(Timmerman Constraint). A random-intercept linear mixed effects model was used with a p ≤ 0.05 threshold to test for statistical significance.Results.The retrospectively generated plans had significantly lower modulation factors (3.65 ± 0.35 versus 4.59 ± 0.54; p < 0.001), lower CIRTOG(0.97 ± 0.02 versus 1.02 ± 0.06; p = 0.001), higher HI (1.35 ± 0.06 versus 1.14 ± 0.04; p < 0.001), lower R50%(4.09 ± 0.45 versus 4.56 ± 0.56; p < 0.001), and lower lungs V8-12.8Gy(Timmerman) (4.61% ± 3.18% versus 4.92% ± 3.37%; p < 0.001). The high dose spillage V105%was borderline significantly lower (0.44% ± 0.49% versus 1.10% ± 1.64%; p = 0.051). The D2cmwas not statistically different (46.06% ± 4.01% versus 46.19% ± 2.80%; p = 0.835).Conclusion.Lung SBRT plans with significantly lower modulation factors can be generated that meet the RTOG constraints, using our planning strategy.


Sensitivity of population energy efficiency indices to differences in mortality rates.
Simulation techniques were used to study the response of population energy efficiencies to changes in survival rates. Efficiency indices are very conservative over a wide range of survivorship curves.


Nerve conduction studies through landmark based recording and effects of hand length.
As per existing guidelines, the distance between stimulator and recording electrodes in nerve conduction studies (NCS) should be the same (fixed) in all the subjects, i.e., it should not be based on anatomical landmarks. However, there are no studies comparing fixed distance recordings with landmark based NCS. We postulated that hand length can influence the NCS parameters in fixed distance recordings and this can be nullified using landmark based recordings. To test this theory, we performed NCS in 48 normal subjects as per standard guidelines (standard protocol) and then compared it to NCS with ulnar styloid as the landmark (modified protocol). NCS were performed on median and ulnar nerves of the right upper limb. Three motor NCS parameters including distal latency, compound muscle action potential (CMAP) amplitudes and nerve conduction velocities were measured. Sensory nerve action potential (SNAP) amplitudes and conduction velocities were the two sensory parameters measured. On analysis, ulnar motor conduction velocity was the only parameter affected by hand length in both standard and modified protocols. Modified protocol did not have any additional advantage to the standard protocol advised by NDTF. We conclude that the NDTF guidelines are therefore reasonable when considering the effects of hand length. Possible reasons for this result including anatomical and anthropometric explanations are discussed.


Characterization of recumbent, ambulatory, and postexercise proteinuria in the adolescent.
To better characterize the effects of body position and exercise on urinary protein excretion, carefully defined random urine samples were obtained during recumbency and following both ambulation and exercise in healthy adolescent student athletes. Albumin, lysozyme, and N-acetyl-B-D-glucosaminidase were measured in all samples. Glomerular permeability and tubular function were assessed using the urinary albumin creatinine ratio (UAlb/UCr), the urinary lysozyme creatinine ratio (ULy/UCr), the urinary N-acetyl-B-D-glucosaminidase creatinine ratio (UNag/UCr), and the urinary lysozyme albumin ratio (ULy/UAlb). UAlb/UCr was significantly (p less than 0.001) lower in recumbent urine samples than in either ambulatory or postexercise samples, although no difference was seen between the latter two groups. Furthermore, recumbent UAlb/UCr was higher in females (p less than 0.01) and postexercise UAlb/UCr varied significantly (p less than 0.001), depending on the type of physical activity. ULy/UCr, UNag/UCr, and ULy/UAlb were unaffected by either posture or physical activity. A significant correlation was found between UAlb/UCr and UNag/UCr (r = 0.60, p = 0.0001) and also between ULy/UCr and ULy/UAlb (r = 0.84, p = 0.001). In addition, urine-specific gravity was found to have a significant negative correlation with UAlb/UCr (r = -0.33, p = 0.001). The results of this study suggest that in the adolescent, recumbent albumin excretion is higher in females and that ambulation increases glomerular permeability. Exercise does not appear to induce any additional alteration in glomerular permeability, although the effects of exercise are likely-related to the type and severity of physical activity. Renal tubular function is unaltered by either ambulation or exercise.(ABSTRACT TRUNCATED AT 250 WORDS)


Mediators of inflammation in children with type I diabetes mellitus: cytokines in type I diabetic children.
Recent evidence favors primary role of cellular autoimmunity and its humoral mediators in pathogenesis and following Type I diabetes mellitus (DM). The present study was carried out to investigate serum concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha in children with type I DM. Potential role of lipid metabolism, glycemic control, body mass index (BMI) and disease duration were evaluated. Thirty-five children with type I DM and 30 age and gender matched nondiabetic controls were recruited for this study. Circulating IL-8 levels were elevated in children with type I DM (12.7 +/- 1.7 pg/mL) compared with nondiabetic controls (5.5 +/- 0.3 pg/mL) and the difference remained significant after adjustment for cofactors and covariates (p: 0.033). Although statistically insignificant serum CRP concentrations were slightly higher in diabetic children (p: 0.075). Serum TNF-alpha and IL-6 levels were comparable in diabetic and nondiabetic groups. However newly diagnosed (<1 yr) cases had higher TNF-alpha and IL-6 levels compared to cases with longer standing DM. In diabetic children BMI was independently associated with an increase in serum IL-8 levels. Serum CRP, lipids, apolipoproteins and glycemic control were not significant predictors of cytokine concentrations in children with type I DM. Circulating levels of IL-8 were elevated and were correlated with BMI in children with type I DM, hinting perhaps at adipose tissue as a site of production. Elevated systemic IL-6 and TNF-alpha were limited to newly diagnosed cases suggesting activation of the inflammatory immune response system at early stages of the disease.


Direct measurement of a non-Hermitian topological invariant in a hybrid light-matter system.
Topology is central to understanding and engineering materials that display robust physical phenomena immune to imperfections. Different topological phases of matter are characterized by topological invariants. In energy-conserving (Hermitian) systems, these invariants are determined by the winding of eigenstates in momentum space. In non-Hermitian systems, a topological invariant is predicted to emerge from the winding of the complex eigenenergies. Here, we directly measure the non-Hermitian topological invariant arising from exceptional points in the momentum-resolved spectrum of exciton polaritons. These are hybrid light-matter quasiparticles formed by photons strongly coupled to electron-hole pairs (excitons) in a halide perovskite semiconductor at room temperature. We experimentally map out both the real (energy) and imaginary (linewidth) parts of the spectrum near the exceptional points and extract the novel topological invariant—fractional spectral winding. Our work represents an essential step toward realization of non-Hermitian topological phases in a condensed matter system.


[Evidence-based practice and nursing: intramuscular injection in psychiatry].
Intramuscular injection is a frequent technical procedure in psychiatry. In France, nurses who perform this care do not have official guidelines for good practice. The advanced practice nurse is a field actor who can promote evidence-based practice to improve the quality of care for the benefit of the patient.


Galactic cosmic ray simulation at the NASA Space Radiation Laboratory.
Most accelerator-based space radiation experiments have been performed with single ion beams at fixed energies. However, the space radiation environment consists of a wide variety of ion species with a continuous range of energies. Due to recent developments in beam switching technology implemented at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), it is now possible to rapidly switch ion species and energies, allowing for the possibility to more realistically simulate the actual radiation environment found in space. The present paper discusses a variety of issues related to implementation of galactic cosmic ray (GCR) simulation at NSRL, especially for experiments in radiobiology. Advantages and disadvantages of different approaches to developing a GCR simulator are presented. In addition, issues common to both GCR simulation and single beam experiments are compared to issues unique to GCR simulation studies. A set of conclusions is presented as well as a discussion of the technical implementation of GCR simulation.


Perforated ileal duplication cyst presenting with right iliac fossa pain mimicking perforated appendicitis.
Enteric duplication is an uncommon malformation of the gastrointestinal tract which is either asymptomatic or presents with vague symptoms mimicking other more common pathology. It is most commonly diagnosed when complications such as bleeding, intestinal obstruction or perforation occurs. This is a case report of a patient with this condition presenting with right iliac fossa pain and localised peritonitis mimicking acute appendicitis.


