GAN Lab: Understanding Complex Deep Generative Models using Interactive Visual Experimentation.
Recent success in deep learning has generated immense interest among practitioners and students, inspiring many to learn about this new technology. While visual and interactive approaches have been successfully developed to help people more easily learn deep learning, most existing tools focus on simpler models. In this work, we present GAN Lab, the first interactive visualization tool designed for non-experts to learn and experiment with Generative Adversarial Networks (GANs), a popular class of complex deep learning models. With GAN Lab, users can interactively train generative models and visualize the dynamic training process's intermediate results. GAN Lab tightly integrates an model overview graph that summarizes GAN's structure, and a layered distributions view that helps users interpret the interplay between submodels. GAN Lab introduces new interactive experimentation features for learning complex deep learning models, such as step-by-step training at multiple levels of abstraction for understanding intricate training dynamics. Implemented using TensorFlow.js, GAN Lab is accessible to anyone via modern web browsers, without the need for installation or specialized hardware, overcoming a major practical challenge in deploying interactive tools for deep learning.


Investigation of length heteroplasmy in mitochondrial DNA control region by massively parallel sequencing.
Accurate sequencing of the control region of the mitochondrial genome is notoriously difficult due to the presence of polycytosine bases, termed C-tracts. The precise number of bases that constitute a C-tract and the bases beyond the poly cytosines may not be accurately defined when analyzing Sanger sequencing data separated by capillary electrophoresis. Massively parallel sequencing has the potential to resolve such poor definition and provides the opportunity to discover variants due to length heteroplasmy. In this study, the control region of mitochondrial genomes from 20 samples was sequenced using both standard Sanger methods with separation by capillary electrophoresis and also using massively parallel DNA sequencing technology. After comparison of the two sets of generated sequence, with the exception of the C-tracts where length heteroplasmy was observed, all sequences were concordant. Sequences of three segments 16184-16193, 303-315 and 568-573 with C-tracts in HVI, II and III can be clearly defined from the massively parallel sequencing data using the program SEQ Mapper. Multiple sequence variants were observed in the length of C-tracts longer than 7 bases. Our report illustrates the accurate designation of all the length variants leading to heteroplasmy in the control region of the mitochondrial genome that can be determined by SEQ Mapper based on data generated by massively parallel DNA sequencing.


The propeptide Asn1-Tyr126 is the storage form of rat atrial natriuretic factor.
Granules from rat atria were isolated by differential centrifugation and by a 53% (v/v) Percoll gradient after tissue homogenization in 0.25 M-sucrose/50 mM-Na2EDTA. About 40% of the immunoreactive ANF (atrial natriuretic factor) sedimented with the atrial granules during differential centrifugations. On the Percoll gradient, two distinct bands were observed. Cell debris, mitochondria, lysosomes, myofilaments and microsomes were mostly contained in the lightest-density (rho) (1.03-1.07 g/ml) fraction, as demonstrated by electron microscopy and by enzymic markers such as lactate dehydrogenase, monoamine oxidase, cytochrome c reductase, beta-glucuronidase and acid phosphatase. Atrial granules were mostly contained in the denser (rho 1.11-1.15 g/ml) band and were only slightly contaminated by lysosomes, as shown by beta-glucuronidase activity. Analysis of the ANF content in these isolated granules by h.p.l.c., amino acid composition and sequencing demonstrated that it was only the pro-ANF [ANF-(Asn1-Tyr126)-peptide]. The precursor was present in all granules, as demonstrated by immunocytochemistry. Since hormonal propeptides usually undergo intracellular processing, and the matured peptides are subsequently stored in the secretory granules, these results indicate that the processing pathway of ANF may be different from that of other hormonal peptides.


Strain Characterization in Two-Dimensional Crystals.
Two-dimensional (2D) crystals provides a material platform to explore the physics and chemistry at the single-atom scale, where surface characterization techniques can be applied straightforwardly. Recently there have been emerging interests in engineering materials through structural deformation or transformation. The strain field offers crucial information of lattice distortion and phase transformation in the native state or under external perturbation. Example problems with significance in science and engineering include the role of defects and dislocations in modulating material behaviors, and the process of fracture, where remarkable strain is built up in a local region, leading to the breakdown of materials. Strain is well defined in the continuum limit to measure the deformation, which can be alternatively calculated from the arrangement of atoms in discrete lattices through methods such as geometrical phase analysis from transmission electron imaging, bond distortion or virial stress from atomic structures obtained from molecular simulations. In this paper, we assess the accuracy of these methods in quantifying the strain field in 2D crystals through a number of examples, with a focus on their localized features at material imperfections. The sources of errors are discussed, providing a reference for reliable strain mapping.


Survey for Listeria monocytogenes in and on Ready-to-Eat Foods from Retail Establishments in the United States (2010 through 2013): Assessing Potential Changes of Pathogen Prevalence and Levels in a Decade.
A multiyear interagency Listeria monocytogenes Market Basket Survey was undertaken for selected refrigerated ready-to-eat foods purchased at retail in four FoodNet sites in the United States. Food samples from 16 food categories in six broad groups (seafood, produce, dairy, meat, eggs, and combination foods) were collected weekly at large national chain supermarkets and independent grocery stores in California, Maryland, Connecticut, and Georgia for 100 weeks between December 2010 and March 2013. Of the 27,389 total samples, 116 samples tested positive by the BAX PCR system for L. monocytogenes , and the pathogen was isolated and confirmed for 102 samples. Among the 16 food categories, the proportion of positive samples (i.e., without considering clustering effects) based on recovery of a viable isolate of L. monocytogenes ranged from 0.00% (95% confidence interval: 0.00, 0.18) for the category of soft-ripened and semisoft cheese to 1.07% (0.63, 1.68) for raw cut vegetables. Among the 571 samples that tested positive for Listeria-like organisms, the proportion of positive samples ranged from 0.79% (0.45, 1.28) for soft-ripened and semisoft cheese to 4.76% (2.80, 7.51) for fresh crab meat or sushi. Across all 16 categories, L. monocytogenes contamination was significantly associated with the four states (P < 0.05) but not with the packaging location (prepackaged by the manufacturer versus made and/or packaged in the store), the type of store (national chain versus independent), or the season. Among the 102 samples positive for L. monocytogenes , levels ranged from <0.036 most probable number per g to 6.1 log CFU/g. For delicatessen (deli) meats, smoked seafood, seafood salads, soft-ripened and semisoft cheeses, and deli-type salads without meat, the percentage of positive samples was significantly lower (P < 0.001) in this survey than that reported a decade ago based on comparable surveys in the United States. Use of mixed logistic regression models to address clustering effects with regard to the stores revealed that L. monocytogenes prevalence ranged from 0.11% (0.03, 0.34) for sprouts (prepackaged) to 1.01% (0.58, 1.74) for raw cut vegetables (prepackaged).


Germ cell tumour of testis.
Germ cell tumour, though rare, represents most common malignancy among young men aged between 15 to 35 years. In 1990's dramatic improvement has taken place in survival rate of testicular tumours (from 10% in 1970's and 90% in 1990's). This has been possible because of effective diagnostic techniques, accurate monitoring with biological markers and use of effective platinum based combination chemotherapy in its management. The most significant improvement in survival rate has occurred in advanced stage germ-cell tumours. Seminomas are sensitive to radiation therapy and NSGCT (Non Seminomatous Germ Cell Tumours). are effectively treated by combination chemotherapy of 3 drugs of which Bleomycin is most expensive and many patient can not afford it and so compliance is poor. In the present series we have tried only 2 drug regimen consisting of Platinum and Etoposide (PE). Since January 1992 to December 1994, 40 cases of testicular tumours were treated. 16 cases received PEB regimen and 24 cases were treated by PE regimen of which only 6 cases in the former and 20 cases in the later group completed the scheduled course. Patients were given 6 cycles of PE regimen (inj. Platinum 20 mg/m2 D1-D5, VP-16 (ETOPOSIDE), 100 MG/M2 1.V. D1-D5) repeated every three weeks. Final evaluation was done in June 1996. 17/20 (85%) patients on PE regiment exhibited complete regression of the disease by the end of June 1996, I was lost to follow up, and 2 of them had the disease in progressive stage and were considered for another regimen. 18 months disease free survival was 85%. Table I. Royal Marsden Staging System Stage I: Disease econfined to testes Stage II: Intradiaphragmatic node involvement A: Less than 2 cm B: 2-5 cm C: Greater than 5 cm Stage III: Supradiaphragmatic node involvement Stage IV: Extralymphatic disease Lung, Liver, Bone etc.


