Specific immunotherapy-induced Sjögren's syndrome.
Allergen-specific immunotherapy (SIT) is a well-documented treatment for allergic rhinitis, asthma, and allergy to bee venoms. Side-effects of SIT in long-term have not been well documented yet. Herein, we report a case of Sjögren's syndrome following SIT. The patient, a 25-year-old Caucasian woman, was started on subcutaneous grass-pollen immunotherapy. The patient's autoantibodies before the SIT screening tests were negative. We determined that anti-extractable nuclear antigen (ENA) was positive (ENA = 98.4, normal range 0-25 U) on routine screening tests at 44 weeks of her treatment, and then SIT was discontinued. The patient complained of burning and itching in her eyes for 6 months. Schirmer's and salivary flow tests were positive. Although antinuclear antigen and rheumatoid factor were negative, anti-SS-A/Ro was positive. Viral hepatitis markers were negative. Minor salivary-gland biopsy was performed, which showed grade 4 sialoadenitis. The HLA type of the patient was B55 (B22), Bw6, Cw1 for class I and DR11, DR52, DQ7 (DQ3) for class II. After the immunotherapy had been stopped, there were no changes in the symptoms and laboratory findings of the patient during the 1st year of follow-up. This is the first case to be reported of Sjögren's syndrome following SIT. Patients undergoing SIT must be carefully followed up for the development of autoimmunity and an autoimmune disease.


Childhood trauma, intraindividual reaction time variability, baseline respiratory sinus arrhythmia, and perceived relapse tendency among males with substance use disorders.
Background: People with substance use disorders (SUDs) who have experienced serious childhood trauma may have executive function impairments contributing to relapse. Baseline respiratory sinus arrhythmia (RSA) reflects physiological regulation capacity, which has been found to buffer the negative effects of childhood trauma. Baseline RSA has also been found to be related to intraindividual reaction time variability (IIRTV), which is an index of executive function.Objectives: The present study examined the relationship between childhood trauma and perceived relapse tendency, the mediation role of IIRTV, and the moderation role of baseline RSA.Methods: The study is cross-sectional, a total of 110 males with SUDs participated (Mage = 46.45 years, SD = 11.24). The Childhood Trauma Questionnaire and Intention to Rehabilitate Questionnaire were used to assess childhood trauma and perceived relapse tendency, the two-choice oddball task was used to measure IIRTV, and electrocardiogram (ECG) data were collected to obtain baseline RSA.Results: IIRTV mediated the relationship between childhood trauma and perceived relapse tendency (Coeff = 0.049, Boot CI [0.004, 0.121]); interaction of childhood trauma and Baseline RSA negatively influences IIRTV (β = -0.208, t = -2.022, p = .046).Conclusion: The results suggest that males with SUDs who have experienced serious childhood trauma may have executive function impairments that contribute to relapse, and baseline RSA may buffer the negative effect of childhood trauma on IIRTV. These findings suggest that the prevention of relapse through cognitive enhancement can be complemented by the enhancement of physiological regulation.


Plasma magnesium in adult Nigerian patients with epilepsy.
The objective of this study was to determine the relationship between plasma magnesium levels and epilepsy. The study was carried out at the Lagos University Teaching Hospital. Plasma magnesium was estimated using the calmigite dye colorimetric method in 45 adults with epilepsy and 35 healthy controls. Plasma concentrations of calcium, phosphorus and albumin were also estimated. The mean plasma magnesium in the patients was 0.98 mm0l/L (0.05) while that in the controls was 1.15 mmol/L (0.28). The mean plasma magnesium in the epileptics was significantly lower than that obtained in the controls (p < 0.001). Age of onset of seizures, seizure frequency and duration of treatment did not influence the plasma magnesium levels. Low plasma magnesium is associated with epilepsy, further studies may determine the influence of anti-epileptic drug therapy on plasma magnesium levels. magnesium, seizures, Nigeria.


Simultaneous Hoffmann reflex measurements in multiple muscles around the ankle.
Measurement of the Hoffmann reflex (H-reflex) provides an estimate of alpha motoneuron activity in the target motoneuron (MN) pool. The H-reflex has been assessed for a wide variety of reasons in neuroscience research. However, the majority of protocols have focused on the assessment of only one muscle and its corresponding motoneuron pool at any instant. Previously established protocols do not simultaneously assess reflex activity in multiple muscles elicited from a single stimulation. This new protocol allows for assessment of alpha motoneuron activity in three muscles around the ankle joint from a single stimulus to the sciatic nerve. To elicit the responses, the sciatic nerve was stimulated just prior to its bifurcation into the tibial and common peroneal nerves in the popliteal fossa. Electromyographic recording electrodes were placed on the tibialis anterior, peroneal longus, and soleus muscles. The 1-ms square wave pulse was delivered every 15 s during the recruitment curve mapping. The maximum H reflex and M waves were measured in each muscle and their ratios calculated. The measurement of these ratios simultaneously allows for assessment of the cumulative alpha motoneuron activity about the ankle at a given point in time.