Comparative genome-wide association studies of a depressive symptom phenotype in a repeated measures setting by race/ethnicity in the Multi-Ethnic Study of Atherosclerosis.
Time-varying phenotypes have been studied less frequently in the context of genome-wide analyses across ethnicities, particularly for mood disorders. This study uses genome-wide association studies of depressive symptoms in a longitudinal framework and across multiple ethnicities to find common variants for depressive symptoms. Ethnicity-specific GWAS for depressive symptoms were conducted using three approaches: a baseline measure, longitudinal measures averaged over time, and a repeated measures analysis. We then used meta-analysis to jointly analyze the results across ethnicities within the Multi-ethnic Study of Atherosclerosis (MESA, n = 6,335), and then within ethnicity, across MESA and a sample from the Health and Retirement Study African- and European-Americans (HRS, n = 10,163). This study uses genome-wide association studies of depressive symptoms in a longitudinal framework and across multiple ethnicities to find common variants for depressive symptoms. Ethnicity-specific GWAS for depressive symptoms were conducted using three approaches: a baseline measure, longitudinal measures averaged over time, and a repeated measures analysis. We then used meta-analysis to jointly analyze the results across ethnicities within the Multi-ethnic Study of Atherosclerosis (MESA, n = 6,335), and then within ethnicity, across MESA and a sample from the Health and Retirement Study African- and European-Americans (HRS, n = 10,163). Several novel variants were identified at the genome-wide suggestive level (5×10(-8) < p-value ≤ 5×10(-6)) in each ethnicity for each approach to analyzing depressive symptoms. The repeated measures analyses resulted in typically smaller p-values and an increase in the number of single-nucleotide polymorphisms (SNP) reaching genome-wide suggestive level. For phenotypes that vary over time, the detection of genetic predictors may be enhanced by repeated measures analyses.


Effects of the 5-lipoxygenase inhibitors AA-863 and U-60,257 on human glioma cell lines.
The effects of two specific 5-lipoxygenase inhibitors AA-863 and U-60,257 (piriprost) on the growth of two human glioma cell lines, U-343 MGa and U-251 MG were investigated. Both monolayer cultured cells and spheroids were studied. The results of the monolayer studies showed potent and dose dependent inhibitory effects on the proliferation of glioma cells (IC50/one week treatment/of AA-863: 9.0 microM, IC50 of U-60,257: 40.0 microM). The experiments made on the tumor spheroids suggested an inhibitory effect on proliferation and volume growth already at lower doses (AA-863: 0.4-2.0 microM, U-60,257: 1.0-5.0 microM), a dose range where effects were not found in monolayers. At higher doses (AA-863: 10.0-30.0 microM, U-60,257: 30.0-90.0 microM) the experiments with spheroids failed to demonstrate a further inhibitory effect on spheroid volume, probably attributed to phenomena such as swelling of cells, dissociation of spheroid structure and development of necrosis. The clearly dose dependent inhibitory effect on the proliferation of human glioma cells in monolayer culture and the inhibitory effects on spheroid growth with these specific inhibitors indicate a role for lipoxygenase products in the growth of gliomas.


Sonographic evaluation of the rotator cuff.
This article emphasizes the utility of ultrasound examination in the diagnosis of rotator cuff disease. A complete description is given of the way in which ultrasound examination of the shoulder is performed, the illustrations demonstrating normal anatomy as well as staging of the disease. The use of ultrasound in this setting can help to prevent a great deal of the pain associated with shoulder injury by establishing the nature and stage of injury before rotator cuff tear occurs.


Desensitization to DNFB in hairless mice.
Naive hairless mice may be rendered partly tolerant to dinitrofluorobenzene (DNFB) by painting DNFB on skin irradiated with 30 mJ.cm-2 ultraviolet B light (UVB) over 4 days. However, DNFB-sensitized hairless mice show no decrease in sensitivity when repainted with DNFB on skin irradiated with the same dose of UVB. Hence, established hypersensitivity appears not to be reduced by this method of inducing tolerance in naive mice.


Levosimendan attenuates hypoxia-induced pulmonary hypertension in a porcine model.
Levosimendan was hypothesized to attenuate hypoxic pulmonary vasoconstriction (HPV). Fourteen anaesthetized pigs (30.9 ± 1.0 kg) were studied in normoxia (FiO₂∼0.21) and hypoxia (FiO₂∼0.10), before and 10-90 minutes after infusion of placebo (n = 7) or levosimendan (n = 7). Compared with normoxia, hypoxia baseline at FiO₂∼0.10 (n = 14) increased pulmonary vascular resistance (PVR) by 1.9 ± 0.4 Wood Units (WU) (P < 0.001), mean pulmonary artery pressure (MPAP) by 14.3 ± 0.9 mm Hg (P < 0.001), mean right atrial pressure (MRAP) by 2.1 ± 0.4 mm Hg (P < 0.001), pulmonary capillary wedge pressure (PCWP) by 1.5 ± 0.3 mm Hg (P < 0.001), cardiac output (CO) by 1.3 ± 0.2 L/minute (P < 0.001) and heart rate (HR) by 19.9 ± 5.5 beats·per minute (P < 0.001). Systemic vascular resistance (SVR) decreased by 7.2 ± 1.0 WU (P < 0.001), MAP and stroke volume (SV) remained unaltered (P = ns). Compared with hypoxia baseline, levosimendan decreased MPAP and PVR (P < 0.05), by approximately 9% and 19%, respectively, plateauing between 10 and 90 minutes. SV increased (P < 0.05) by approximately 22%, plateauing after 60 minutes. MRAP, PCWP, HR, CO, MAP, SVR, and blood-O₂ consumption remained unaltered (P = ns). Compared with hypoxia baseline, with placebo, MPAP remained stable (P = ns), PVR increased (P < 0.05) and CO decreased (P < 0.05) by approximately 20% and 11% after 60-90 and 30-90 minutes, respectively. SV decreased (P < 0.05) by approximately 8%, plateauing after 60-90 minutes. PCWP and MRAP decreased (P < 0.05) by approximately 12%, plateauing after 10-60 and 10-90 minutes, respectively. MPAP, HR, MAP, SVR, and blood-O₂ consumption remained unchanged (P = ns), except at 60 minutes where MAP decreased (P < 0.05) by approximately 4%. Levosimendan attenuated HPV and the cardiodepressive effect of sustained hypoxia.


Potassium excretion in renal failure in the rat: the role of distal tubule flow and aldosterone.
1. This study examines the contribution of an increased distal tubule flow and of aldosterone to the handling of a potassium load in conscious rats with renal failure induced by subtotal nephrectomy or by gentamicin on a control of high K+ diet. 2. Glomerular filtration rate was reduced by subtotal nephrectomy to 40% and by gentamicin treatment to 60% of control. Subtotal nephrectomy induced significant hypertrophy of glomeruli and proximal and distal tubules, but gentamicin did not. Both experimental groups had a normal iothalamate space and plasma potassium after a 20 h fast. 3. Two hours after an acute KCl load rats with renal failure excreted less potassium than control rats. There was also a lesser natriuretic effect of KCl in the renal failure groups. 4. A high K+ diet, given for 5-7 days, increased excretion of an acute KCl load in control rats and rats with renal failure. 5. (UNaV + UKV) was used as an estimate of distal tubule flow. Potassium excretion, related to distal tubule flow, was similar in the renal failure and control rats when on the same diet. This is consistent with potassium excretion being strongly, but not necessarily solely, dependent on distal flow. 6. Adrenalectomy reduced, and aldosterone restored, potassium excretion in the renal failure and control groups. This suggests a role for aldosterone in excretion of an acute potassium load with this degree of renal failure.


Effects of induced motor fatigue on walking mechanics and energetics.
Lower-body robotic exoskeletons can be used to reduce the energy demand of locomotion and increase the endurance of wearers. Understanding how motor fatigue affects walking performance may lead to better exoskeleton designs to support the changing physical capacity of an individual due to motor fatigue. The purpose of this study was to investigate the effects of motor fatigue on walking mechanics and energetics. Treadmill walking with progressively increased incline gradient was used to induce motor fatigue. Twenty healthy young participants walked on an instrumented treadmill at 1.25 m/s and 0° of incline for 5 min before (PRE) and after (POST) motor fatigue. We examined lower-limb joint mechanics, metabolic cost, and the efficiency of positive mechanical work (η+work). Compared to PRE, participants had increased net metabolic power by ∼14% (p < 0.001) during POST. Participants also had increased total-limb positive mechanical power (Total P+mech) by ∼4% during POST (p < 0.001), resulting in a reduced η+work by ∼8% (p < 0.001). In addition, the positive mechanical work contribution of the lower-limb joints during POST was shifted from the ankle to the knee while the negative mechanical work contribution was shifted from the knee to the ankle (all p < 0.017). Although greater knee positive mechanical power was generated to compensate for the reduction in ankle positive power after motor fatigue, the disproportionate increase in metabolic cost resulted in a reduced walking efficiency. The findings of this study suggest that powering the ankle joint may help delay the onset of the lower-limb joint work redistribution observed during motor fatigue.