Age-adjusted D-dimer cut-off in the diagnostic strategy for deep vein thrombosis: a systematic review.
Studies have indicated that use of an age-adjusted D-dimer cut-off value for patients above 50 years increases utility of the diagnostic strategy for pulmonary embolism. Evidence for the same approach regarding diagnosis of deep vein thrombosis (DVT) is, however, unclear. A systematic literature review was conducted following the PRISMA Statement guideline to gather the existing knowledge on the use of an age-adjusted D-dimer cut-off in the diagnostic strategy for DVT. Studies were extracted from Medline and the Cochrane Library. The search period ended in November 2016. Out of 73 articles retrieved, only eight studies addressed DVT either specifically or along with PE. None of these were randomized controlled trials, but were either prospective studies of consecutive outpatients or retrospective studies. Despite differences in study design, DVT prevalence, and D-dimer assay used, all studies were in favour of the age-adjusted D-dimer cut-off with negative predictive values (NPV) ranging from 91.8-100% compared to 89.7-100% for the standard D-dimer cut-off. All the studies concluded that use of an age-adjusted D-dimer cut-off resulted in an improved utility, although the results due to heterogeneity in reporting did not allow a direct comparison. Use of an age-adjusted D-dimer cut-off for patients above 50 years of age for ruling out DVT seems as safe as using a standard D-dimer cut-off. The recommended (and most used) adjustment is by the formula (patient's age ×10) μg/L.


Relationship of net chloride flow across the human erythrocyte membrane to the anion exchange mechanism.
The parallel effects of the anion transport inhibitor DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonate) on net chloride flow and on chloride exchange suggest that a major portion of net chloride flow takes place through the anion exchange system. The "slippage" model postulates that the rate of net anion flow is determined by the movement of the unloaded anion transport site across the membrane. Both the halide selectivity of net anion flow and the dependence of net chloride flux on chloride concentration over the range of 75 to 300 mM are inconsistent with the slippage model. Models in which the divalent form of the anion exchange carrier or water pores mediate net anion flow are also inconsistent with the data. The observations that net chloride flux increases with chloride concentration and that the DIDS-sensitive component tends to saturate suggest a model in which net anion flow involves "transit" of anions through the diffusion barriers in series with the transport site, without any change in transport site conformation such as normally occurs during the anion exchange process. This model is successful in predicting that the anion exchange inhibitor NAP-taurine, which binds to the modifier site and inhibits the conformational change, has less effect on net chloride flow than on chloride exchange.


Sea urchin prosome: characterization and changes during development.
A cytoplasmic particle displaying properties in common with a structure present in duck erythroblasts, termed the prosome, has been isolated from eggs and embryos of two species of sea urchin. This particle was partially purified by sedimentation in sucrose gradients containing 0.5 M KCl, and some of its physical properties and its behavior during early development were determined. The prosome sediments between 16 and 19 S and has a buoyant density of 1.30 g/cm3 in Cs2SO4 gradients. Biochemically, the particle is characterized as 20-25 polypeptides of molecular size 24-35 kDa with about 10 small RNAs. A monoclonal antibody directed against the 27-kDa protein of duck erythroblast prosome recognizes a 27-kDa protein of the sea urchin prosome. We have used this protein, as representative of the prosome, to immunologically determine the level and the subcellular localization of the particle during development. Immunoblotting and cellular fractionation studies show that the 27-kDa prosome polypeptide is present almost entirely in the postribosomal supernatant of unfertilized egg lysates. After fertilization and during early development, the total amount of 27-kDa protein per embryo remains constant, but the amount in the postribosomal supernatant decreases; there is a concomitant increase in the level of the 27-kDa protein in a rapidly sedimenting, particulate fraction containing nuclei. Immunofluorescence studies further show that the 27-kDa protein is located mainly in the cytoplasm of eggs and two-cell embryos. The subcellular location of the prosome, therefore, appears to change during development. In vivo labeling experiments have failed to detect the synthesis of either the prosome proteins or RNAs in eggs and embryos up to 48 hr of development, suggesting that this cytoplasmic particle is not synthesized de novo in early embryogenesis and thus is metabolically stable. The prosome is thus a normal cellular constituent of the sea urchin and is most likely synthesized during oogenesis and stored in the unfertilized egg.


ASC-expressing Pyroptotic Extracellular Vesicles Alleviate Sepsis by Protecting B Cells.
Pyroptosis is an inflammatory programmed cell death process characterized by membrane rupture. Interestingly, pyroptotic cells can generate plenty of nanosized vesicles. Non-inflammatory apoptotic cell death-derived apoptotic vesicles (apoVs) were systemically characterized and displayed multiple physiological functions and therapeutic potentials. However, the characteristics of pyroptotic cell-generated EVs are largely unknown. Here, we identified a group of pyroptotic extracellular vesicles (pyroEVs) from in vitro cultured pyroptotic mesenchymal stem cells (MSCs) as well as from septic mouse blood. Compared to apoVs, pyroEVs express similar levels of annexin V, calreticulin, and common EV markers but express reduced level of apoptotic marker cleave caspase-3. PyroEVs, but not apoVs and exosomes, specifically express pyroptotic maker apoptosis-associated speck-like protein containing CARD (ASC). More importantly, MSC-derived pyroEVs protect B cells in the spleen and bone marrow to relieve inflammatory responses and enhance the survival rate of the septic mice. Mechanistically, pyroEV membrane-expressed ASC binds to B cells to repress cell death by repressing toll-like receptor 4 (TLR4). This study uncovered the characteristics of pyroEVs and their therapeutic role in sepsis and B cell-mediated immune response.


Open access efforts begin to bloom: ESC Heart Failure gets full attention and first impact factor.
In 2014, the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) founded the first open access journal focusing on heart failure, called ESC Heart Failure (ESC-HF). In the first 5 years, in ESC-HF we published more than 450 articles. Through ESC-HF, the HFA gives room for heart failure research output from around the world. A transfer process from the European Journal of Heart Failure to ESC-HF has also been installed. As a consequence, in 2018 ESC-HF received 289 submissions, and published 148 items (acceptance rate 51%). The journal is listed in Scopus since 2014 and on the PubMed website since 2015. In 2019, we received our first impact factor from ISI Web of Knowledge / Thomson-Reuters, which is 3.407 for 2018. This report reviews which papers get best cited. Not surprisingly, many of the best cited papers are reviews and facts & numbers mini reviews, but original research is also well cited.


The identification of genes from the oyster Crassostrea gigas that are differentially expressed in progeny exhibiting opposed susceptibility to summer mortality.
Summer mortality associated with juveniles of the oyster Crassostrea gigas is probably the result of a complex interaction between the host, pathogens and environmental factors. Genetic variability in the host appears to be a major determinant in its sensitivity to summer mortality. Previously, divergent selection criteria based on summer survival have been applied to produce oyster families with resistant and susceptible progeny. In this paper, we describe the use of suppression subtractive hybridization to generate 150 C. gigas clones that were differentially regulated between resistant and susceptible F2 progeny. The nucleotide sequence of these clones was determined. In 28%, the inferred amino sequence was found to match the products of known genes, 14% matched hypothetical proteins and a further 14% appeared to contain open reading frames (ORFs) whose product had no obvious homologue in the nucleotide databases. It has been hypothesized that differences exist in the level of energy generation and immune function between resistant and susceptible progeny. In light of this, clones encoding homologues of cavortin, cyclophilin, isocitrate dehydrogenase, sodium glucose cotransporter, fatty acid binding protein, ATPase H+ transporting lysosomal protein, precerebellin, and scavenger receptor were analyzed by real-time PCR. These transcripts were induced in resistant progeny when compared to their susceptible counterparts. A bacterial challenge of oysters resulted in the suppression of six of these transcripts in only those that were resistant to summer mortality. This study has identified potential candidates for further investigation into the functional basis of resistance and susceptibility to summer mortality.


Screening of the Men1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors.
Hyperparathyroidism is the first manifestation in a majority of multiple endocrine neoplasia (MEN1) patients. To discriminate between sporadic and hereditary parathyroid tumors and characterize MEN1 somatic mutations, we examined MEN1 gene mutations in patients who had undergone surgery for sporadic parathyroid tumors. DNA was extracted from fresh frozen parathyroid tumor specimens from 112 patients as well as from peripheral blood leukocytes from 64 of the 112 patients. Sequence analysis was performed to examine exons 2-10 of the MEN1 gene for mutations. Loss of heterozygosity (LOH) was also examined by an analysis of codon 418 and 541, which lie within a polymorphic region of MEN1. Somatic MEN1 mutations were found in 25 of the 112 patients (22%). Two patients had two point mutations (508del33 and Y341X and 363insT and 1767delT, respectively). A total of 27 mutations were characterized, 20 of which have not been reported previously. There were 7 nonsense mutations, 10 frameshift mutations, 2 splice site deletions, 5 missense mutations, and 3 in-frame mutations. Nineteen mutations (70%) predicted truncation of the menin protein. Germ-line MEN1 mutations were found in 3 of 64 patients (5%) who had no family history of endocrine tumors associated with MEN1, and these patients were identified as MEN1 gene probands. LOH at the MEN1 locus was detected in three parathyroid tumors showing germ-line mutation. LOH was significantly frequent in parathyroid tumors with somatic MEN1 mutations (15 of 22 tumors, 68%) but not in those without germ-line or somatic MEN1 mutations (14 of 51 tumors, 28%; P = 0.0011). Our findings suggest that alterations of both alleles of the MEN1 gene may be associated not only with endocrine tumors of affected MEN1 patients but also with sporadic parathyroid tumors. Germ-line MEN1 gene analysis can distinguish heritable from nonheritable parathyroid tumors, and MEN1 gene evaluation of patients with apparently sporadic parathyroid tumor is recommended before parathyroid surgery.