Modality-Specific Circuits for Skylight Orientation in the Fly Visual System.
In the fly optic lobe, ∼800 highly stereotypical columnar microcircuits are arranged retinotopically to process visual information. Differences in cellular composition and synaptic connectivity within functionally specialized columns remain largely unknown. Here, we describe the cellular and synaptic architecture in medulla columns located downstream of photoreceptors in the dorsal rim area (DRA), where linearly polarized skylight is detected for guiding orientation responses. We show that only in DRA medulla columns both R7 and R8 photoreceptors target to the bona fide R7 target layer where they form connections with previously uncharacterized, modality-specific Dm neurons: two morphologically distinct DRA-specific cell types (termed Dm-DRA1 and Dm-DRA2) stratify in separate sublayers and exclusively contact polarization-sensitive DRA inputs, while avoiding overlaps with color-sensitive Dm8 cells. Using the activity-dependent GRASP and trans-Tango techniques, we confirm that DRA R7 cells are synaptically connected to Dm-DRA1, whereas DRA R8 form synapses with Dm-DRA2. Finally, using live imaging of ingrowing pupal photoreceptor axons, we show that DRA R7 and R8 termini reach layer M6 sequentially, thus separating the establishment of different synaptic connectivity in time. We propose that a duplication of R7→Dm circuitry in DRA ommatidia serves as an ideal adaptation for detecting linearly polarized skylight using orthogonal e-vector analyzers.


Understanding the influence of codon translation rates on cotranslational protein folding.
Protein domains can fold into stable tertiary structures while they are synthesized by the ribosome in a process known as cotranslational folding. If a protein does not fold cotranslationally, however, it has the opportunity to do so post-translationally, that is, after the nascent chain has been fully synthesized and released from the ribosome. The rate at which a ribosome adds an amino acid encoded by a particular codon to the elongating nascent chain can vary significantly and is called the codon translation rate. Recent experiments have illustrated the profound impact that codon translation rates can have on the cotranslational folding process and the acquisition of function by nascent proteins. Synonymous codon mutations in an mRNA molecule change the chemical identity of a codon and its translation rate without changing the sequence of the synthesized protein. This change in codon translation rate can, however, cause a nascent protein to malfunction as a result of cotranslational misfolding. In some situations, such dysfunction can have profound implications; for example, it can alter the substrate specificity of an ABC transporter protein, resulting in patients who are nonresponsive to chemotherapy treatment. Thus, codon translation rates are crucial in coordinating protein folding in a cellular environment and can affect downstream cellular processes that depend on the proper functioning of newly synthesized proteins. As the importance of codon translation rates makes clear, a necessary aspect of fully understanding cotranslational folding lies in considering the kinetics of the process in addition to its thermodynamics. In this Account, we examine the contributions that have been made to elucidating the mechanisms of cotranslational folding by using the theoretical and computational tools of chemical kinetics, molecular simulations, and systems biology. These efforts have extended our ability to understand, model, and predict the influence of codon translation rates on cotranslational protein folding and misfolding. The application of such approaches to this important problem is creating a framework for making quantitative predictions of the impact of synonymous codon substitutions on cotranslational folding that has led to a novel hypothesis regarding the role of fast-translating codons in coordinating cotranslational folding. In addition, it is providing new insights into proteome-wide cotranslational folding behavior and making it possible to identify potential molecular mechanisms by which molecular chaperones can influence such behavior during protein synthesis. As we discuss in this Account, bringing together these theoretical developments with experimental approaches is increasingly helping answer fundamental questions about the nature of nascent protein folding on the ribosome.


Seeing more clearly through the fog of encephalopathy.
Patients with acute confusional states (often referred to as encephalopathy or delirium) pose diagnostic and management challenges for treating physicians. Encephalopathy is associated with a high morbidity and mortality rate, and the diagnosis rests on clinical grounds but may also be supported by the finding of electroencephalographic (EEG) evidence for diffuse cerebral dysfunction. The myriad cerebral transmitter and metabolic disruptions are generated by systemic organ system failures, principal among which are those of the liver, kidneys, lungs, heart, and endocrine system, along with the effects of exogenous toxins and medications. In most cases, several of these organ failures together contribute to the confusional state, frequently in the context of a diffuse cerebral atrophy that affects the aging brain. This special issue of the Journal of Clinical Neurophysiology is dedicated to exploring the electrophysiology of these conditions. It reviews the pathophysiology, psychiatric manifestations, clinical and imaging correlations of the many causes and types of encephalopathy. A literature review of the EEG abnormalities in the various types of encephalopathy provides an overview that ranges from paraneoplastic causes, through organ system failures, postcardiorespiratory arrest, to postoperative delirium. The issue is supplemented by tables of relevant clinical correlations, graphs, Venn diagrams, and the use of mathematical modeling used to explain how defects in the neuronal interplay might generate the EEG patterns seen in encephalopathy. We hope that this assembly will act as a springboard for further discussion and investigation into the EEG underpinnings, clinical correlations, diagnosis. and prognostication of these common and morbid disturbances of brain function.


N-Terminal dual protein functionalization by strain-promoted alkyne-nitrone cycloaddition.
Strain-promoted alkyne-nitrone cycloadditon (SPANC) was optimized as a versatile strategy for dual functionalization of peptides and proteins. The usefulness of the dual labeling protocol is first exemplified by the simultaneous introduction of a chloroquine and a stearyl moiety, two endosomal escape-improving functional groups, into the cell-penetrating peptide hLF (human lactoferrin). Additionally, we demonstrate that dual labeling of proteins is feasible by combining metal-free and copper-catalyzed click chemistry. First, SPANC is applied to enhanced green fluorescent protein to introduce both biotin and a terminal alkyne. The terminal acetylene then serves as a convenient anchor point for the CuAAC reaction with azido-containing fluorescein, thereby demonstrating the potential of combined SPANC and CuAAC for the straightforward, dual functionalization of proteins.