Isolation, biochemical characterization, and development of a biodegradable antimicrobial film from Cirrhinus mrigala scale collagen.
Collagen is a promising candidate for food and pharmaceutical applications due to its excellent biocompatibility, low antigenicity, and controlled biodegradability; however, its heavy price restricts its utilization. Fish scales generated during the processing are generally regarded as waste material and an environmental pollutant, though they are a promising source of collagen. In the present study, Cirrhinus mrigala scales were demineralized and extracted for acid-soluble collagen (ASC) using acetic acid, with a collagen yield of 2.7%. UV-Vis spectra, SDS-PAGE, FTIR analyses, and amino acid composition confirmed the type I nature of the collagen extracted. The denaturation temperature of the collagen was found to be 30.09 °C using differential scanning calorimetry (DSC). The collagen was highly soluble at acidic pH and lower NaCl concentrations while its solubility was lowered in alkaline conditions and NaCl concentrations above 0.5 M. The collagen exhibited good emulsifying potential with an emulsion activity index (EAI) and emulsion stability index (ESI) of 21.49 ± 0.22 m2 g-1 and 15.67 ± 0.13 min, respectively. Owing to the good physicochemical characteristics of the extracted collagen, collagen-chitosan-neem extract (CCN) films were prepared subsequently which showed good antimicrobial activity against Bacillus subtilis NCIM 2635, Staphylococcus aureus NCIM 2654, Escherichia coli NCIM 2832, and Pseudomonas aeruginosa NCIM 5032, suggesting the potential of collagen in the development of antimicrobial films. These results demonstrate that the collagen from fish waste could be valorized and used effectively along with chitosan and neem extract for the synthesis of novel biodegradable films with antimicrobial efficacy.


Effects of N-acetyl-l-cysteine on chronic heat stress-induced oxidative stress and inflammation in the ovaries of growing pullets.
The aims of this study were to investigate the effects of supplemental N-acetyl-l-cysteine (NAC) on chronic heat stress-induced oxidative stress and inflammation in the ovaries of growing pullets. A total of 120, 12-wk-old, Hy-Line Brown hens were randomly separated into 4 groups with 6 replicates of 5 birds in each group for 21 d. The 4 treatments were as follows: the CON group and CN group were supplemented with basal diet or basal diet with 1 g/kg NAC, respectively; and the HS group and HSN group were heat-stressed groups supplemented with basal diet or basal diet with 1 g/kg NAC, respectively. The results indicated that the ovaries suffered pathological damage due to chronic heat stress and that NAC effectively ameliorated these changes. Compared with the HS group, antioxidant enzyme activities (including SOD, GSH-Px, CAT, and T-AOC) were enhanced, while the MDA contents and the expression levels of HSP70 were decreased in the HSN group. In addition, NAC upregulated the expression levels of HO-1, SOD2, and GST by upregulating the activity of Nrf2 at different time points to mitigate oxidative stress caused by heat exposure. Simultaneously, NAC attenuated chronic heat stress-induced NF-κB pathway activation and decreased the expression levels of the proinflammatory cytokines IL-8, IL-18, TNF-α, IKK-α, and IFN-γ. Cumulatively, our results indicated that NAC could ameliorate chronic heat stress-induced ovarian damage by upregulating the antioxidative capacity and reducing the secretion of proinflammatory cytokines.


Enhanced on-chip phase measurement by inverse weak value amplification.
Optical interferometry plays an essential role in precision metrology such as in gravitational wave detection, gyroscopes, and environmental sensing. Weak value amplification enables reaching the shot-noise-limit of sensitivity, which is difficult for most optical sensors, by amplifying the interferometric signal without amplifying certain technical noises. We implement a generalized form of weak value amplification on an integrated photonic platform with a multi-mode interferometer. Our results pave the way for a more sensitive, robust, and compact platform for measuring phase, which can be adapted to fields such as coherent communications and the quantum domain. In this work, we show a 7 dB signal enhancement in our weak value device over a standard Mach-Zehnder interferometer with equal detected optical power, as well as frequency measurements with 2 kHz sensitivity by adding a ring resonator.


The effect of raw carrot on serum lipids and colon function.
Two hundred grams of raw carrot eaten at breakfast each day for 3 weeks significantly reduced serum cholesterol by 11%, increased fecal bile acid and fat excretion by 50%, and modestly increased stool weight by 25%. This suggests an associated change in bacterial flora or metabolism. The changes in serum cholesterol, fecal bile acids, and fat persisted 3 weeks after stopping treatment.


p16(INK4a) is selectively silenced in the tumoral progression of mycosis fungoides.
Knowledge about the molecular mechanisms involved in the pathogenesis of tumoral progression in mycosis fungoides (MF) is still scarce. Because the 9p21 locus seems to be a good target for a detailed study in MF, this prompted us to compare the mechanisms of inactivation of the p16(INK4a), p15(INK4b), and p14(ARF) genes in aggressive and stable forms of MF, performing microsatellite analysis, methylation-specific polymerase chain reaction, direct sequencing, and p16(INK4a) protein expression by immunohistochemistry. Additionally, the p53 gene was also sequenced in tumoral lesions. Thirty-nine patients with stable MF were studied. Alterations in p16(INK4a) and p15(INK4b) genes were detected in 18% and 5% of the cases, respectively. None of the cases analyzed showed alterations of the p14(ARF) gene. In contrast with these findings, in the 11 patients with aggressive MF, alterations of the p16(INK4a), p15(INK4b), or p14(ARF) genes were found in 8 (73%), 3 (27%), and 2 (18%) cases, respectively. A significant proportion (4/11) of these alterations were already present in the p16(INK4a) gene in the initial plaque lesions in these aggressive forms of MF. Alterations in the p16(INK4a) gene, either methylation or loss of heterozygosity, were clearly more frequent than those in the p15(INK4b) and p14(ARF) genes. These p16(INK4A) alterations were confirmed using immunohistochemistry. None of the nine tumoral lesions analyzed showed mutations in exons 1-2 of the p16(INK4a) gene or in exons 5-8 of the p53 gene. These results seem to suggest that 9p21 alterations, and selectively p16(INK4a) silencing, could be a characteristic phenomenon in MF progression.


The Draft Genome of Hariotina reticulata (Sphaeropleales, Chlorophyta) Provides Insight into the Evolution of Scenedesmaceae.
Hariotina reticulata P. A. Dangeard 1889 (Sphaeropleales, Chlorophyta) is a common member of the summer phytoplankton of meso- to highly eutrophic water bodies with a worldwide distribution. Here, we report the draft whole-genome shotgun sequencing of H. reticulata strain SAG 8.81. The final assembly comprises 107,596,510bp with over 15,219 scaffolds (>100bp). This whole-genome project is publicly available in the CNSA (https://db.cngb.org/cnsa/) of CNGBdb under the accession number CNP0000705.


Solid-phase extraction approach for phospholipids profiling by titania-coated silica microspheres prior to reversed-phase liquid chromatography-evaporative light scattering detection and tandem mass spectrometry analysis.
A novel strategy for selectively adsorbing phospholipids (PLs) on titania-coated silica core-shell microspheres (TiO2/SiO2) was developed. The TiO2/SiO2 microspheres were prepared through water-vapor-induced internal hydrolysis and then characterized by SEM, UV-vis spectroscopy, X-ray diffraction, and measurements of Brunauer-Emmett-Teller surface area. Analyses showed that the titania layer was uniformly distributed onto the surface of silica particles. The TiO2/SiO2 microspheres were employed as sorbent in solid-phase extraction (SPE), and their absorptive ability was investigated by reversed-phase liquid chromatography-evaporative light scattering detection (RPLC-ELSD). Important factors that affect the extraction, such as loading buffer, eluting buffer, and elution volume, were investigated in detail and optimized by using standard samples. Results reveal that the developed SPE approach had higher recoveries for PLs than that based on pure TiO2 particles. The proposed SPE method was used for extraction of PLs from serum and showed great potential for identifying more kinds of endogenous PL metabolites by ultra performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-QTOF MS). The proposed SPE method with the composite sorbent was used to screen PLs from a biological matrix with high selectivity and efficiency. This approach is a promising method for selective extraction of PLs in lipidomics or phospholipidomics.