Vernalization, gibberellic acid and photo period are important signals of yield formation in timothy (Phleum pratense).
Timothy (Phleum pratense) is a widely grown perennial forage grass in the Nordic region. The canopy consists of three tiller types, of which the stem forming vegetative elongating (ELONG) tiller and generative (GEN) tillers contribute the most to dry matter yield. In this study, the regulation of tiller formation by vernalization, day length (DL) [12 h, short day length (SD); 16 h, long day length (LD)] and gibberellic acid (GA) was investigated in two timothy cultivars. Vernalization resulted in a shift of ELONG to GEN tillers. No vernalization was required for the development of ELONG tillers but SD strictly arrested stem elongation. Vernalization is an important regulator of tiller development but it seemed to be upstream regulated by DL. LD was essential for floral transition and could not be substituted by GA and/or vernalization treatments. Genotypic variation was found in the development of GEN tillers. The ability to produce GEN tillers was associated with significant upregulation of PpVRN3. PpVRN1 expression peaked at the time of vegetative/generative transition, and PpVRN3 after the transfer to LD, suggesting them to have similar functions with cereal vernalization genes. PpVRN1 alone was not sufficient to activate flowering, and upregulation of PpVRN3 possibly together with PpPpd1 was required. Although vernalization downregulated PpMADS10, this gene did not act as a clear flowering repressor. Our results show that flowering signals alter the tiller composition, so they have important effects on yield formation of timothy.


Modeling the impacts of climate change and technical progress on the wheat yield in inland China: An autoregressive distributed lag approach.
This study aims to evaluate the impacts of climate change and technical progress on the wheat yield per unit area from 1970 to 2014 in Henan, the largest agricultural province in China, using an autoregressive distributed lag approach. The bounded F-test for cointegration among the model variables yielded evidence of a long-run relationship among climate change, technical progress, and the wheat yield per unit area. In the long run, agricultural machinery and fertilizer use both had significantly positive impacts on the per unit area wheat yield. A 1% increase in the aggregate quantity of fertilizer use increased the wheat yield by 0.19%. Additionally, a 1% increase in machine use increased the wheat yield by 0.21%. In contrast, precipitation during the wheat growth period (from emergence to maturity, consisting of the period from last October to June) led to a decrease in the wheat yield per unit area. In the short run, the coefficient of the aggregate quantity of fertilizer used was negative. Land size had a significantly positive impact on the per unit area wheat yield in the short run. There was no significant short-run or long-run impact of temperature on the wheat yield per unit area in Henan Province. The results of our analysis suggest that climate change had a weak impact on the wheat yield, while technical progress played an important role in increasing the wheat yield per unit area. The results of this study have implications for national and local agriculture policies under climate change. To design well-targeted agriculture adaptation policies for the future and to reduce the adverse effects of climate change on the wheat yield, climate change and technical progress factors should be considered simultaneously. In addition, adaptive measures associated with technical progress should be given more attention.


Novel drugs and intervention strategies for the treatment of chronic kidney disease.
Chronic kidney disease (CKD) is a worldwide health problem. The disease is most often progressive of nature with a high impact on patients and society. It is increasingly recognized that CKD can be detected in the early stages and should be managed as early as possible. Treatment of the cause, but in particular control of the main risk markers, such as high blood pressure, glucose and albuminuria, has been instrumental in delaying the progression to end-stage renal disease (ESRD). However, despite the state of the art therapy, the absolute risk of renal and cardiovascular morbidity and mortality in CKD patients remains devastatingly high. Novel drugs are therefore highly desirable to halt effectively the progressive renal (and cardiovascular) function loss. Recently, several novel strategies have been tested targeting traditional risk factors such as blood pressure (combination therapy of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) and novel mineralocorticoid receptor antagonists) as well as dyslipidaemia (statins) with surprising results. In addition, drug targets specifically related to the kidney, such as vitamin D, uric acid, erythropoietin and phosphate, have been the subject of clinical trials, in some instances with unexpected results. Finally, novel targets including endothelin receptors and inflammatory pathways are increasingly explored as potential avenues to improve renal and cardiovascular protection, albeit that the drugs tested have not been unequivocally successful. In this article we review novel drugs or intervention strategies for the management of CKD, we try to provide explanations for the failure of some promising drugs and hypothesize on the potential success of new strategies.


Localized semi-nonnegative matrix factorization (LocaNMF) of widefield calcium imaging data.
Widefield calcium imaging enables recording of large-scale neural activity across the mouse dorsal cortex. In order to examine the relationship of these neural signals to the resulting behavior, it is critical to demix the recordings into meaningful spatial and temporal components that can be mapped onto well-defined brain regions. However, no current tools satisfactorily extract the activity of the different brain regions in individual mice in a data-driven manner, while taking into account mouse-specific and preparation-specific differences. Here, we introduce Localized semi-Nonnegative Matrix Factorization (LocaNMF), a method that efficiently decomposes widefield video data and allows us to directly compare activity across multiple mice by outputting mouse-specific localized functional regions that are significantly more interpretable than more traditional decomposition techniques. Moreover, it provides a natural subspace to directly compare correlation maps and neural dynamics across different behaviors, mice, and experimental conditions, and enables identification of task- and movement-related brain regions.


Depressive symptoms, ruminative thinking, marijuana use motives, and marijuana outcomes: A multiple mediation model among college students in five countries.
Previous studies have evidenced that rumination and drinking motives may mediate the association between depressive symptoms and alcohol outcomes. The present study cross-culturally examined whether a similar mediation model may extend to marijuana. Specifically, we tested distinct rumination facets (problem-focused thoughts, counterfactual thinking, repetitive thoughts, and anticipatory thoughts) and marijuana use motives (social, coping, expansion, conformity, enhancement) as double-mediators of the paths from depressive symptoms to marijuana outcomes (use and consequences). A comprehensive mediation path model was tested in a cross-sectional sample of college student marijuana users (n = 1175) from five countries (U.S., Argentina, Uruguay, Spain, Netherlands). Multi-group models were tested to determine if the proposed mediational model was invariant across sex and different cultures/countries. Depressive symptoms and marijuana outcomes were indirectly associated through ruminative thinking and marijuana motives. Specifically, higher depressive symptoms were associated with higher problem-focused thoughts; which in turn were associated with: a) higher endorsement of coping motives which in turn was associated with higher marijuana use and related consequences and b) lower endorsement of enhancement motives which in turn was associated with lower marijuana use and related consequences. The multi-group analyses showed that the model was invariant across sex and the five countries. The present research supports the existence of a universal (i.e., cross-national invariant) negative affect regulation pathway to marijuana use/misuse similar to those previously found with alcohol. Additional research is needed to confirm the role of enhancement motives in the associations of depression, rumination and marijuana outcomes.


Frequency of hyper-, hypohaploidy and diploidy in ejaculate, epididymal and testicular germ cells of infertile patients.
The hypothesis that sperm aneuploidy and diploidy increase as a function of spermatogenesis impairment was addressed. Ejaculated semen samples from a series of men (n = 22) with very low total normal motile count (1 x 10(6)) was analysed in terms of sperm aneuploidy and diploidy by in-situ hybridization and compared with controls (n = 10). Germ cell aneuploidy was also analysed in an additional series of infertile patients presenting unexplained infertility (n = 3), congenital absence of the vas deferens (CAVD) (n = 6) and non-obstructive azoospermia (n = 3) undergoing IVF, microsurgical epididymal sperm aspiration (MESA)/ICSI and testicular sperm extraction (TESE)/ICSI cycles respectively. In-situ hybridization for chromosomes 1, 17, X and Y was performed on ejaculate, epididymal and testicular spermatozoa. Significantly higher sperm aneuploidy and diploidy rates where found (for the four chromosomes analysed) in spermatozoa from oligoasthenoteratozoospermia (OAT) over controls (18 versus 2.28% and 2.8 versus 0.13% respectively; P < 0.001). Testicular germ cells had even higher rates of sperm aneuploidy and diploidy. However, in this group it was difficult to determine whether the cells analysed were dysmorphic spermatozoa or spermatids. The data warrant further investigation on the cytogenetic abnormalities found in most germ cells identified in testicular tissue biopsies of azoospermic patients.