Congruent mammalian trees from mitochondrial and nuclear genes using Bayesian methods.
Analyses of mitochondrial and nuclear gene sequences have often produced different mammalian tree topologies, undermining confidence in the merit of molecular approaches with respect to "traditional" morphological classification. The recent sequencing of the complete mitochondrial genomes of two additional rodents (Spalax judaei and Jaculus jaculus) and one lagomorph (Ochotona princeps) has prompted us to reinvestigate the issue. Using Bayesian phylogenetics, we found phylogenetic relationships between mammalian species highly congruent with previous results based on nuclear genes. Our results show the existence of four primary lineages of placental mammals: Xenarthra, Afrotheria, Laurasiatheria, and Euarchontoglires. Relationships between and within these lineages strongly suggest that the gene trees may also be congruent with the underlying species phylogeny.


Precision-milled simulated curved root canals in bovine dentine for the assessment of chemo-mechanical root canal preparation.
The aim was to develop a standardized curved root canal model in bovine dentine and to assess whether that natural substrate would behave differently from the resin in standard plastic training blocks when prepared chemo-mechanically. The impact of substrate microhardness on simulated canal transportation was considered. High-precision computer numerical control (CNC) milling was used to recreate a simulated root canal from a resin training block (Endo Training Bloc J-Shape, size 15) in longitudinally sectioned, dis- and re-assembled bovine incisor roots. Optical overlays obtained from 10 resin blocks were used to identify an average canal and program the CNC milling apparatus accordingly. Resin and dentine microhardness were measured. Simulated root canals in resin training blocks and their bovine counterparts were then instrumented at 37°C using Reciproc R25 instruments (VDW) with water or 17% EDTA (n = 10). Open-access image processing software was used to superimpose and analyse pre- and postoperative images obtained with a digital microscope. Centering ratios were averaged to indicate canal transportation. The effects of substrate and irrigant on canal transportation were assessed by two-way anova. Superimposed images showed that resin blocks under investigation varied considerably in terms of simulated canal length and curvature, whilst the milled canals were highly similar. The microhardness of dentine was more than three times higher than that of the resin. Conversely, canal transportation was considerably greater in dentine compared to resin, and in dentine had a tendency to be increased by EDTA. There was a strong effect of substrate on canal transportation (p < .001), no overall effect of irrigant, and a marginally significant interaction between irrigant and substrate (p = .077). CNC milling allows to create standardized simulated curved root canals in bovine dentine. These models may be useful to test and compare materials and concepts of chemo-mechanical root canal instrumentation. Microhardness is a bulk feature that does not predict the response to chemo-mechanical instrumentation of a composite material such as dentine.


Effects of Panax ginseng supplementation on muscle damage and inflammation after uphill treadmill running in humans.
The purpose of this investigation was to determine whether Panax ginseng extract intake would influence exercise-induced muscle damage and inflammation responses. Eighteen male college students were randomly assigned to either an RG intake group (RG, n = 9) or a placebo group (P, n = 9). All subjects performed a high-intensity uphill treadmill running task (two rounds of 45 min at 10 km/h speed with a 15 degree uphill slope separated by 5 min of rest). The RG group ingested 20 g/day of Korean red ginseng extract (mixed with 200 ml of water) three times/day for seven days prior to performing the uphill treadmill exercise test and for four days after the treadmill test, while the P group ingested 200 ml of water containing Agastachis Herba on the same schedule. Plasma creatine kinase activity (CK) and interlukin-6 (IL-6) levels were measured at pre-exercise and 24, 48, 72, and 96 h post-exercise; the IL-6 level was also measured at 1 and 2 h post-exercise. To evaluate insulin sensitivity, the oral glucose tolerance test (OGTT) was performed 24 h post-exercise. Plasma CK level in RG was significantly lower than that in P 72 h post-exercise (p < 0.05), and IL-6 level was significantly decreased in RG during the 2 h and 3 h recovery period compared to that of P (p < 0.05). Plasma glucose and insulin responses in RG were significantly reduced compared to those of P (p < 0.05). The results of this study suggest that RG supplementation could reduce exercise-induced muscle damage and inflammatory responses, resulting in improvements in insulin sensitivity.


A comparison of neutral and charged species of one- and two-dimensional models of graphene nanoribbons using multireference theory.
This study examines the dependence of the polyradical character of charged quasi-linear n-acenes and two-dimensional periacenes used as models for graphene nanoribbons in comparison to the corresponding neutral compounds. For this purpose, high-level ab initio calculations have been performed using the multireference averaged quadratic coupled cluster theory. Vertical ionization energies and electron affinities have been computed. Systematic tests show that the dependence on chain length of these quantities can be obtained from a consideration of the π system only and that remaining contributions coming from the σ orbitals or extended basis sets remain fairly constant. Using best estimate values, the experimental values for the ionization energy of the acene series can be reproduced within 0.1 eV and the experimental electron affinities within 0.4 V. The analysis of the natural orbital occupations and related unpaired electron densities shows that the ionic species exhibit a significant decrease in polyradical character and thus an increased chemical stability as compared to the neutral state.