The inhibitory effect of cartilage proteoglycans on hydroxyapatite growth.
The calcification of connective tissues, including cartilage, is under the control of many interacting systems. Proteoglycans are thought to retard the deposition of hydroxyapatite crystals, and modification of the proteoglycans presumably facilitates mineralization in those tissues that are actively calcifying. The mechanism underlying these regulations remains speculative. This study investigates this question by comparing the inhibitory effectiveness of several macromolecules at neutral pH and approximately physiological ionic strengths. Inhibitors tested include bovine nasal proteoglycan monomer A1D1D1 and aggregate-containing A1 fractions, glycosaminoglycan chains (chondroitin 4-sulfate), and neutral dextran (as an uncharged analog). Hydroxyapatite growth was assessed either by measuring the time-dependent decreases in solution calcium and phosphate concentrations, or by determining utilization of hydroxyl ion in a pH-Stat. All species studied inhibit hydroxyapatite growth, and the extent of inhibition for each class is concentration-dependent. The proteoglycan aggregate-containing A1 fraction is more effective than the proteoglycan monomer at the same concentration, and the proteoglycan monomer is more effective than chondroitin 4-sulfate. Neutral dextran inhibits hydroxyapatite growth less effectively than proteoglycans. These results suggest that inhibition of hydroxyapatite growth by proteoglycans critically depends on both status (aggregate, monomer, etc.) and hydrodynamic size of this macromolecule, supporting the hypothesis that modification of proteoglycans in vivo functions to modulate the effectiveness of proteoglycans as a hydroxyapatite growth inhibitor.


Healthcare provider's adherence to immediate postpartum care guidelines in Gondar province hospitals, northwest Ethiopia: A multicenter study.
The immediate postpartum period is the most critical time for both the mother and the newborn. However, it is the most neglected part of the maternal continuum of care, and evidence in this regard was scarce in Ethiopia. Therefore, this study aimed to assess the healthcare provider's adherence to immediate postpartum care guidelines and associated factors in hospitals of Gondar province. A multicenter observational cross-sectional study was conducted among 406 healthcare providers from 15th November 2020 to 10th March 2021. Data were collected through face-to-face interviews and direct observation using a structured questionnaire and standardized checklist respectively. Data was entered into EPI INFO 7.1.2 and analyzed by SPSS version 25. Both bivariable and multivariable logistic regression analyses were carried out. The level of significance was declared based on the adjusted odds ratio (AOR) with a 95% confidence interval (CI) at a p-value of ≤ 0.05. Overall, 42.4% (95% CI: 37.5, 47.2) of healthcare providers had complete adherence to immediate postpartum care guidelines. Having birth assistant (AOR = 1.87; 95% CI: 1.10, 9.67), being married (AOR = 1.59; 95% CI: 1.15, 3.31), availability of postpartum care guidelines at the maternity ward (AOR = 2.39; 95% CI: 1.44, 3.98), received basic emergency obstetric and newborn care (BEmONC) training (AOR = 2.1; 95% CI: 1.2, 3.6), monthly income of ≥ 10001 Ethiopian birr (AOR = 3.55; 95% CI: 1.30, 9.67), and work experience of ≥ 6 years (AOR = 0.15; 95% CI: 0.06, 0.38) were significantly associated with healthcare providers adherence to immediate postpartum care guidelines. This study indicated that health worker's adherence to immediate postpartum care guidelines was low. Hiring adequate health workers, availing postpartum guidelines at the maternity ward, improving the salary and education opportunities for healthcare workers of healthcare workers, and provision of BEmONC training will have a great role in improving healthcare provider's adherence to immediate postpartum care guidelines.


Communication Skills Training for Practitioners to Increase Patient Adherence to Home-Based Rehabilitation for Chronic Low Back Pain: Results of a Cluster Randomized Controlled Trial.
To assess the effect of an intervention designed to enhance physiotherapists' communication skills on patients' adherence to recommendations regarding home-based rehabilitation for chronic low back pain. Cluster randomized controlled trial. Publicly funded physiotherapy clinics. A sample (N=308) of physiotherapists (n=53) and patients with chronic low back pain (n=255; 54% female patients; mean age, 45.3y). Patients received publicly funded individual physiotherapy care. In the control arm, care was delivered by a physiotherapist who had completed a 1-hour workshop on evidence-based chronic low back pain management. Patients in the experimental arm received care from physiotherapists who had also completed 8 hours of communication skills training. (1) Patient-reported adherence to their physiotherapists' recommendations regarding home-based rehabilitation measured at 1, 4, 12, and 24 weeks after the initial treatment session. (2) Pain and pain-related function measured at baseline and at 4, 12, and 24 weeks. A linear mixed model analysis revealed that the experimental arm patients' ratings of adherence were higher than those of controls (overall mean difference, .41; 95% confidence interval, .10-.72; d=.28; P=.01). Moderation analyses revealed that men, regardless of the intervention, showed improvements in pain-related function over time. Only women in the experimental arm showed functional improvements; female controls showed little change in function over time. The Communication Style and Exercise Compliance in Physiotherapy intervention did not influence patients' pain, regardless of their sex. Communication skills training for physiotherapists had short-term positive effects on patient adherence. This training may provide a motivational basis for behavior change and could be a useful component in complex interventions to promote adherence. Communication skills training may also improve some clinical outcomes for women, but not for men.


Thiol-Disulfide Exchange Coordinates the Release of Nitric Oxide and Dexamethasone for Synergistic Regulation of Intestinal Microenvironment in Colitis.
The cell-specific functions of nitric oxide (NO) in the intestinal microenvironment orchestrate its therapeutic effects in ulcerative colitis. While most biomaterials show promise by eliciting the characteristics of NO, the insufficient storage, burst release, and pro-inflammatory side effects of NO remain as challenges. Herein, we report the development of thiol-disulfide hybrid mesoporous organosilica nanoparticles (MONs) that improve the storage and sustained release of NO, broadening the therapeutic window of NO-based therapy against colitis. The tailored NO-storing nanomaterials coordinated the release of NO and the immunoregulator dexamethasone (Dex) in the intestinal microenvironment, specifically integrating the alleviation of oxidative stress in enterocytes and the reversal of NO-exacerbated macrophage activation. Mechanistically, such a synchronous operation was achieved by a self-motivated process wherein the thiyl radicals produced by NO release cleaved the disulfide bonds to degrade the matrix and release Dex via thiol-disulfide exchange. Specifically, the MON-mediated combination of NO and Dex greatly ameliorated intractable colitis compared with 5-aminosalicylic acid, even after delayed treatment. Together, our results reveal a key contribution of synergistic modulation of the intestinal microenvironment in NO-based colitis therapy and introduce thiol-disulfide hybrid nanotherapeutics for the management of inflammatory diseases and cancer.


Double staining of the muscle fibers and interstitial tissue components for automatic analysis of muscle biopsies.
A staining technique is presented in order to facilitate the automatic analysis of muscle biopsies. It renders possible the visualization on the same section of the myofibrillary adenosine-triphosphatase (ATPase) activity under the microscope with transmitted light, and of the fluorescent staining of fibronectin which marks the outlines of the muscle fibers by a simple switch to ultraviolet (UV) light.


Tissue transglutaminase-induced alterations in extracellular matrix inhibit tumor invasion.
Alterations in the extracellular matrix (ECM) can affect host-tumor interactions and tumor growth and metastasis. Tissue transglutaminase (TG2, EC 126.96.36.199), a calcium-dependent enzyme that catalyzes covalent cross-linking of proteins, can render the ECM highly stable and resistant to proteolytic degradation. So we determined whether TG2 expression in a tumor or nontumor (stroma) environment could affect the process of metastasis. Two hundred archived samples from patients with breast cancer were studied for the TG2 expression. Also, in an in vitro model the invasive behavior of MDA-MB-231 cells in the presence or absence of exogenous TG2 was determined. Tumors associated with negative nodes showed significantly higher expression of TG2 in the stroma (P < 0.001). TG2 in the stroma was catalytically active, as revealed by the presence of isopeptide cross-links. Pretreatment of Matrigel with catalytically active TG2 resulted in strong inhibition of invasion of MDA-MB-231 cells through the Matrigel Transwell filters. TG2-induced alterations in the ECM could effectively inhibit the process of metastasis. Therefore, selective induction of catalytically active TG2 at the site of tumor may offer promising approach for limiting the metastasis.