Demonstrations of neural network computations involving students.
David Marr famously proposed three levels of analysis (implementational, algorithmic, and computational) for understanding information processing systems such as the brain. While two of these levels are commonly taught in neuroscience courses (the implementational level through neurophysiology and the computational level through systems/cognitive neuroscience), the algorithmic level is typically neglected. This leaves an explanatory gap in students' understanding of how, for example, the flow of sodium ions enables cognition. Neural networks bridge these two levels by demonstrating how collections of interacting neuron-like units can give rise to more overtly cognitive phenomena. The demonstrations in this paper are intended to facilitate instructors' introduction and exploration of how neurons "process information."


Whey Protein Lipid Concentrate High in Milk Fat Globule Membrane Components Inhibit Porcine and Human Rotavirus in vitro.
Background: The milk fat globule membrane (MFMG) is a complex milk component that has been shown to inhibit rotavirus (RV) binding to cell membranes in vitro. Herein, a whey protein lipid concentrate high in MFGM components (WPLC) and whey protein concentrate (WPC; control) were screened for anti-infective activity against porcine OSU and human Wa strains of RV in both the African Green Monkey kidney (MA104) and the human colorectal adenocarcinoma (Caco-2) cell lines. Materials and Methods: Confluent cells were exposed to OSU or Wa RV in the presence of WPLC or WPC (control) at 0, 0.1, 0.5, 1.0, 2.5, or 5 mg/ml. Infectivity was detected by immunohistochemistry and expressed as % inhibition relative to 0 mg/ml. WPLC efficacy over WPC was expressed as fold-change. One-way ANOVA analyzed data for the independent and interactive effects of concentration, test material, and RV strain. Results: Both WPLC and WPC exhibited concentration-dependent inhibition of human Wa and porcine OSU RV infectivity in MA104 and Caco-2 cells (p < 0.0001). WPLC was 1.5-4.8-fold more effective in reducing infectivity than WPC. WPLC efficacy was independent of RV strains, but varied between cell lines. WPLC and WPC at concentrations ≥0.5 mg/mL were most effective in reducing human Wa RV infectivity in MA104 cells (p < 0.0001). Conclusions: WPLC decreased infectivity of two strains for RV which differ in their dependency on sialic acid for binding to cells. Inhibition was observed in the most commonly used cell type for RV infectivity assays (MA104) and an intestinal cell line (Caco-2). An effect on virus infectivity might be a potential mechanisms of action contributing to beneficial effects of supplementation of infant formula with MGFM reducing the risk of infections and consequently diarrhea incidence in infants.


[Lipid peroxidation in the rat liver during macrophage stimulation].
The content of malonyl dialdehyde, one of the final products of lipid peroxidation, was determined at different stages after zymosan stimulation of mononuclear phagocyte system in the rat liver. The gradual increase (with the maximum on day 7) of colloidal carbon clearance from the blood and the number of nonparenchymal cells, especially their nonphagocytic fraction, was noted in the rat liver after zymosan injection. A considerable reduction of hepatic malonyl dialdehyde was observed after the initial (on day 1) rising of its level. The distinct antioxidant effect developed by day 7 and coincided with maximal activity of hepatic macrophages.


One-Pot Synthesis of a Zwitterionic Small Molecule Bearing Disulfide Moiety for Antibiofouling Macro- and Nanoscale Gold Surfaces.
The goal of this study is to develop a simple one-pot method for the synthesis of a zwitterionic small molecule bearing disulfide moiety, which can effectively inhibit nonspecific protein adsorption on macroscopic and nanoscopic gold surfaces. To this end, the optimal molecular structure of a pyridine disulfide derivative was explored and a zwitterionic small molecule was successfully synthesized from the tertiary amine residue on the pyridine ring through a one-pot method. The coating conditions of the synthesized zwitterionic molecules on the gold surface were optimized through contact angle measurements, and the strong interactions between the gold surface and the disulfide moiety of the zwitterion small molecule were confirmed by surface plasmon resonance (SPR) analysis and X-ray photoelectron spectroscopy. The antibiofouling properties of the coated gold surface were analyzed by fluorescence microscopic observations after contacting with FITC-labeled bovine serum albumin (BSA) and SPR sensor as contacting with BSA solution. In addition, the effect of zwitterion-coating on the salt stability of and protein adsorption on nanoscopic gold surfaces were examined through a NaCl stability test and BSA adsorption test, respectively. From the obtained results, it was confirmed that the simply synthesized zwitterionic small molecule was effective in inhibiting nonspecific protein adsorption on macroscopic and nanoscopic gold surfaces; further, it enhanced the salt stability of gold nanoparticle surfaces.


Purification and characterization of the alanine aminotransferase from the hyperthermophilic Archaeon pyrococcus furiosus and its role in alanine production.
Alanine aminotransferase (AlaAT) was purified from cell extracts of the hyperthermophilic archaeon Pyrococcus furiosus by multistep chromatography. The enzyme has an apparent molecular mass of 93.5 kDa, as estimated by gel filtration, and consists of two identical subunits of 46 kDa, as deduced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the gene sequence. The AlaAT displayed a broader substrate specificity than AlaATs from eukaryal sources and exhibited significant activity with alanine, glutamate, and aspartate with either 2-oxoglutarate or pyruvate as the amino acceptor. Optimal activity was found in the pH range of 6. 5 to 7.8 and at a temperature of over 95 degrees C. The N-terminal amino acid sequence of the purified AlaAT was determined and enabled the identification of the gene encoding AlaAT (aat) in the P. furiosus genome database. The gene was expressed in Escherichia coli, and the recombinant enzyme was purified. The pH and temperature dependence, molecular mass, and kinetic parameters of the recombinant were indistinguishable from those of the native enzyme from P. furiosus. The k(cat)/K(m) values for alanine and pyruvate formation were 41 and 33 s(-1) mM(-1), respectively, suggesting that the enzyme is not biased toward either the formation of pyruvate, or alanine. Northern analysis identified a single 1.2-kb transcript for the aat gene. In addition, both the aat and gdh (encoding the glutamate dehydrogenase) transcripts appear to be coregulated at the transcriptional level, because the expression of both genes was induced when the cells were grown on pyruvate. The coordinated control found for the aat and gdh genes is in good agreement with these enzymes acting in a concerted manner to form an electron sink in P. furiosus.


[Purification and properties of inhibitor from vegetative portion of alfalfa].
Trypsin inhibitor was isolated from the vegetative portion of alfalfa and purified 270-fold by affinity chromatography on Trypsin-Sepharose. The inhibitor was eluted by gel-filtration as a single peak with molecular weight of 6900. Disc-electrophoresis of the purified inhibitor revealed the presence of only one protein band. Trypsin inhibition is a mixed process. The trypsin inhibitor from alfalfa does not prevent the activity of cathepsin D from bovine brain. Trypsin inhibitor was immobilized on BrCN-activated Sepharose 4B. The binding of trypsin to the immobilized trypsin inhibitor was studied: 5 mg of the immobilized trypsin inhibitor were found to bind 1 mg of trypsin.


Ginger and the beetle: Evidence of primitive pollination system in a Himalayan endemic alpine ginger (Roscoea alpina, Zingiberaceae).
The Himalayan endemic alpine genus Roscoea, like other members of ginger family, exhibits the combination of floral traits that would fit pollination by long distant foragers such as bees, birds or flies. We studied the pollination biology of Roscoea alpina, observed potential floral visitors and determined their foraging behaviour, visitation frequency and pollination efficiency, to seek evidence in support of the pollination syndrome hypothesis. We also measured the floral spectra of R. alpina flowers to evaluate if signals fit with the currently known framework for observed floral visitors. We found that R. alpina have autonomous selfing and pollinator-mediated crossing, but lack apomixis. We observed that a beetle (Mylabris sp.), and a moth (Macroglossum nycteris) visit the flowers of R. alpina for pollen and nectar feeding respectively. Our field observations, the stigmatic pollen count and fruit set data indicated that the visit by the beetle was legitimate, while that of the moth was illegitimate. Emasculated flowers visited by beetles set as many fruits and seeds/fruit as auto-selfed and naturally pollinated flowers, while emasculated flowers excluded from beetle visits did not set fruit and seed; indicating that a single visit of a beetle to the flowers of R. alpina can facilitate pollination. We found that flower spectral signal of R. alpina does not fit typical spectra previously reported for beetle or bee-visited flowers. Our results suggest that, to ensure reproductive success in alpine habitat, R. alpina has evolved autonomous selfing as a predominant mode of reproduction, while beetle pollination would promote genetic diversity of this plant species. The visitation of beetles to the flowers of R. alpina, despite floral signal mismatch with the classically associated beetle vision, suggests that a different visual processing may operate in this plant-pollinator interaction at high altitudes.