Biological therapies for atrial fibrillation.
Atrial fibrillation is a prominent cause of morbidity and mortality in developed countries. Current treatment strategies center on controlling heart rate while allowing fibrillation to persist or targeting fibrillation primarily and attempting to maintain sinus rhythm. Pharmacological therapies are largely successful for rate control, although mild toxicities are common. Rhythm control strategies are often unsuccessful, leaving patients in atrial fibrillation despite attempts to maintain sinus rhythm. This review will discuss novel biological strategies that are currently under development and may eventually have impact on the management of atrial fibrillation.


Postoperative prophylactic antibiotics and surgical site infection rates in breast surgery patients.
A single preoperative prophylactic dose of an intravenous antibiotic with antistaphylococcal activity is standard of care for breast and axillary surgical procedures. Some surgeons also prescribe postoperative prophylaxis for all patients with drains to prevent infection despite its lack of proven efficacy. A retrospective chart review of patients with breast and/or axillary surgical procedures between July 2004 and June 2006 were included. Data were collected on patient demographics, procedure types, and use of prophylactic antibiotics. Surgical site infection (SSI) was defined by means of Centers for Disease Control and Prevention criteria, including patients meeting the physician diagnosis criterion if an antibiotic was prescribed for a clinical diagnosis of cellulitis. chi(2) and Fisher's exact tests were used to compare SSI rates. Three hundred fifty-three patients with 436 surgical sites who received either preoperative or both pre- and postoperative antibiotic were analyzed. Overall, the SSI rate was 7.8% (34 of 436 surgical sites). Eighty-five patients (24%) with 127 surgical sites were provided both preoperative and postoperative prophylactic antibiotics. The SSI rates did not differ statistically (P = .67) for the groups that did (95% confidence interval, 4.8-15.0; 11 of 127 surgical sites, 8.7%) and did not receive postoperative antibiotic prophylaxis (95% confidence interval, 5.0-11.0; 23 of 309, 7.4%). Although the overall number of patients who developed SSI was relatively small, there was no reduction in the SSI rate among those who received postoperative antibiotic prophylaxis. Because of the potential adverse events associated with antibiotic use, further evaluation of this practice is required.


Cell Adhesion on Surface-Functionalized Magnesium.
The biocompatibility of commercially pure magnesium-based (cp Mg) biodegradable implants is compromised of strong hydrogen evolution and surface alkalization due to high initial corrosion rates of cp Mg in the physiological environment. To mitigate this problem, the addition of corrosion-retarding alloying elements or coating of implant surfaces has been suggested. In the following work, we explored the effect of organic coatings on long-term cell growth. cp Mg was coated with aminopropyltriehtoxysilane + vitamin C (AV), carbonyldiimidazole (CDI), or stearic acid (SA). All three coatings have been previously suggested to reduce initial corrosion and to enhance protein adsorption and hence cell adhesion on magnesium surfaces. Endothelial cells (DH1+/+) and osteosarcoma cells (MG63) were cultured on coated samples for up to 20 days. To quantify Mg corrosion, electrochemical impedance spectroscopy (EIS) was measured after 1, 3, and 5 days of cell culture. We also investigated the speed of initial cell spreading after seeding using fluorescently labeled fibroblasts (NIH/3T3). Hydrogen evolution after contact with cell culture medium was markedly decreased on AV- and SA-coated Mg compared to uncoated Mg. These coatings also showed improved cell adhesion and spreading after 24 h of culture comparable to tissue-treated plastic surfaces. On AV-coated cp Mg, a confluent layer of endothelial cells formed after 5 days and remained intact for up to 20 days. Together, these data demonstrate that surface coating with AV is a viable strategy for improving long-term biocompatibility of cp Mg-based implants. EIS measurements confirmed that the presence of a confluent cell layer increased the corrosion resistance.


The world population explosion: causes, backgrounds and -projections for the future.
At the beginning of the nineteenth century, the total world population crossed the threshold of 1 billion people for the first time in the history of the homo sapiens sapiens. Since then, growth rates have been increasing -exponentially, reaching staggeringly high peaks in the 20th century and slowing down a bit thereafter. Total world population reached 7 billion just after 2010 and is expected to count 9 billion by 2045. This paper first charts the differences in population growth between the world regions. Next, the mechanisms behind unprecedented population growth are explained and plausible scenarios for future developments are discussed. Crucial for the long term trend will be the rate of decline of the number of births per woman, called total fertility. Improvements in education, reproductive health and child survival will be needed to speed up the decline of total fertility, particularly in Africa. But in all scenarios, world population will continue to grow for some time due to population momentum. Finally, the paper outlines the debate about the consequences of the population explosion, involving poverty and food security, the impact on the natural environment, and migration flows. Fertility, family planning, world population, population growth, demographic transition, urbanization, population momentum, population projections.


Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs.
People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic.


Motivation to change among residential treatment patients with an eating disorder: assessment of the multidimensionality of motivation and its relation to treatment outcome.
To examine the multidimensional nature of motivation to change in an adolescent sample in residential eating disorder (ED) treatment and relate it to outcome. To determine whether different dimensions of motivation (benefits, burdens, and functional avoidance) are differentially associated with symptom severity and outcome, we assessed eating pathology and motivation to change in consecutively admitted female patients (n = 67) with AN, BN, and EDNOS in a residential ED program with the Eating Disorder Examination Questionnaire (EDE-Q) and the Decisional Balance Scale (DB). Pretreatment DB benefits and functional avoidance subscales were correlated with ED and comorbid psychopathology. Admission to discharge change in DB benefits-but not other measured dimensions of motivation was significantly associated with post-treatment EDE-Q global scores. Our findings support that motivation to change is a multidimensional construct among ED patients. A reduction in perceived benefits of illness is associated with less severe post-treatment eating pathology.