Genome- and exome-wide association study of serum lipoprotein (a) in the Jackson Heart Study.
Lipoprotein (a) (Lp(a)) is an independent risk factor for cardiovascular disease. Lp(a) levels in African Americans (AAs) are much higher compared with that in European Americans. We conducted a genome- and an exome-wide association study of Lp(a) among 2895 AAs participating in the Jackson Heart Study. We observed that local ancestry at 6q25.3 was an important risk factor for Lp(a) in AAs, and that multiple single-nucleotide polymorphisms (SNPs) at the well-established LPA locus were significantly associated with Lp(a) (P<5 × 10(-8)) after adjusting for the local ancestry at 6q25.3. Interestingly, before adjusting for local ancestry, we observed significant (P<5 × 10(-8)) associations for hundreds of SNPs spanning ~10 Mb region on 6q surrounding the LPA gene, whereas after adjusting for local ancestry, the region containing significantly associated SNPs got much narrower and was centered over the LPA gene (<1 Mb). We observed a single nonsynonymous SNP in APOE significantly associated with Lp(a) (P<5 × 10(-8)). A high burden of coding variants in LPA and APOE were also associated with higher Lp(a) levels. Our study provides evidence that ancestry-specific causal risk variant(s) resides in or near LPA and that most of the observed associations outside this narrower region are spurious associations.


Are French orthopedic and trauma surgeons affected by burnout? Results of a nationwide survey.
Burnout is a pathology that can affect care-giving professionals. It associates emotional exhaustion (EE), depersonalization (DP) and impaired personal accomplishment (PA). Surgery entails great responsibility and frequently heavy workloads, incurring risk of burnout. Data, however, are not available for French orthopedic and trauma surgeons. We therefore conducted a prospective survey to 1) assess burnout prevalence in French orthopedic surgeons, and 2) investigate risk factors and protective factors. Burnout prevalence is at least as high in French orthopedic surgeons as in other medical and surgical specialties. A nationwide survey was conducted in France between February and April 2017, using a digitized questionnaire sent out by e-mail. Burnout was assessed on the MBI (Maslach Burnout Inventory), and depressive symptoms on the GHQ-12 (General Health Questionnaire-12). Demographic and occupational data were also collected. Out of 1,900 surgeons contacted, 441 (23%) responded. Mean age was 50.2±10.1 years; 413 (93.7%) were male. Sixty one (14%) reported elevated EE, 100 (23%) elevated DP, and 82 (19%) impaired AP. One hundred and seventy two (39%) showed burnout symptomatology (e.g., pathologic score on one MBI scale), while 47 (10%) had pathologic scores on 2 or 3 scales, indicating severe burnout. One hundred and ninety three (43%) would not advise their children to take up orthopedic surgery. Thirty eight (8%) expressed suicidal ideation. Statistical analysis identified public-sector practice (OR=4.6; 95% CI: 2.1-10.7; p=0.0002) and pathologic GHQ-12 score (OR=6.3; 95% CI: 2.2-17.8; p=0.0006) as risk factors for burnout. Outside activity (OR=0.39; 95% CI: 0.1-0.9; p=0.0406) and male gender (OR=0.2; 95% CI: 0.05-0.7; p=0.0160) emerged as protective factors. Despite a response rate of only 23% (n=441/1,900), the present study sheds light on burnout rates in French orthopedic surgeons, with 39% burnout symptoms and 10% severe burnout. Burnout impacts personal and occupational life, with increased suicidal ideation and impaired quality of life. The present results confirm the importance of screening and treatment in care-providers. Level IV, prospective descriptive transverse study without control group.


Human thermal sensation algorithm modelization via physiological thermoregulatory responses based on dynamic thermal environment tests on males.
Thermal conditions are changeable in cabin space, where occupants could suffer consecutive self-thermoregulation to such changing thermal stresses. Thermal environment management is expected to be purposefully auto-adjustable for the environment by recognizing individual real-time thermal sensations. Current thermal sensation evaluation models are developed for virtual simulations rather than for realistic scenarios, challenging to evaluate human thermal sensation in the field surveys. The study constructs a human thermal sensation model via human physiological responses to evaluate the human thermal sensation in the actual vehicle environment. The thermal sensation model forms with exponential functions to clarify the relationship between thermal sensation and pulse rate and blood pressure, which successfully expresses the approximately linear trend around neutral sensation and compensates for the end-points bias. The study set up experimental cases to determine the parameter states in the thermal sensation model. Firstly, subjective thermal sensation scoring was performed by combing with an established seven-point-scale questionnaire survey system for human thermal sensation. Wearable sensors are then applied to measure the human physiological response, including blood pressure BP, pulse rate PR and blood oxygen saturation SpO2. The subjects revealed significantly higher pulse rates (positively correlated) and lower blood pressure (negatively correlated) in the warm chamber than in the cool chamber. The defined parameter change rate effectively reveals the trend of human thermal sensation and avoids the inconsistency of raw physiological response levels. The change rate in PR and MAP between the thermal sensation in cold -3 and hot +3 is about a 10% difference. Based on the thermal sensation model algorithm, model parameters were fitted by the subjects' thermal sensation voting and the change rate of their physiological responses. With the coefficient of determination (R2) of the regression over 0.8, the proposed thermal sensation model can be employed for human thermal sensation evaluation. The physiological thermoregulatory responses effectively indicate the thermal state of the human body and can be used in thermal environments in conjunction with human smart wearable devices.


Preparation of difluoro analogs of CCGs and their pharmacological evaluations.
All the stereoisomers of 2-(2-carboxy-3,3-difluorocyclopropyl)glycines (F2CCGs) were synthesized in enantiomerically pure forms using (R)-2,3-O-isopropyl-ideneglyceraldehyde as a chiral precursor. L-F2CCG-I, one of the stereoisomers corresponding to an extended form of L-glutamate was found to be a potent agonist for metabotropic glutamate receptors (mGluRs).


Irradiation of the recipient site does not adversely affect successful free flap transfer in the repair of head and neck defects after salvage surgery for recurrent nasopharyngeal carcinoma originally treated with radiotherapy.
Irradiation of the recipient site has been associated with postoperative complications and an increased rate of flap failure in facial reconstruction. The aim of this study was to report the outcomes of our use of four different types of flaps (two free and two pedicled) for the reconstruction of patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy, who subsequently received salvage surgery after the development of recurrence or secondary primary tumours. The records of 12 NPC patients who underwent salvage surgery and reconstruction from 2002-2007 were retrospectively reviewed. There were no intraoperative or significant postoperative complications. All flaps survived. The average cosmetic outcome was 2.7 (1 = poor, 4 = excellent), all patients could tolerate a liquid to normal diet, and nine patients had normal or intelligible speech, while three exhibited slurred speech. These results indicate that the effects of irradiation on the recipient site do not appear to adversely affect successful flap transfer or outcomes.


Knife wound or nosebleed-where does the blood at the crime scene come from?
Secretion analysis is a useful tool in forensic genetics, since it establishes the (cellular) origin of the DNA prior in addition to the identification of the DNA donor. This information can be crucial for the construction of the crime sequence or verification of statements of people involved in the crime. For some secretions, rapid/pretests already exist (blood, semen, urine, and saliva) or can be determined via published methylation analyses or expression analyses (blood, saliva vaginal secretions, menstrual blood, and semen). To discriminate nasal secretion/blood from other secretions (like oral mucosa/saliva, blood, vaginal secretion, menstrual blood, and seminal fluid), assays based on specific methylation patterns at several CpGs were set up in this study. Out of an initial 54 different CpG markers tested, two markers showed a specific methylation value for nasal samples: N21 and N27 with a methylation mean value of 64.4% ± 17.6% and 33.2% ± 8.7%, respectively. Although identification or discrimination was not possible for all nasal samples (due to partial overlap in methylation values to other secretions), 63% and 26% of the nasal samples could be unambiguously identified and distinguished from the other secretions using the CpG marker N21 and N27, respectively. In combination with a blood pretest/rapid test, a third marker (N10) was able to detect nasal cells in 53% of samples. Moreover, the employment of this pretest increases the proportion of identifiable or discriminable nasal secretion samples using marker N27 to 68%. In summary, our CpG assays proved to be promising tools in forensic analysis for the detection of nasal cells in samples from a crime scene.