Epitope specificity of 30 monoclonal antibodies against cytokeratin antigens: the ISOBM TD5-1 Workshop.
The epitope specificities of 30 monoclonal antibodies (MAbs) against the most common human cytokeratins. i.e., Nos. 8, 18, and 19, in epithelial cells were investigated in the ISOBM TD-5 Workshop. Seven research groups from universities or companies participated independently in the evaluation of the antibody specificities. The complex assembly of cytokeratins in vivo, with obligatory heterologous dimeric combinations of different cytokeratins from each of the two major groups, comprising together more than 20 different individual cytokeratins, made analysis of the antibody reactivity patterns with isolated single cytokeratins necessary. The concordance of the evaluations was striking and independent of the technologies used. As antigens purified individual cytokeratins, chemically degraded purified cytokeratins, recombinant intact and truncated cytokeratins, as well as specific synthesized shorter peptides were used. In order to elucidate the epitope specificity, reactivity patterns in ELISA assays and immunoblots with partial enzymatic degradation of the antigens were performed. Competitive cross-inhibition experiments between antibodies using antigens and antibodies in all possible combinations were performed with radioimmunometric assays, BIAcore, and ELISA technology. All 30 antibodies could convincingly be classified with regard to target cytokeratin. One MAb (192) had to be deleted due to dual specificities in both isotype and epitope specificity against its target. Six antibodies bound selectively to cytokeratin 8, 14 to cytokeratin 18, and 10 to cytokeratin 19, as demonstrated by using native, recombinant, and synthesized antigens. The immunodominant part of the molecule for all three types of cytokeratins was located in the region of amino acid (aa) 270-400. Out of the six MAbs reactive with cytokeratin 8, four MAbs, i.e., 178, 199, 202, and 206, were reactive with a sequence in the interval aa 340-365, and MAb 191 reacted with a closely related epitope. The remaining antibody, 192, presented dual specificities. At least two closely related major immunogenic epitopes could be identified in cytokeratin 8. In cytokeratin 18 four distinct epitopes could be documented, again with the dominating sequence region 270-429 as target for 10 (181, 184, 186, 188, 189, 190, 193, 196, 198, and 200) out of 14 antibodies. Since MAb 193 is known to react with the M3 epitope, aa 322-342 in cytokeratin 18, this entire group is reactive in the region close to the charge shift, in the middle of the rod 2B region, as shown by competitive binding. The remaining four anticytokeratin 18 antibodies (180, 185, 203, and 205) displayed unique, noncompetitive binding to this filament. Cytokeratin 19, reactive with altogether ten antibodies, displayed two major epitopes, all of them also within the large immunodominant region. MAbs 179, 195, 197, and 204 were reactive with the peptides aa 311-335 also known as the KS 19.1 epitope, and MAbs 182, 183, 187, 194, and 201 bound to peptide aa 346-367, known as the BM 19.21 epitope. One antibody, 231, was selectively reactive with aa 356-370 in cytokeratin 19. A complex pattern of binding specificities comprising at least ten different, noncompetitive epitopes, mainly situated in the rod portion, 2A and 2B, situated close to the charge shift in the rod of all three cytokeratins was documented. Out of the 29 classifiable antibodies, altogether 22 were reactive in this very short region, i.e., from aa 311 to 370 in all cytokeratin filaments. The remaining seven antibodies displayed unique binding properties. The implications of the findings are of significance both for immunohistochemistry and for assaying circulating heterodimeric, partially degraded complexes in patients' blood for tumor marker evaluation.


Shift from first generation antipsychotics to olanzapine may improve health-related quality of life of stable but residually symptomatic schizophrenic outpatients: a prospective, randomized study.
The aim of this study was to elucidate, whether shift from first generation antipsychotics (FGA) to olanzapine can affect health-related quality of life (HRQoL) of residually symptomatic schizophrenic outpatients. Patients were randomized to either olanzapine or to continuation on their FGA. The 15D-measured HRQoL at baseline and end-point (after 12 weeks) was compared. Patients (n = 21) randomized to olanzapine achieved better HRQoL than those (n = 21) who continued on their FGA. This difference on the 15D (0.048 on a 0-1 scale; p = .037) was clinically important and comparable to that resulting from common surgical interventions, for example, hip or knee replacement. HRQoL of stable outpatients with residual symptoms or adverse effects may improve substantially after shift from FGAs to olanzapine.


18F-FDG PET/CT in non-small-cell lung cancer patients: a potential predictive biomarker of response to immunotherapy.
The aim of this study was to assess the predictive role of fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in the evaluation of response to immunotherapy in patients affected by metastatic lung cancer. From a single-center database, data for 32 patients (median age: 69 years; range: 37-78) with metastatic lung cancer were retrospectively retrieved. All patients were treated with nivolumab. PD-L1 expression was available in 19/32 patients. All patients underwent F-FDG PET/CT before immunotherapy. Whole-body maximum standardized uptake value (SUVmaxwb), metabolic tumor volume (MTVwb), and total lesion glycolysis (TLGwb) were obtained as the sum of SUVmax, metabolic tumor volume, and total lesion glycolysis in all metabolic lesions. The best response to therapy was considered in terms of partial response (PR), stable disease (SD), and progressive disease (PD) on the basis of clinical and radiological follow-up. F-FDG PET/CT was positive in 30/32 (94%) patients. The majority of them had a pathological F-FDG uptake in the lung, lymph nodes, and bones. SUVmaxwb, MTVwb, and TLGwb were higher in patients with a positive PD-L1 expression than those with negative expression. Twenty-one patients achieved disease control (PR+SD), whereas 11 did not (PD). SUVmaxwb was significantly higher in patients without a response to therapy than those with a response to immunotherapy (median: 48.97 vs. 20.85; Student t-test: P = 0.002). Similarly, TLGwb and MTVwb were also higher in nonresponders than responders, although not statistically significant. However, the difference was more evident in women than men (median SUVmaxwb in responders and nonresponders for women and men: 17.86 vs. 85.89 and 21.38 vs. 44.38, respectively). The entire tumor burden evaluated by F-FDG PET/CT can be predictive of response to immunotherapy in patients with metastatic lung cancer. A large prospective multicenter trial is warranted to definitively assess the usefulness of F-FDG PET/CT as a predictive biomarker of response to immunotherapy.


Applications of Lab on a Chip in Antimicrobial Susceptibility of Staphylococcus aureus: A Systematic Review.
Background and Objectives: Staphylococcus aureus is a prevalent bacterium capable of inducing various infections, including skin and soft tissue infections, bloodstream infections, pneumonia, and surgical site infections. The emergence of antimicrobial resistance in S. aureus, particularly methicillin-resistant S. aureus, has raised substantial concerns within global healthcare settings. Prior to antibiotic prescription, the ideal approach is antimicrobial susceptibility testing (AST); however, this is frequently perceived as excessively complex and time-intensive. Lab-on-a-chip (LOC) technology holds promise in addressing these challenges and advancing fundamental microbiological research while also aiding in the development of therapeutic strategies. This systematic review aims to evaluate the potential utility of LOC for AST of S. aureus. Materials and Methods: This study adhered to the PRISMA guidelines. Various databases, including SCOPUS, PubMed/MEDLINE, SCIELO, and LILACS, in addition to gray literature sources, were employed in the review process. Results: Sixteen studies were included in this systematic review. All these studies detailed the effectiveness, rapidity, and predictability of LOC systems for assessing S. aureus susceptibility to various antibiotics. When comparing the LOC approach to traditional manual methods, it was evident that LOC requires a minimal quantity of reagents. Furthermore, most studies reported that the entire LOC procedure took 10 min to 7 h, with results being equally accurate as those obtained through traditional AST protocols. Conclusions: The potential application of LOC for AST of S. aureus is emphasized by its ability to provide rapid access to minimum inhibitory concentration data, which can substantially aid in selecting the most suitable antibiotics and dosages for treating challenging infections caused by this microorganism. Moreover, the rapid AST facilitated by LOC holds promise for enhancing the appropriateness and efficacy of therapy in clinical settings.


α-Tomatine inhibits growth and induces apoptosis in HL-60 human myeloid leukemia cells.
α‑Tomatine is a glycoalkaloid that occurs naturally in tomatoes (Lycopersicon esculentum). In the present study, the effects of α‑tomatine on human myeloid leukemia HL‑60 cells were investigated. Treatment of HL‑60 cells with α‑tomatine resulted in growth inhibition and apoptosis in a concentration‑dependent manner. Tomatidine, the aglycone of tomatine had little effect on the growth and apoptosis of HL‑60 cells. Growth inhibition and apoptosis induced by α‑tomatine in HL‑60 cells was partially abrogated by addition of cholesterol indicating that interactions between α‑tomatine and cell membrane‑associated cholesterol may be important in mediating the effect of α‑tomatine. Activation of nuclear factor‑κB by the phorbol ester, 12‑O‑tetradecanoylphorbol‑13‑acetate failed to prevent apoptosis in HL‑60 cells treated with α‑tomatine. In animal experiments, it was found that treatment of mice with α‑tomatine inhibited the growth of HL‑60 xenografts in vivo. Results from the present study indicated that α‑tomatine may have useful anti‑leukemia activities.