Evaluation of variables influencing success and complication rates in canine total hip replacement: results from the British Veterinary Orthopaedic Association Canine Hip Registry (collation of data: 2010-2012).
The objective of this study was to assess the variables associated with complications of total hip replacement (THR) and report owner-assessed outcomes. Entries into the British Veterinary Orthopaedic Association-Canine Hip Registry (BVOA-CHR) between September 2011 and December 2012 were reviewed separately and in conjunction with previous data (January 2010-August 2011). An outcomes assessment questionnaire was used to collect data from owners. Incidences of surgeon-reported and owner-reported complications were 8.2 per cent and 4.3 per cent, respectively. THR using the BioMedtrix BFX cup/stem prosthesis had a greater incidence of complications compared with THR using the BioMedtrix CFX cup/stem prosthesis (P=0.002); complications were 4.48 times more likely when using the BioMedtrix BFX cup/stem prosthesis versus the BioMedtrix CFX cup/stem prosthesis. THR using the BioMedtrix BFX cup/stem prosthesis had a higher incidence of complications compared with THR using a hybrid prosthesis (BioMedtrix BFX cup/CFX stem, BioMedtrix CFX cup/BFX stem) (P=0.046); complications were 2.85 times more likely when using the BioMedtrix BFX cup/stem prosthesis versus a hybrid prosthesis. In 95 per cent of cases, owner satisfaction with the outcome of THR was 'very good' or 'good'. Complication rates from the BVOA-CHR are similar to previous studies. The data suggest that prosthesis type is associated with complication rate, with BioMedtrix BFX (circa 2012) having a high short-term complication rate.


[Effect of the dietary fiber content in nutrition on various stool parameters, in man].
Ten subjects were studied for two periods of six days each during which they were fed respectively a regular diet (control diet) followed by a fiber-supplemented diet (experimental diet). The experimental diet consisted of a regular diet in which some foods where substracted and some bran biscuits, specially produced for this investigation, were added. The experimental diet produced a significant increase in daily stool weight, dried stool weight, water contents of the stools and intestinal transit time. The study has shown that special bran biscuits is effective in promoting a increase in bowel transit time, and therefore should be submitted to therapeutic trial in patients with constipation.


How should support for hospital staff during health shocks be improved? A discussion from Japan's experience during the COVID-19 pandemic.
Human resources for health are at the center of healthcare service delivery and play an important role in ensuring the resilience of health systems. Utilizing the results from a case study examining hospital resilience during COVID-19, this article draws on the experience of individual hospital staff during the first and second waves of the pandemic, briefly describes government responses to support human resources for health during the early stages of the pandemic, and argues the importance of constructive discussions about strategies to create an enabling work environment for healthcare providers, both clinical and non-clinical, during future health shocks.


Exciton condensation driving the periodic lattice distortion of 1T-TiSe2.
We address the lattice deformation of 1T-TiSe2 within the exciton condensate phase. We show that, at low temperature, condensed excitons influence the lattice through electron-phonon interaction. It is found that at zero temperature, in the exciton condensate phase of 1T-TiSe2, this exciton condensate exerts a force on the lattice generating ionic displacements comparable in amplitude to what is measured in experiment. This is thus the first quantitative estimation of the amplitude of the periodic lattice distortion observed in 1T-TiSe2 as a consequence of the exciton condensate phase.


Structural and energetic responses to cavity-creating mutations in hydrophobic cores: observation of a buried water molecule and the hydrophilic nature of such hydrophobic cavities.
We have solved the 2.0-A resolution crystal structures of four cavity-creating Ile/Leu-->Ala mutations in the hydrophobic core of barnase and compare and contrast the structural responses to mutation with those found for Leu-->Ala mutations in T4 lysozyme. First, there are rearrangements of structure of barnase that cause the cavities to collapse partly, and there is an approximately linear relationship between the changes in stability and the volume of the cavity similar to that found for the mutants of T4 lysozyme. Second, although it is currently accepted that hydrophobic cavities formed on the mutation of large hydrophobic side chains to smaller ones are not occupied by water molecules, we found a buried water molecule in the crystal structure of the barnase mutant Ile76-->Ala. A single hydrogen bond is formed between the water molecule and a polar atom, the carbonyl oxygen of Phe7, in the hydrophobic cavity that is formed on mutation. A survey of hydrophobic cavities produced by similar mutations in different proteins reveals that they all contain a proportion of polar atoms in their linings. The availability of such polar sites has implications for understanding folding pathways because a solvated core is presumed present in the transition state for folding and unfolding. Notably, the hydrogen bond between the cavity-water and the carbonyl group of Phe7 is also a marked early feature of very recent molecular dynamics simulations of barnase denaturation [Caflisch, A., & Karplus, M. (1995) J. Mol. Biol. 252, 672-708]. It is possible that cavities engineered into the hydrophobic cores of other proteins may contain water molecules, even though they cannot be detected by crystallographic analysis.