Sidechain rotational isomerization in proteins. Dynamic simulation with solvent surroundings.
Molecular dynamics simulations are used to study the rotational isomerization of the tyrosine 35 ring in bovine pancreatic trypsin inhibitor immersed in liquid water. Inclusion of the solvent surroundings improves the agreement with experimental results significantly, although the theoretical free energy barrier (13 kcal/mol at 300K) is still approximately 3 kcal/mol below that found by nuclear magnetic resonance studies. This remaining discrepancy will probably be eliminated in future calculations by the use of a more accurate model for the hydrogen atoms on the tyrosine ring. An important finding in the present work is that frictional effects due to solvent damping appear to be small for the tyrosine 35 ring, which is largely but not completely buried in the protein surface.


[The vascular surgeon's role in interdisciplinary treatment of diabetic foot syndrome].
There are more than 6 million diabetes patients in Germany. Due to long-term neuropathic and angiopathic sequelae, the number of patients with "diabetic foot syndrome" has increased dramatically in recent years. Diabetic foot ulcers have become one of the most common pathologies in interdisciplinary wound care centers. Because of its complex pathogenesis, diabetic foot syndrome needs a multidisciplinary therapeutic approach. More than 150,000 diabetics per year develop foot ulcers that often heal slowly and progress into chronic wounds. Despite all efforts at prevention, early diagnosis, and adequate therapy, more than 20,000 diabetics suffer major limb amputation in Germany every year. Applying stringent standards of care in interdisciplinary wound care centers, the amputation rate in patients with diabetic foot syndrome can be reduced to less than 50%. This article describes the complexity of diabetic foot syndrome with respect to pathogenesis, diagnostics, and therapy from a vascular surgeon's point of view. The importance of an interdisciplinary approach is emphasized.


Experimental data on the nature of postresuscitation alpha frequency activity.
Synchronized activity of alpha frequency recorded from a number of dog brain formations in the initial stages of postischaemic (postresuscitation) restoration was studied. Using the methods of destruction and elimination it was shown that the amygdaloid nuclei were the main source of such activity. Analysis of the general and particular coherence functions at the frequencies of alpha-like activity has shown that subcortical formations (thalamus, nucleus caudatus) become secondarily active sources of the generation of the bursts and of their generalization in the brain. Investigations and available literature lay the basis for the hypothesis that the activity observed in experiments and the activity described during postresuscitation alpha-pattern coma in humans have similar mechanisms of development and are, probably, identical.


Comparative evaluation of the efficacy of amniotic membrane with collagen membrane along with demineralized freeze-dried bone allograft in the treatment of periodontal intrabony defects - A clinico-radiographic study.
The use of human-derived amniotic barrier membranes in regenerative procedures along with allograft like demineralized freeze-dried bone allograft (DFDBA) has displayed promising outcomes. The objective of the current research was to clinically and radiographically evaluate and compare amniotic membrane (AM) and collagen membrane (CM) in combination with open flap debridement (OFD) along with DFDBA in the management of human periodontal intrabony defects. The present research-based study was a randomized controlled clinical trial of 6 months duration. A total of twenty chronic periodontitis patients with intrabony defects were randomly divided into two groups: Group 1 treated with OFD + DFDBA + AM and Group 2 with OFD + DFDBA + CM. Clinical parameters such as plaque index (PI), gingival index (GI), pocket probing depth (PPD), and relative attachment level were recorded and evaluated at baseline, 3 months, and 6 months. The relative intrabony defect component level (rIBD) was recorded at baseline and after 6 months employing a millimeter X-ray grid. For comparison of clinical parameters and radiographic parameters at various intervals unpaired t-test, repeated measures ANOVA test, and paired t-test were used. The P value was taken statistically significant when less than 0.05 (P < 0.05). A statistically significant difference in PI, GI, PPD, and RAL for both the groups were found on intragroup comparison between baseline, 3 months, and 6 months (P < 0.05). On intragroup comparison, the difference in mean rIBD was statistically significant from baseline to 6 months. However, for all the clinical and radiographic parameters, no statistically significant difference was noted between both the groups (P > 0.05). In the treatment of intrabony defects AM being an allograft can be considered an alternative novel membrane for regenerative procedures.


Effect of body position on tidal volume and minute ventilation in very low birthweight infants.
To progress the clinical treatment of neonates, especially in the management of respiration, we have to be able to measure their pulmonary function appropriately. Various methods have been developed, but little is known about the pulmonary function of very low birthweight infants (VLBWI) because of the difficulty in taking their measurements with existing equipment. We have developed a very low dead space pneumotachograph to measure lung function in VLBWI. We used our pneumotachograph on 30 infants each weighing less than 1500 g at birth. The infants were intubated with endotracheal tubes of 2.5 or 2.0 mm diameter to measure tidal volume and minute ventilation in the prone and supine position. The tidal volume in the supine position was 6.99 +/- 0.42 mL/kg and 7.58 +/- 0.38 mL/kg in the prone position (mean +/- SE). The tidal volume was significantly larger in the prone than the supine position (P < 0.05). However, no significant difference was observed in minute ventilation and respiratory rates. The tidal volume significantly increased in the prone position in VBLWI, confirming the previous observation of larger healthy infants is also applicable to the very low birthweight infants.


Effect of calcitonin gene-related peptide on the neuroeffector mechanism of sympathetic nerve terminals in rat vas deferens.
In order to evaluate the mode of action of calcitonin gene-related peptide (CGRP) on the neuroeffector mechanism of peripheral sympathetic nerve fibers, the effects of CGRP were tested on the electrical stimulated and the non-stimulated preparations of the isolated rat vas deferens. The contractile responses, which were mediated predominantly by activation of postganglionic noradrenergic nerve fibers, were dose-dependently inhibited by CGRP in concentrations ranging from 0.1 to 10 nM. The inhibitory response produced by CGRP in high concentrations (greater than 2 nM) usually returned to the control level at 20-30 min and were rarely tachyphylactic. The inhibitory action of CGRP was not modified by pretreatment with 10(-7) M propranolol or 10(-7) M atropine. Contractions produced by exogenous norepinephrine (NE) and 5-hydroxytryptamine (5-HT) in unstimulated preparations were not affected by pretreatment with CGRP in a low concentration (less than 2 nM). On the other hand, the contractions were slightly reduced 1 min after pretreatment with CGRP in high concentrations (greater than 5 nM), which recovered in 15 min after constant flow washout. High concentrations of CGRP also caused a concentration-dependent relaxation on the precontracted preparations produced by high potassium (60 mM K+) solution. These results suggest that CGRP in high concentrations (greater than 5 nM) may have a non-specific inhibitory action on the postsynaptic plasma membrane of the smooth muscle cell and a postulated CGRP receptor exists presynaptically in the rat vas deferens and that CGRP may inhibit the release of NE during adrenergic nerve stimulation.


Significant improvement of miRNA target prediction accuracy in large datasets using meta-strategy based on comprehensive voting and artificial neural networks.
Identifying mRNA targets of miRNAs is critical for studying gene expression regulation at the whole-genome level. Multiple computational tools have been developed to predict miRNA:mRNA interactions. Nonetheless, many of these tools are developed in various small datasets, which each represent a limited sample space. Thus, the prediction accuracy of these tools has not been systematically validated at a larger scale. Accordingly, comparing the prediction accuracy of these tools and determining their applicability become challenging. In addition, the accuracy of these tools, especially in large datasets, needs to be improved for broader applications. In this project, a large dataset containing more than 46,600 miRNA:mRNA interactions was assembled and split into eleven subsets based on the availability of prediction scores of four individual predictors, which are miRanda, miRDB, PITA, and TargetScan. In each of these subsets, the predictive results of four individual predictors were integrated using decision-tree based artificial neural networks to make the meta-prediction. The decision-tree is used here to sort the predictive results of four individual predictors, and artificial neural networks are applied to make meta-prediction based on the outputs of individual predictors. In the decision tree, dual-threshold and two-step significance-voting were incorporated, information gain was analysed to select threshold values. The prediction performance of this new strategy was improved significantly in most of the eleven datasets comparing to the individual predictors and other meta-predictors, such as ComiR, under multi-fold cross-validation, as well as in independent datasets. The overall improvement of prediction accuracy in independent datasets is at least 9 percentile points comparing to the other predictors, and the percentage of improvement of F1 and MCC scores is at least 40% compared to the other predictors. The combination of dual-threshold, two-step significance-voting, and analysis of information gain is very effective in optimizing the outcome of decision-tree, and further integration with artificial neural networks is critical for further improving the performance of meta-predictor. A new pipeline based on this integration for miRNA target prediction has been developed. A strategy using outputs of individual predictors to reorganize large-scale miRNA:mRNA interaction dataset has also been validated and used to evaluate the prediction accuracy of predictors. The predictor is available at: https://github.com/xueLab/mirTarDANN ).