Distance Metric Learning for Conditional Anomaly Detection.
Anomaly detection methods can be very useful in identifying unusual or interesting patterns in data. A recently proposed conditional anomaly detection framework extends anomaly detection to the problem of identifying anomalous patterns on a subset of attributes in the data. The anomaly always depends (is conditioned) on the value of remaining attributes. The work presented in this paper focuses on instance-based methods for detecting conditional anomalies. The methods depend heavily on the distance metric that lets us identify examples in the dataset that are most critical for detecting the anomaly. To optimize the performance of the anomaly detection methods we explore and study metric learning methods. We evaluate the quality of our methods on the Pneumonia PORT dataset by detecting unusual admission decisions for patients with the community-acquired pneumonia. The results of our metric learning methods show an improved detection performance over standard distance metrics, which is very promising for building automated anomaly detection systems for variety of intelligent monitoring applications.


Reappraising Risk Factors for Inflammatory Bowel Disease-associated Neoplasia: Implications for Colonoscopic Surveillance in IBD.
One of the most feared complications of inflammatory bowel disease [IBD]-associated colitis is colorectal cancer. When considering the substantial increase in the prevalence of IBD, without any anticipated decline, coupled with decreasing colectomy rates for dysplasia and expanding medical options for effectively controlling inflammation, it is predicted that the pool of people living with-and ageing with-colonic IBD, who are recommended to undergo lifelong colonoscopic surveillance for colorectal neoplasia, will strain existing resources and challenge the sustainability of current guideline-based surveillance recommendations. At the same time, we are missing the opportunity for early detection in a group that is overlooked as high-risk, as a substantial proportion of colorectal cancers are being diagnosed in individuals with colonic IBD who have disease duration shorter than when guidelines recommend surveillance initiation. Here, we reappraise: 1] inflammation as a dynamic risk factor that considers patients' cumulative course; 2] time of screening initiation that is not based primarily on absolute disease duration; and 3] surveillance intervals as an iterative determination based on individual patient factors and consecutive colonoscopic findings. This Viewpoint supports a paradigm shift that will ideally result in a more effective and higher-value colorectal cancer prevention approach in IBD.


Early results of penetrating keratoplasty after cultivated limbal epithelium transplantation.
To describe the early results of penetrating keratoplasty (PKP) in patients who had previously undergone cultivated limbal epithelium transplantation. Medical records of patients with limbal stem cell deficiency due to chemical burns who underwent PKP after cultivated limbal epithelium transplantation were reviewed for demographics, primary etiology, type of limbal transplantation, ocular surface stability, visual acuity, graft clarity, and complications. Histopathologic features of the recipient corneal buttons were studied with special attention to epithelial status. Of the 125 patients with limbal stem cell deficiency treated with cultivated limbal epithelium transplantation, 15 underwent PKP at a mean interval of 7 months (range, 2-12 months) following cultivated limbal epithelium transplantation (autologous, n = 11; allogenic, n = 4). All 4 patients treated with allogenic cultivated limbal epithelium transplantation were undergoing immunosuppressive therapy. Fourteen (93%) of the 15 eyes had a successful corneal graft with a stable corneal epithelium. Preoperative best-corrected visual acuity was less than 20/200 in 14 of the 15 eyes. At a mean +/- SD follow-up of 8.3 +/- 5.0 months after PKP, the best-corrected visual acuity was more than 20/60 in 8 eyes, 20/200 to 20/60 in 5 eyes, and less than 20/200 in 2 eyes. Three of the 15 eyes experienced corneal allograft rejection, which was managed successfully. One eye with graft rejection also had glaucoma. None of the limbal epithelial allografts showed signs of rejection. Early results of PKP following cultivated limbal epithelium transplantation are favorable when performed after stabilizing the ocular surface. Adequate immunosuppression is essential for allogenic cultivated limbal epithelium transplantation to avoid rejection. Corneal allografts can separately reject the limbal allografts.


Urban health: a look out our windows.
Approximately 80% of Americans live in cities or immediately adjacent communities. Such urban environments are complex amalgams of people of disparate backgrounds, economic status, and expectations, with extraordinary disparities in health status and outcomes between groups just blocks apart. Urban health as a framing paradigm is of recent vintage and offers a perspective on health and disease that integrates clinical medicine and public health and draws on the social and political sciences to seek understanding of the impact of cities on the health of populations and individuals. Ironically, disparate outcomes and increased mortality among poor minority populations in cities are not primarily related to the consequences of the urban epidemics of drugs and violence but rather are due to the increased prevalence and severity of common diseases such as asthma, cardiovascular disease, diabetes, and kidney disease. Several factors may be responsible for such disparities, including stress, racism, perceptions of deprivation, economic inequalities, and lack of access to quality health care. It is time for leaders in medical education and health care delivery to focus on the populations that surround their institutions in order to study urban health and meet the challenge of caring for all the residents of our cities.


Central T cell tolerance: Identification of tissue-restricted autoantigens in the thymus HLA-DR peptidome.
Promiscuous gene expression (pGE) of tissue-restricted self-antigens (TRA) in medullary thymic epithelial cells (mTECs) is in part driven by the Autoimmune Regulator gene (AIRE) and essential for self-tolerance. The link between AIRE functional mutations and multi-organ autoimmunity in human and mouse supports the role of pGE. Deep sequencing of the transcriptome revealed that mouse mTECs potentially transcribe an unprecedented range of >90% of all genes. Yet, it remains unclear to which extent these low-level transcripts are actually translated into proteins, processed and presented by thymic APCs to induce tolerance. To address this, we analyzed the HLA-DR-associated thymus peptidome. Within a large panel of peptides from abundant proteins, two TRA peptides were identified: prostate-specific semenogelin-1 (an autoantigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome) and central nervous system-specific contactin-2 (an autoantigen in multiple sclerosis). Thymus expression of both genes was restricted to mTECs. SEMG1 expression was confined to mature HLA-DR(hi) mTECs of male and female donors and was AIRE-dependent, whereas CNTN2 was apparently AIRE-independent and was expressed by both populations of mTECs. Our findings establish a link between pGE, MHC-II peptide presentation and autoimmunity for bona fide human TRAs.


A comparison of induced and expectorated sputum for the microbiological diagnosis of community acquired pneumonia.
Sputum induction has proved useful in the diagnosis of Pneumocystis carinii pneumonia and mycobacterial infections but there are scant data on its use in the diagnosis of community-acquired pneumonia (CAP). To better define the usage of sputum induction by hypertonic saline in the setting of CAP. A retrospective review of records of patients admitted to a community teaching hospital in the year 1995 with a diagnosis of CAP. Of 492 patients admitted with CAP, 71 (14%) had attempted sputum induction. A group of 66 patients with CAP and attempted sputum collection by spontaneous expectoration was compared with this group. Sputum induction failed to yield a sample in 22 patients (31%). Forty-five of 49 patients (92%) with induced sputum had received prior antibiotics as compared to 23 of 34 patients (68%) with expectorated samples (p < 0.05), due to sputum induction often being attempted later in the hospital course. The diagnostic yield of sputum induction was 14 of 71 (20%) compared to 16 out of 66 (24%) for attempted spontaneously expectorated samples. Antibiotic therapy was changed for 5 of 34 patients (15%) who spontaneously expectorated samples and for 9 of 49 patients (18%) with successful induction. Sputum induction is effective in obtaining sputum in some patients with CAP who fail to expectorate a sample. Attempting induction early, preferably before starting antibiotics, may increase its diagnostic yield.


Complex and simple translational readthrough signals in pea enation mosaic virus 1 and potato leafroll virus, respectively.
Different essential viral proteins are translated via programmed stop codon readthrough. Pea enation mosaic virus 1 (PEMV1) and potato leafroll virus (PLRV) are related positive-sense RNA plant viruses in the family Solemoviridae, and are type members of the Enamovirus and Polerovirus genera, respectively. Both use translational readthrough to express a C-terminally extended minor capsid protein (CP), termed CP-readthrough domain (CP-RTD), from a viral subgenomic mRNA that is transcribed during infections. Limited incorporation of CP-RTD subunits into virus particles is essential for aphid transmission, however the functional readthrough structures that mediate CP-RTD translation have not yet been defined. Through RNA solution structure probing, RNA secondary structure modeling, site-directed mutagenesis, and functional in vitro and in vivo analyses, we have investigated in detail the readthrough elements and complex structure involved in expression of CP-RTD in PEMV1, and assessed and deduced a comparatively simpler readthrough structure for PLRV. Collectively, this study has (i) generated the first higher-order RNA structural models for readthrough elements in an enamovirus and a polerovirus, (ii) revealed a stark contrast in the complexity of readthrough structures in these two related viruses, (iii) provided compelling experimental evidence for the strict requirement for long-distance RNA-RNA interactions in generating the active readthrough signals, (iv) uncovered what could be considered the most complex readthrough structure reported to date, that for PEMV1, and (v) proposed plausible assembly pathways for the formation of the elaborate PEMV1 and simple PLRV readthrough structures. These findings notably advance our understanding of this essential mode of gene expression in these agriculturally important plant viruses.