Structure-activity relationships of beta-amino acid-containing integrin antagonists.
Interest in the development of specific antagonists of the beta3 family of integrins (platelet alphaIIbbeta3 and the vitronectin receptor alphavbeta3) has been principally driven by efforts to design more potent antithrombotic agents than either aspirin or the thienopyridine-type ADP receptor modulators. The platelet fibrinogen receptor (aIIbb3) and the vitronectin receptor (alphavbeta3) bind the RGD tripeptide sequence found within adhesive ligands. Because of this, many approaches to antagonists of beta3 receptors have utilized an RGD mimetic to identify antagonists. Integrin antagonists of many structurally diverse classes have been discovered. One of the larger beta3 integrin antagonist classes employs beta-amino acids to mimic the aspartate residue of the RGD mimetic. Structure-activity investigations have revealed the potent activity of agents which have substituents appended to both the alpha and beta position of the beta-amino acid units of these antagonists. Several clinical candidates targeting platelet aIIbb3 contain these beta-amino acid units and are currently being evaluated clinically.


Resolving the phylogeny of Thladiantha (Cucurbitaceae) with three different target capture pipelines.
Despite recent advances, reliable tools to simultaneously handle different types of sequencing data (e.g., target capture, genome skimming) for phylogenomics are still scarce. Here, we evaluate the performance of the recently developed pipeline Captus in comparison with the well-known target capture pipelines HybPiper and SECAPR. As test data, we analyzed newly generated sequences for the genus Thladiantha (Cucurbitaceae) for which no well-resolved phylogeny estimate has been available so far, as well as simulated reads derived from the genome of Arabidopsis thaliana. Our pipeline comparisons are based on (1) the time needed for data assembly and locus extraction, (2) locus recovery per sample, (3) the number of informative sites in nucleotide alignments, and (4) the topology of the nuclear and plastid phylogenies. Additionally, the simulated reads derived from the genome of Arabidopsis thaliana were used to evaluate the accuracy and completeness of the recovered loci. In terms of computation time, locus recovery per sample, and informative sites, Captus outperforms HybPiper and SECAPR. The resulting topologies of Captus and SECAPR are identical for coalescent trees but differ when trees are inferred from concatenated alignments. The HybPiper phylogeny is similar to Captus in both methods. The nuclear genes recover a deep split of Thladiantha in two clades, but this is not supported by the plastid data. Captus is the best choice among the three pipelines in terms of computation time and locus recovery. Even though there is no significant topological difference between the Thladiantha species trees produced by the three pipelines, Captus yields a higher number of gene trees in agreement with the topology of the species tree (i.e., fewer genes in conflict with the species tree topology).


Confocal-based fluorescence fluctuation spectroscopy with a SPAD array detector.
The combination of confocal laser-scanning microscopy (CLSM) and fluorescence fluctuation spectroscopy (FFS) is a powerful tool in studying fast, sub-resolution biomolecular processes in living cells. A detector array can further enhance CLSM-based FFS techniques, as it allows the simultaneous acquisition of several samples-essentially images-of the CLSM detection volume. However, the detector arrays that have previously been proposed for this purpose require tedious data corrections and preclude the combination of FFS with single-photon techniques, such as fluorescence lifetime imaging. Here, we solve these limitations by integrating a novel single-photon-avalanche-diode (SPAD) array detector in a CLSM system. We validate this new implementation on a series of FFS analyses: spot-variation fluorescence correlation spectroscopy, pair-correlation function analysis, and image-derived mean squared displacement analysis. We predict that the unique combination of spatial and temporal information provided by our detector will make the proposed architecture the method of choice for CLSM-based FFS.


Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context.
Chemoprotective phytochemicals exhibit multiple activities and interact with several cellular receptors, including the aryl hydrocarbon (Ah) receptor (AhR). In this study we investigated the AhR agonist/antagonist activities of the following flavonoids: chrysin, phloretin, kaempferol, galangin, naringenin, genistein, quercetin, myricetin, luteolin, baicalein, daidzein, apigenin, and diosmin. We also investigated the AhR-dependent activities of cantharidin and emodin (in herbal extracts) in Ah-responsive MCF-7 human breast cells, HepG2 human liver cancer cells, and mouse Hepa-1 cells transiently or stably transfected with plasmids expressing a luciferase reporter gene linked to multiple copies of a consensus dioxin-responsive element. The AhR agonist activities of the compounds (1 and 10 micro M) were as high as 25% of the maximal response induced by 5 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and their potencies were dependent on cell context. Galangin, genistein, daidzein, and diosmin were active only in Hepa-1 cells, and cantharidin induced activity only in human HepG2 and MCF-7 cells. Western blot analysis confirmed that baicalein and emodin also induced CYP1A1 protein in the human cancer cell lines. The AhR antagonist activities of four compounds inactive as agonists in MCF-7 and HepG2 cells (kaempferol, quercetin, myricetin, and luteolin) were also investigated. Luteolin was an AhR antagonist in both cell lines, and the inhibitory effects of the other compound were dependent on cell context. These data suggest that dietary phytochemicals exhibit substantial cell context-dependent AhR agonist as well as antagonist activities. Moreover, because phytochemicals and other AhR-active compounds in food are present in the diet at relatively high concentrations, risk assessment of dietary toxic equivalents of TCDD and related compounds should also take into account AhR agonist/antagonist activities of phytochemicals.