A europium- and terbium-coated magnetic nanocomposite as sorbent in dispersive solid phase extraction coupled with ultra-high performance liquid chromatography for antibiotic determination in meat samples.
A new magnetic dispersive solid-phase extraction approach based on Eu- and Tb-coated magnetic nanocomposites, combined with ultra-high performance liquid chromatography with fluorometric detection, is reported for the extraction and simultaneous determination of veterinary antibiotics. The method is aimed at monitoring of potential residues of three tetracyclines, namely oxytetracycline, tetracycline, chlortetracycline and three acidic quinolones, such as oxolinic acid, nalidixic acid and flumequine, chosen as model analytes, in animal muscle samples. The nanocomposites were obtained by synthesizing magnetic nanoparticles by a co-precipitation method and their coating with terbium and europium ions. The limits of detection obtained using standard solutions were: 1.0, 1.5, 3.8, 0.25, 0.7 and 1.2ngmL(-1), which corresponds to 3.3, 5.0, 12.7, 0.8, 2.3 and 4.0μgkg(-1) for oxytetracycline, tetracycline, chlortetracycline, oxolinic acid, nalidixic acid and flumequine, respectively, in meat samples. The precision values, obtained in the presence of the sample matrix, were in the ranges 0.12-2.0% and 2.6-15.4% for retention times and areas, respectively. The selectivity of the method was checked by assaying different veterinary drugs, finding that most of them did not interfere at the same concentration levels as that of analytes. A recovery study was performed in the presence of chicken and pork muscle samples, which provided values in the range of 61.5-102.6%.


Structures of spiroindicumides A and B, unprecedented carbon skeletal spirolactones, and determination of the absolute configuration by vibrational circular dichroism exciton approach.
Spiroindicumides A (1) and B (2), novel spirolactone polyketides, were isolated from a filamentous fungus, Chaetomium indicum, cultivated in the presence of a histone deacetylase inhibitor. Their structures including relative configurations were determined by spectroscopic analyses. Their absolute configurations were unambiguously assigned by the vibrational circular dichroism (VCD) exciton chirality method using only ca. 0.3 mg of each sample. This study presents the first application of the VCD exciton approach to novel natural products. A possible biosynthetic pathway of the new compounds was also proposed.


High levels of BACH2 associated with lower levels of BCL2 transcript abundance in t(14;18)(q21;q34) translocation positive non-Hodgkin's lymphoma.
The t(14;18)(q21;q34) BCL2 translocation is a common genetic alteration in follicular and diffuse large B-cell lymphoma. However, it is not invariably associated with BCL2 gene overexpression due to undefined mechanisms that regulate expression from the proximal immunoglobulin heavy-chain (IgH) promoter. The BACH2 transcriptional repressor is able to modulate activity of this promoter. Here we have shown that, in tumor samples with BCL2 translocation, those with high levels of BACH2 had significantly lower BCL2 transcript abundance compared to those with low levels of BACH2. This indicates that BACH2 may be partially responsible for regulation of BCL2 expression from the t(14;18)(q21;q34) translocation.


Incidence of Side-effects After Weekly Iron and Folic Acid Consumption Among School-going Indian Adolescents.
To estimate incidence of side effects after weekly iron and folic acid supplementation (WIFS) in Delhi and Haryana. In this cross-sectional school-based study, data were collected from 4,183 adolescents on WIFS consumption and side effects experienced first time of receipt of WIFS (week 1), and in last two consecutive weeks (week 2,3). Week 3 was 48 hours preceding the survey. WIFS consumption in week 1, 2 and 3 was 85%, 63% and 52%, respectively. Side effects reported were highest in first week (25%) and reduced to 7% (week 2) and 5% (week 3). Side effects most reported were abdominal pain (80%) and nausea (10%). Adolescents (45%) who faced a side-effect in week 1 did not consume WIFS in subsequent week. Incidence of side effects was low, but it affected compliance. Positive reinforcement to students who face side effects requires strengthening by teachers.


Interstitial IgG antibody pharmacokinetics assessed by combined in vivo- and physiologically-based pharmacokinetic modelling approaches.
For therapeutic antibodies, total tissue concentrations are frequently reported as a lump sum measure of the antibody in residual plasma, interstitial fluid and cells. In terms of correlating antibody exposure to a therapeutic effect, however, interstitial pharmacokinetics might be more relevant. In the present study, we collected total tissue and interstitial antibody biodistribution data in mice and assessed the composition of tissue samples aiming to correct total tissue measurements for plasma and cellular content. All data and parameters were integrated into a refined physiologically-based pharmacokinetic model for monoclonal antibodies to enable the tissue-specific description of antibody pharmacokinetics in the interstitial space. We found that antibody interstitial concentrations are highly tissue-specific and dependent on the underlying capillary structure but, in several tissues, they reach relatively high interstitial concentrations, contradicting the still-prevailing view that both the distribution to tissues and the interstitial concentrations for antibodies are generally low. For most therapeutic antibodies, the interstitium is the target space. Although experimental methods for measuring antibody pharmacokinetics (PK) in this space are not well established, thus making quantitative assessment difficult, the interstitial antibody concentration is assumed to be low. In the present study, we combined direct quantification of antibodies in the interstitial fluid with a physiologically-based PK (PBPK) modelling approach, with the aim of better describing the PK of monoclonal antibodies in the interstitial space of different tissues. We isolated interstitial fluid by tissue centrifugation and conducted an antibody biodistribution study in mice, measuring total tissue and interstitial concentrations in selected tissues. Residual plasma, interstitial volumes and lymph flows, which are important PBPK model parameters, were assessed in vivo. We could thereby refine the PBPK modelling of monoclonal antibodies, better interpret antibody biodistribution data and more accurately predict their PK in the different tissue spaces. Our results indicate that, in tissues with discontinuous capillaries (liver and spleen), interstitial concentrations are reflected by the plasma concentration. In tissues with continuous capillaries (e.g. skin and muscle), ∼50-60% of the plasma concentration is found in the interstitial space. In the brain and kidney, on the other hand, antibodies are restricted to the vascular space. Our data may significantly impact the interpretation of biodistribution data of monoclonal antibodies and might be important when relating measured concentrations to a therapeutic effect. By contrast to the view that the antibody distribution to the interstitial space is limited, using direct measurements and model-based data interpretation, we show that high antibody interstitial concentrations are reached in most tissues.


Dietary (n-3) fatty acids alter plasma fatty acids and leukotriene B synthesis by stimulated neutrophils from healthy geriatric Beagles.
The study objective was to determine the effect of feeding food enriched in (n-3) fatty acids (FA) on plasma FA profiles and leukotriene B (LTB) synthesis by stimulated peripheral blood neutrophils from dogs. For 36 weeks, two groups of dogs (n = 5) were fed food that contained either a low ratio of (n-6)-(n-3) FA (1.31:1; fish oil-enriched food) or a high ratio of (n - 6)-(n-3) FA (40.6:1; corn oil-enriched food). Consumption of food enriched in fish oil resulted in higher plasma concentrations of eicosapentaenoic acid and docosahexaenoic acid and lower concentrations of arachidonic acid. Neutrophils from dogs fed fish oil-enriched food produced 7.6-fold more LTB(5)(P = 0.002), and the ratio of LTB(5)-LTB(4) concentrations was 8.3-fold higher (P < 0.001) compared with dogs fed corn oil-enriched food. Dietary FA can modulate leukotriene production by neutrophils in dogs, and suggests that foods enriched in (n-3) FA from fish oil may have value in the treatment of canine inflammatory diseases.