MXenes stretch hydrogel sensor performance to new limits.
The development of wearable electronics, point-of-care testing, and soft robotics requires strain sensors that are highly sensitive, stretchable, capable of adhering conformably to arbitrary and complex surfaces, and preferably self-healable. Conductive hydrogels hold great promise as sensing materials for these applications. However, their sensitivities are generally low, and they suffer from signal hysteresis and fluctuation due to their viscoelastic property, which can compromise their sensing performance. We demonstrate that hydrogel composites incorporating MXene (Ti3C2T x ) outperform all reported hydrogels for strain sensors. The obtained composite hydrogel [MXene-based hydrogel (M-hydrogel)] exhibits outstanding tensile strain sensitivity with a gauge factor (GF) of 25, which is 10 times higher than that of pristine hydrogel. Furthermore, the M-hydrogel exhibits remarkable stretchability of more than 3400%, an instantaneous self-healing ability, excellent conformability, and adhesiveness to various surfaces, including human skin. The M-hydrogel composite exhibits much higher sensitivity under compressive strains (GF of 80) than under tensile strains. We exploit this asymmetrical strain sensitivity coupled with viscous deformation (self-recoverable residual deformation) to add new dimensions to the sensing capability of hydrogels. Consequently, both the direction and speed of motions on the hydrogel surface can be detected conveniently. Based on this effect, M-hydrogel demonstrates superior sensing performance in advanced sensing applications. Thus, the traditionally disadvantageous viscoelastic property of hydrogels can be transformed into an advantage for sensing, which reveals prospects for hydrogel sensors.


[Role of ribonucleic acids in organizing the structure of Escherichia coli ribosomes].
The paper summarizes recent data on the secondary and tertiary structure of RNA in ribosomes. The participation of RNA in intraribosomal interactions and the role of these interactions in organization of ribosomal subunits are discussed. The following conclusions are made: 1) the structure of ribosomal subunits is predominantly created with their RNA components; 2) RNA molecules in ribosomal subunits have a very compact structure; the formation of this structure is followed by the rearrangement of the secondary structure of RNA; 3) the small group of ribosomal proteins plays an important role in the folding of RNA in the compact conformation: they not only stabilize intraribosomal RNA conformation but probably induce new RNA-RNA contacts.


Compensation for coarticulation: disentangling auditory and gestural theories of perception of coarticulatory effects in speech.
According to one approach to speech perception, listeners perceive speech by applying general pattern matching mechanisms to the acoustic signal (e.g., Diehl, Lotto, & Holt, 2004). An alternative is that listeners perceive the phonetic gestures that structured the acoustic signal (e.g., Fowler, 1986). The two accounts have offered different explanations for the phenomenon of compensation for coarticulation (CfC). An example of CfC is that if a speaker produces a gesture with a front place of articulation, it may be pulled slightly backwards if it follows a back place of articulation, and listeners' category boundaries shift (compensate) accordingly. The gestural account appeals to direct attunement to coarticulation to explain CfC, whereas the auditory account explains it by spectral contrast. In previous studies, spectral contrast and gestural consequences of coarticulation have been correlated, such that both accounts made identical predictions. We identify a liquid context in Tamil that disentangles contrast and coarticulation, such that the two accounts make different predictions. In a standard CfC task in Experiment 1, gestural coarticulation rather than spectral contrast determined the direction of CfC. Experiments 2, 3, and 4 demonstrated that tone analogues of the speech precursors failed to produce the same effects observed in Experiment 1, suggesting that simple spectral contrast cannot account for the findings of Experiment 1.


Cytokine and immune system abnormalities in fibromyalgia and other central sensitivity syndromes.
The nervous system as well as the immune system use common signaling molecules for intra- and inter-system communications. Specifically, both entities produce a similar array of peptide and non-peptide transmitters that act on a common set of receptors present in the two systems. One important set of such signaling molecules are cytokines. The wide distribution of cytokine receptors throughout the body, including the immune and the nervous system allows direct communication between these two entities. In addition to cytokines the nervous system and immune system also communicate with each other using shared ligands such as neurotransmitters and neuroendocrine hormones, and their respective receptors. Some of the most important clinical interactions between these two systems are associated with the "sickness response" as well as pain and analgesia. This "sickness response" which has been frequently attributed to inflammatory cytokines, strongly resembles the core symptoms of fibromyalgia and other Central Sensitivity Syndromes (CSS). Therefore a large number of research studies have focused on the relationship between peripheral cytokines and CSS. However, a lack of consistent associations was observed between CSS symptoms and peripheral cytokines which seem to suggest that maybe cytokines abnormalities of the central nervous system contribute to the pathogenesis of these illnesses. Better knowledge of cytokine -nervous system interactions may ultimately benefit the development of interventions that improve CSS manifestations including the "sickness response" and chronic pain.


Potential risk of proton pump inhibitors for Parkinson's disease: A nationwide nested case-control study.
Proton pump inhibitor (PPI) use is a potential risk factor for neurodegenerative disease development; however, its role in Parkinson's disease (PD) remains unclear. This study aimed to investigate the association between PPI use and PD risk. A total of 31,326 patients with newly diagnosed PD were matches by age, sex, body mass index, diabetes, and hypertension with 125,304 controls at a ratio of 1:4. The data were collected from the Korean National Health Insurance Services Database from January 2010 to December 2019. Cumulative defined daily doses of PPIs were extracted from treatment claims. We examined the association between PPI use and PD risk using conditional logistic regression. To prevent protopathic bias, we excluded patients diagnosed with PD within a 1-year lag period after PPI exposure. We applied 2- and 3-year lag periods for sensitivity analysis. PPI use was associated with an increased risk of PD when a 1-year lag period was applied between PPI exposure and PD development (adjusted odds ratio, 1.10; 95% confidence interval, 1.07-1.13). A significant positive dose-response relationship existed between the cumulative defined daily doses of PPIs and PD development (P<0.001). Similar results were obtained for the 2- or 3-year lag periods. The association did not vary based on gender. Older age, a higher Charlson Comorbidity Index score, no alcohol consumption, and a non-smoking status were associated with a significantly increased PD risk with PPI use. We observed an association between PPI use and PD risk, although long-term follow-up studies are necessary to verify this association.


A study of the native-denatured (N in equilibrium with D) transition in lysozyme. II. Kinetic analysis of protease digestion.
Kinetic analyses of the protease digestion of several chemical derivatives of lysozyme [EC 22.214.171.124] showed that only the D(denatured) state of the protein is digested and that the reaction velocity is proportional to the equilibrium constant (KD) of the N in equilibrium with D transition of the protein. Alteration of the net charge of lysozyme by acetylation caused a shift of the N in equilibrium with D transition to the right (ten-fold increase in KD compared to that of native enzyme). Both the formation of a lysozyme-inhibitor complex and the introduction of a covalent bond in the lysozyme molecule restricted the transition. The magnitude of the N in equilibrium with D transition is related to the susceptibility of lysozyme to protease digestion and it is estimated that the N in equilibrium with D transition in proteins is generally important in the intracellular catabolism of proteins.


Simultaneous quantitation of zinc protoporphyrin and free protoporphyrin in erythrocytes by acetone extraction.
Erythrocyte protoporphyrin content is increased in several human and veterinary disorders in which heme synthesis is disrupted. The nature of the defect determines whether zinc protoporphyrin, unchelated (free) protoporphyrin, or both are present in the erythrocytes. Extraction of the protoporphyrin into acetone/water (80/20 by vol) is a simple, rapid technique by which each protoporphyrin species is delivered into solution without removing zinc from zinc protoporphyrin. The ratio of zinc protoporphyrin to total protoporphyrin concentration correlated significantly with the ratio of fluorescence emission intensities at the zinc protoporphyrin peak and at an isosbestic point. This concentration ratio may be used with a quantitative measure of total erythrocyte protoporphyrin to define the absolute zinc protoporphyrin and free protoporphyrin content of erythrocytes.