Differential distribution of glycine transporters in Müller cells and neurons in amphibian retinas.
Amphibian retinas are commonly used for electrophysiological studies on neural function and transduction because they share the same general properties as higher vertebrate retinas. Glycinergic synapses have been well described in amphibian retinas. However, the role of glycine transporters in the synapses is largely unknown. We studied the distribution and function of glycine transporters in the retinas from tiger salamanders, mudpuppies, and leopard frogs by immunofluorescence labeling and whole-cell recording methods. Our results indicated that GlyT1- and GlyT2-like transporters were present in Müller cells and neurons, respectively. GlyT1 labeling was present in Müller glial cells and co-localized with Glial fibrillary acidic protein (GFAP), a Müller cell marker, whereas the GlyT2 immunoreactivity was present in the somas of amacrine cells (ACs) and processes in the inner plexiform layer (IPL) and the outer plexiform layer (OPL). Because the axon processes of glycinergic interplexiform cells (IPCs) are the only source of glycine input in the OPL, GlyT2 staining revealed a spatial pattern of the axon processes of IPCs in the OPL. The function of GlyT2 in the IPCs was studied in tiger salamander retinal horizontal cells (HCs) by whole-cell gramicidin perforated recording. The results demonstrated that inhibition of GlyT2 by a specific inhibitor, amoxapine, increased a tonic glycine input to HCs. Thus, the GlyT2 transporter is responsible for uptake of synaptic glycine in the outer retina. We also compared the distribution of glycine transporters in other amphibian species: salamander, mudpuppy, and frog. The results are consistent with the general pattern that GlyT1-like transporters are present in Müller cells and GlyT2-like transporters in neurons in amphibian retinas.


A comparative investigation of biochemical and histopathological effects of thiamine and thiamine pyrophosphate on ischemia-reperfusion induced oxidative damage in rat ovarian tissue.
In this study, the biochemical and histopathological effects of thiamine and thiamine pyrophosphate on ischemia-reperfusion induced oxidative damage in rat ovarian tissue were investigated. Animals were divided into four groups of six rat each, ovarian ischemia-reperfusion (IR), 25 mg/kg thiamine + ovarian ischemia-reperfusion (TIR), 25 mg/kg thiamine pyrophosphate + ovarian ischemia-reperfusion (TPIR) and Sham group (SG). The results of the biochemical experiments have shown that the rat ovarian tissue with thiamine treatment, the level of MDA, GSH and the 8-hydroxyguanine are almost the same as the IR group; while in the group with thiamine pyrophosphate treatment, the level of MDA, GSH and the 8-hydroxyguanine are almost the same as the SG. Ovarian tissue of rats in the IR group were congested and dilated vessels, edema, hemorrhage, necrotic and apoptotic cells. In this group, the migration and the adhesion of the polymorphonuclear leucocytes to the endothelium were observed. Both ovaries in TPIR group, there was no difference according to the SG. Histopathology of ovarian tissues in the TIR group was almost the same with the IR group. Our results indicate that thiamine pyrophosphate significantly prevents the ischemia-reperfusion induced oxidative damage in ovarian tissue, whereas thiamine has no effect. In conclusion, we have found that thiamine pyrophosphate prevents oxidative damage due to ischemia-reperfusion injury, whereas thiamine does not have this effect. Furthermore, we have confirmed that the results of our biochemical analyses are in concordance with the histopathological findings.


Towards a model of back pain. The 3 circles of pain.
A new model for back pain is introduced. Three major groups (or ''circles'') of pain are described for the use of clinicians. The 1(st) circle is comprised of patients with pain from genuine spinal (mainly discs or facets) origin. The main feature identifying this group is the organic pattern of pain, a concept which is described and discussed, and which is based on the history, the clinical signs, imaging tests and response to treatments. The 2(nd)circle consists in patients with diffuse and permanent back pain, without any organic pattern. The pain, presumed to be not spinal in origin, is attributed to a dysfunction in the pain pathways. The 3(rd) circle is comprised of patients with clear psychosocial risk factors and no evidence for a spinal origin of their pain. This model applies for lumbar or cervical pain, with or without radiculopathy. Classifying a given patient in one of the 3 circles is relatively easy. It should allow an easier management of the back pain patients.


Synaptotagmin I-DeltaC2B. A novel synaptotagmin isoform with a single C2 domain in the bovine adrenal medulla.
Synaptotagmin I is a 65 kDa type 1 membrane glycoprotein found in secretory organelles that plays a key role in regulated exocytosis. We have characterised two forms (long and short) of synaptotagmin I that are present in the bovine adrenal medulla. The long form is a type I integral membrane protein which has two cytoplasmic C2 domains and corresponds to the previously characterised full-length synaptotagmin I isoform. The short-form synaptotagmin I-DeltaC2B has the same structure in the lumenal and transmembrane sequences, but synaptotagmin I-DeltaC2B is truncated such that it only has a single cytoplasmic C2 domain. Analysis of synaptotagmin I-DeltaC2B expression indicates that synaptotagmin I-DeltaC2B is preferentially expressed in the bovine adrenal medulla. However, it is absent from the dense core chromaffin granules. Furthermore, when expressed in the rat pheochromocytoma cell line PC12 bovine synaptotagmin I-DeltaC2B is largely absent from dense core granules and synaptic-like microvesicles. Instead, indirect immunofluorescence microscopy reveals the intracellular location of synaptotagmin I-DeltaC2B to be the plasma membrane.