Mapping the distributions of blood-sucking mites and mite-borne agents in China: a modeling study.
Emerging mite-borne pathogens and associated disease burdens in recent decades are raising serious public health concerns, yet their distributions and ecology remain under-investigated. We aim to describe the geographical distributions of blood-sucking mites and mite-borne agents and to assess their ecological niches in China. We mapped 549 species of blood-sucking mites belonging to 100 genera at the county level and eight mite-associated agents detected from 36 species of blood-sucking mites in China during 1978-2020. Impacts of climatic and environmental factors on the ecology of 21 predominant vector mites and a leading pathogen, Orientia tsutsugamushi, were assessed using boosted regression tree (BRT) models, and model-predicted risks were mapped. We also estimated the model-predicted number, area and population size of affected counties for each of the 21 mite species in China. Laelaps echidninus is the leading mite species that potentially affects 744 million people, followed by La. jettmari (517 million) and Eulaelaps stabularis (452 million). Leptotrombidium scutellare is the mite species harboring the highest variety of mite-borne agents including four Rickettsia species and two viruses, followed by Eu. stabularis (2 agents), L. palpale (2) and La. echidninus (2). The top two agents that parasitize the largest number of mite species are O. tsutsugamushi (28 species) and hantavirus (8). Mammalian richness, annual mean temperature and precipitation of the driest quarter jointly determine the ecology of the mites, forming four clusters of major mite species with distinct geographic distributions. High-risk areas of O. tsutsugamushi are mainly distributed in southern and eastern coastal provinces where 71.5 million people live. Ecological niches of major mite species and mite-borne pathogens are much more extensive than what have been observed, necessitating expansion of current filed surveillance.


Discovery of a 2-hydroxyacetophenone derivative as an outstanding linker to enhance potency and β-selectivity of liver X receptor agonist.
Our research found that the 2-hydroxyacetophenone derivative is an outstanding linker between the 1,1-bistrifluoromethylcarbinol moiety and the imidazolidine-2,4-dione moiety to enhance the potency and β-selectivity of liver X receptor (LXR) agonist in our head-to-tail molecular design. The incorporation of this linker is 20-fold more potent than our previous compound (2) for LXR β agonistic activity (EC50) in a GAL-4 luciferase assay. Furthermore, we also identified 5-[5-(1-methylethoxy)pyridyl-2-yl]-5-methylimidazoline-2,4-dione (54), which lowers the lipophilicity of 2-hydroxyacetophenone derivative. We revealed that a combination of our newly developed linker and hydantoin (54) plays a pivotal role in improving the potency and selectivity of LXRβ. The optically separated (-)-56 increases high-density lipoprotein cholesterol levels without elevating plasma triglyceride levels and results in a decrease of the lipid accumulation area in the aortic arch in a high-fat- and cholesterol-fed low-density lipoprotein receptor knock-out mice. In this manuscript, we report that (-)-56 is a highly potent and β-selective LXR agonist for use in the treatment of atherosclerosis.


Risk of fractures and subsequent mortality in non-alcoholic fatty liver disease: A nationwide population-based cohort study.
Studies suggest an association between osteoporosis and non-alcoholic fatty liver disease (NAFLD), but whether patients with NAFLD are at increased risk of fractures is unknown. The aim was to determine the rate and risk of fractures and the mortality rate after fracture in patients with NAFLD compared to the general population. This was a nationwide population-based cohort study using data from the Swedish National Patient Registry on 10,678 patients with NAFLD from 1987 to 2016. Patients were matched for sex, age, and municipality with 99,176 controls from the Swedish Total Population Registry. Cox regression was used to estimate fracture rates. The risk of fractures was assessed while accounting for competing risks (death and liver transplantation). A total of 12,312 fractures occurred during 761,176 person-years of follow-up. Patients with NAFLD (17.5 per 1000 person-years) had a slightly higher fracture rate than controls (16.1 per 1000 person-years; adjusted hazard ratio 1.11, 95% confidence interval [CI] 1.05-1.19), although the 5-year risk of fractures was similar (8.0%, 95% CI 7.4-8.6 versus 7.3%, 95% CI 7.2-7.5). Additionally, 1-year mortality after fracture was similar in NAFLD and controls. Patients with NAFLD have a slightly higher rate of fractures but long-term risk of fractures comparable to the general population. This suggests that broad surveillance of risk factors for fractures in patients with NAFLD is not motivated.


Mycobiota of Underground Habitats: Case Study of Harmanecká Cave in Slovakia.
Harmanecká Cave is located in the Harmanec Valley to the northwest of Banská Bystrica city, in the southern part of the Great Fatra Mountains, Slovakia. This cave is the most important underground locality of bat occurrence in Slovakia (population of 1000 to 1500 individuals). The study aimed at mycological evaluation of the air, the water, and the rock surface of Harmanecká Cave in Slovakia. The samples were taken on 24 July 2014. To examine the air, the Air Ideal 3P sampler was used. Microbiological evaluation of the rock surface was performed using swab sampling and the water by using the serial dilution technique. The authors observed a relationship between air temperature and the concentration of fungi. The concentration of airborne fungi increased with the increase in the air temperature and decreased with distance from the entrance to the cave. The density of airborne fungi isolated from the outdoor air samples was 810.5 colony-forming units (CFU) per 1 m3 of air and from 27.4 to 128.5 CFU for the indoor air samples. From the rock surface inside the cave, 45.0 to 106.6 CFU per 1 cm2 were isolated, whereas from the water, 29.9 CFU per 1 ml were isolated. Seven species of filamentous fungi were isolated from the external air samples and 12 species of filamentous fungi and 3 species of yeast-like fungi from the internal air samples. From the surface of the rocks inside the cave, 5 species of filamentous fungi and 1 species of yeast-like fungi were cultured, whereas from the water samples, 6 species of filamentous fungi were cultured. Cladosporium spp. were the fungi most frequently isolated from the external air; from the internal air, Penicillium urticae was most frequently isolated; from the rock surface, it was Gliocladium roseum; and from the water, it was P. chrysogenum. The species found in the cave can be pathogenic for humans and animals, especially for immunocompromised persons, and they can also cause biodegradation of the rocks. However, the concentration of airborne fungi inside the cave did not exceed official limits and norms stated as dangerous for the health of tourists.


Surgical Resection for Extensive Pleural Epithelioid Hemangioendothelioma.
A 35-year-old man who presented with months of symptomatic nonproductive cough was found to have a large right-sided pleural effusion, diffuse pleural thickening, lymphadenopathy, and partial collapse of the right lung. He was diagnosed with a rare form of vascular tumor: pleural epithelioid hemangioendothelioma. He underwent a successful right extrapleural pneumonectomy with diaphragm and pericardial resection and reconstruction. Although often managed with firstline chemotherapy or radiation therapy, our case shows that upfront surgical resection is feasible for extensive pleural epithelioid hemangioendothelioma at a high-volume regional center. Whether aggressive resection improves survival is yet to be determined.


Protocol for a Steady-State FRET Assay in Cancer Chemoprevention.
Cancer chemoprevention is an important strategy to prevent, reverse, or suppress the development of cancer. One of the target pathways that has emerged in recent years is the Keap1-Nrf2-ARE system that regulates the protection of cells against various carcinogens and their metabolites. Increased concentrations of the redox transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) induces the activation of antioxidant and phase 2 detoxifying genes. Nrf2 is regulated by substrate adaptor protein Kelch-like ECH-associated protein 1 (Keap1) that can target Nrf2 for ubiquitination and degradation by the proteasome. The interaction between Nrf2 and Keap1 can be disrupted at the protein-protein interface in order to increase Nrf2 activity for potential therapeutic purposes. This chapter describes a protocol for a steady-state fluorescence or Förster resonance energy transfer (FRET) assay to examine the Keap1-Nrf2 protein-protein interaction (PPI), to investigate the effects of Nrf2 mutations on Keap1 binding and finally to identify potential inhibitors of this PPI. In the assay system Keap1 is conjugated to an YFP protein at the N-terminus whereas an Nrf2-derived 16-mer peptide containing a high-affinity "ETGE" motif is conjugated to a CFP protein at the N-terminus.