Identification of two distinct pathways of protein kinase Calpha down-regulation in intestinal epithelial cells.
Signal transduction pathways are controlled by desensitization mechanisms, which can affect receptors and/or downstream signal transducers. It has long been recognized that members of the protein kinase C (PKC) family of signal transduction molecules undergo down-regulation in response to activation. Previous reports have indicated that key steps in PKCalpha desensitization include caveolar internalization, priming site dephosphorylation, ubiquitination of the dephosphorylated protein, and degradation by the proteasome. In the current study, comparative analysis of PKCalpha processing induced by the PKC agonists phorbol 12-myristate 13-acetate and bryostatin 1 in IEC-18 rat intestinal epithelial cells demonstrates that: (a) at least two pathways of PKCalpha down-regulation can co-exist within cells, and (b) a single PKC agonist can activate both pathways at the same time. Using a combined biochemical and morphological approach, we identify a novel pathway of PKCalpha desensitization that involves ubiquitination of mature, fully phosphorylated activated enzyme at the plasma membrane and subsequent down-regulation by the proteasome. The phosphatase inhibitors okadaic acid and calyculin A accelerated PKCalpha down-regulation and inhibitors of vesicular trafficking did not prevent degradation of the protein, indicating that neither internalization nor priming site dephosphorylation are requisite intermediate steps in this ubiquitin/proteasome dependent pathway of PKCalpha down-regulation. Instead, caveolar trafficking and dephosphorylation are involved in a second, proteasome-independent mechanism of PKCalpha desensitization in this system. Our findings highlight subcellular distribution and phosphorylation state as critical determinants of PKCalpha desensitization pathways.


Comparison of inguinal nerve block and intravenous fentanyl in relieving postinguinal herniorrhaphy pain for pediatric outpatients.
The purpose of this study was to compare the effects of ilioinguinal/iliohypogastric (IG/IH) nerve block and intravenous fentanyl for pain control following inguinal herniorrhaphy in pediatric outpatients. Seventy-five ASA physical status I and II children (aged 1 to 10 yr) with unilateral inguinal herniorrhaphy under general anesthesia were randomly divided into three groups. Group A received IG/IH nerve block, using 0.25% bupivacaine (1 mg/kg) immediately after induction. Group B received intravenous fentanyl (1 microgram/kg) immediately after induction. Group C received only general anesthesia as control. At postanesthetic care unit (PACU), we recorded the degree of pain/or discomfort at 5, 15, 30, 45 and 60 min using modified Hannallah's scoring system after the patient was fully awake. The degree of recovery was also evaluated using Steward's scoring system. After discharge, the parents were interrogated about the condition of child within 24 h by telephone. Follow-up items raised included vomiting, drowsiness, pain and shivering. Our results showed that children in both study groups had lower pain score than those in the control group, and in the fentanyl group children had lower pain score than in the nerve block group during the first 30 min at PACU. The recovery time was also longer in the fentanyl group. There was no significant difference among the three groups regarding the raised items over telephone interrogation. In sum, inguinal nerve block was effective for postoperative pain relief in children undergoing inguinal herniorraphy. We also suggested that small dose of intravenous fentanyl would serve as an easy, simple and effective means for relieving postinguinal herniorrhaphy pain during the first 30 min of the initial postoperative period.


[Effect of surface-active agents on Na, K-ATPase from guinea pig kidneys].
The effect of surface active agents on the activity of Na, K-ATPase and on the direct medium 18O exchange in the membrane preparations of the guinea pig kidney has been studied. The medium 18O exchange was considered as a character of the K+-dependent stage in ATPase reaction. Low concentration of all the surface active agents were shown to stimulate, and high concentrations -- to inhibit both ATPase and medium 18O exchange. The relation between medium 18O exchange and Na,K-ATPase activity was found to be equal to 1.5 +/- 0.1. The treatment of preparations by activating amounts of the surface active agents resulted in lowering this relation up to 1.0 +/- 0.09 and 1.3 +/- 0.04 for DOC and triton X-100, correspondently, due to a stronger stimulation of ATPase activity than of medium 18O exchange. With the inhibiting amounts of triton X-100 and histone H2a, this relation did not change, but it decreased in the presence of equal amounts of DOC.


Confirmation of Xp22.11 Duplication as a Germline Susceptibility Alteration in a Wilms Tumor Arising in Horseshoe Kidney.
BackgroundThere is strong evidence of a genetic contribution to Wilms tumor, such as WT1 gene variation or epigenetic changes at chromosome locus 11p15. A previous genome wide association study (GWAS) of Wilms tumor identified other significant association loci including Xp22. Case report: A 4-year-old girl developed a Wilms tumor of the left isthmus of a horseshoe kidney. Chromosomal microarray analysis (CMA) of peripheral blood showed a 563 kb copy number gain at Xp22.11 that included PRDX4 and ZFX. PRDX4 has been shown to play an active role in the tumorigenesis of malignant neoplasms in various organs. Beckwith-Wiedemann methylation analysis and WT1 sequencing were negative. Whole exome sequencing of peripheral blood revealed pathogenic variant in PMS2 gene (c.765C > A), which is consistent with Lynch syndrome. Conclusion: We report a case of Wilms tumor with germline Xp22.11 duplication which further supports this locus as germline susceptibility alteration for Wilms Tumor.


[Sebaceous carcinoma of salivary gland. Report of two cases of infrequent location].
Sebaceous carcinoma is an infrequent tumor of tardy increase, locally aggressive, potentially recurrent, with natural propensity for metastasize, both loco-regional or remote (lymphogenous or hematogenus metastases). Principal sitting are the annexed glands to ocular sense (Zeis glands and specially Meibomian's). Its origin in salivary glands is exceedingly uncommon, only those arising in the parotid have been reported. Our contribution are 2 cases which source were the sublingual gland and a minor palatine salivary gland, respectively. The perusal of the literature has been negative: no one previous case of sebaceous carcinoma could be discovered in the literature.


Effects of smoking on cure of Helicobacter pylori infection and duodenal ulcer recurrence in patients treated with clarithromycin and omeprazole.
Smoking may affect adversely the cure rate for Helicobacter pylori infection in patients treated with amoxicillin and omeprazole. Therapy with clarithromycin and omeprazole was tested for its effectiveness in the treatment of H. pylori infection in smokers and nonsmokers. Patients with verified duodenal ulcer and H. pylori infection received clarithromycin 500 mg tid, in combination with omeprazole 40 mg/ day, for 2 weeks, followed by omeprazole (20 or 40 mg daily) for 2 additional weeks according to a randomized, double-blind, multicenter design. Patients were analyzed by their smoking status for the cure of H. pylori infection, ulcer healing, and prevention of duodenal ulcer recurrence. After treatment with clarithromycin and omeprazole, H. pylori infection was cured in 71% of the smokers and in 77% of the nonsmokers (evaluated 4-6 weeks after treatment). Overall ulcer healing was 95%, and overall ulcer recurrence was 19%. For H. pylori-negative patients, ulcer recurrence was 12% in both smokers and nonsmokers. None of these values was significantly different when smokers were compared to nonsmokers. Therapy with clarithromycin and omeprazole is effective for cure of H. pylori infection in smokers and nonsmokers. Smoking has no effect on duodenal ulcer healing or duodenal ulcer recurrence for patients treated with this regimen.


Cross-Sectional Associations Between Wake-Time Movement Compositions and Mental Health in Preschool Children With and Without Motor Coordination Problems.
Movement behaviors have been found to be important correlates of health for children and may be particularly important for children with Developmental Coordination Disorder (DCD) who often experience greater mental health problems. To date, however, little research has investigated the daily movement composition of preschool children with Developmental Coordination Disorder (DCD) and/or its association with mental health. The purpose of the current study was to: (1) examine whether differences in movement compositions (i.e., sedentary time, light physical activity, moderate-to-vigorous physical activity) exist between typically developing (TD) preschool-age children and those at risk for DCD (rDCD); and (2) investigate associations between movement compositions and mental health indicators. This cross-sectional study used the baseline cohort data from the Coordination and Activity Tracking in CHildren (CATCH) study. A total of 589 preschool-age children (Mage = 4.94 ± 0.59 years; 57.4% boys) were included in this analysis, of which 288 scored at or below the 16th percentile on the Movement Assessment Battery for Children-2 and were thus classified as rDCD. Wake time movement behaviors were measured using accelerometers and parents completed the Child Behavior Checklist to assess their child's mental health (i.e., internalizing and externalizing problems). Compositional data analysis techniques were used. After adjusting for potential confounders, the results demonstrated similar movement compositions between TD and rDCD children. Among the full sample, findings revealed a significant association between sedentary time and externalizing problems, however, each of the other associations did not reach statistical significance. These results are consistent with emerging evidence demonstrating similar patterns of physical activity and sedentary time among TD children and those classified as rDCD during the preschool years. Although movement behaviors explained little variance in mental health during this period, future research should investigate when movement compositions diverge, and how these changes may impact the mental health of TD children and those classified as rDCD later in childhood.


The ArcB sensor kinase of Escherichia coli: genetic exploration of the transmembrane region.
The Arc two-component signal transduction system of Escherichia coli regulates the expression of numerous operons in response to respiratory growth conditions. Cellular redox state or proton motive force (Delta(H(+))) has been proposed to be the signal for the membrane-associated ArcB sensor kinase. This study provided evidence for a short ArcB periplasmic bridge that contains a His47. The dispensability of this amino acid, the only amino acid with a pK in the physiological range, renders the Delta(H(+)) model unlikely. Furthermore, results from substituting membrane segments of ArcB with counterparts of MalF indicate that the region does not play a stereospecific role in signal reception.