Positive direct antiglobulin tests and heteroimmune hemolysis in patients with severe aplastic anemia and pure red cell anemia treated with antilymphocytic globulin.
Forty-six patients with severe aplastic anemia (SAA), 1 with adult pure red cell aplasia (PRCA), 1 with congenital hypoplastic anemia (Diamond-Blackfan) and 1 with severe polymyositis were treated with intravenous antilymphocyte globulins (ALG) of different sources (2 of equine and 1 of rabbit origin). In all patients, direct and indirect antiglobulin tests (DAT and IAT) were performed, and in all patients treated with one type of equine ALG, positive DATs were found in Rh0(D)-positive patients, while the serum of Rh0(D)-negative patients treated with the same ALG reacted in vitro with Rh0(D)-positive erythrocytes. The antibody was eluted and shown to be of equine origin. Two patients suffered from frank heteroimmune hemolytic anemia. Since October 1984, the ALG of this particular source has not displayed any overt anti-erythrocyte activity any more. However, all clinicians treating patients with this type of immune immunosuppression should know that ALG may retain human erythrocyte (presumably anti-LW) activity.


Population, community, and public health: measuring the benefits.
Population, community, and public health notions are addressed separately in the Patient Protection and Affordable Care Act (ACA), have different foci and stakeholders, build on different frameworks to achieve their aims, and apply different measures to determine the long-term impact of interventions. This paper attempts to clarify each concept and proposes a method of evaluating each of these sets of health-related activities based on the benefits that accrue to the respective stakeholders. In addition to indicating how to affect change and improvements in health, the ecological model of health also provides insight into how the benefits from health-related activities may or may not flow back to the entities sponsoring health interventions. By clearly defining each of the concepts and examining the methods and metrics being used to select activities and measure benefits, a valuation model is developed that measures the financial impact on the targeted population as well as the sponsoring institution. Defining, measuring, and evaluating are important to bring clarity to how individual organizations can contribute to the overall health of the population, as well as the limits of any single organization in doing so. Collective and upstream action will be required to improve the population's health, but identifying and justifying the role of each participating organization is a challenge that still lacks an overarching vision that can be explained and measured to the satisfaction of all stakeholders. VALUE: Decision makers must justify how resources are committed in an era of scarcity and limited financial means. Moreover, methods must be in place to measure the impact of potential collaborations. The proposed valuation framework lays out the natural incentives, the responses to those incentives, and how to select initiatives that maximize value from the perspective of the various stakeholders.


Real-time noninvasive estimation of intrapleural pressure in mechanically ventilated patients: a feasibility study.
A method for real-time noninvasive estimation of intrapleural pressure in mechanically ventilated patients is proposed. The method employs a simple first-order lung mechanics model that is fitted in real-time to flow and pressure signals acquired non-invasively at the opening of the patient airways, in order to estimate lung resistance (RL), lung compliance (CL) and intrapleural pressure (Ppl) continuously in time. Estimation is achieved by minimizing the sum of squared residuals between measured and model predicted airway pressure using a modified Recursive Least Squares (RLS) approach. Particularly, two different RLS algorithms, namely the conventional RLS with Exponential Forgetting (EF-RLS) and the RLS with Vector-type Forgetting Factor (VFF-RLS), are considered in this study and their performances are first evaluated using simulated data. Simulations suggest that the conventional EF-RLS algorithm is not suitable for our purposes, whereas the VFF-RLS method provides satisfactory results. The potential of the VFF-RLS based method is then proved on experimental data collected from a mechanically ventilated pig. Results show that the method provides continuous estimated lung resistance and compliance in normal physiological ranges and pleural pressure in good agreement with invasive esophageal pressure measurements.


The cell biology of the cardiac interstitium.
The cardiac interstitium represents a system of diverse extracellular matrix (ECM) components organized into a complex, three-dimensional network that surrounds the cellular components of the heart (Borg and Caulfield 1981, Weber et al. 1994, Comper 1995). The interaction of the cellular components with the interstitium is dynamic and occurs in response to physiological signals during development, normal homeostasis, and disease (Borg and Caulfield 1981, Weber et al. 1994). Both the quantitative and qualitative expression of ECM components play an important role in cardiac function; however, the mechanisms that regulate the expression and function are not well understood. The manner in which the terminally differentiated myocyte perceives its external environment is of critical importance to the function of the heart. These external signals are delivered via the other two major components of the heart: the vascular system and the surrounding interstitium or ECM. Although it is obvious that the vascular system provides the transport of a variety of regulatory components that influence the contractile ability of the myocyte, the role of the interstitium in relation to cardiac function is less understood and is the focus of this review.


Clinical significance of serum laminin levels in patients with lung cancer.
Cellular adhesion molecules are considered useful markers in the diagnosis and prognosis of several types of malignant tumors. Laminin, a major structural component of the basement membrane, is a strong promoter of cell adhesion, migration, differentiation and proliferation via integrins and other cell surface receptors. The present study aimed to evaluate the clinical significance of the serum level of laminin in lung cancer patients. A total of 80 patients with lung cancer were enrolled in the study. The serum laminin level was measured by the solid-phase sandwich enzyme-linked immunosorbent assay method. The median age was 58.5 years (range, 36-80 years). The majority of the patients had non-small cell lung carcinoma (85%) and stage IV disease (56%). The baseline serum laminin levels of patients were significantly higher compared to the control group (median values 1.17 vs. 0.78 ng/ml, P=0.033). However, the clinical variables, such as age, gender, histology, stage of disease and response to chemotherapy, were not correlated with serum laminin level (P>0.05). Similarly, serum laminin level was not associated with survival (P=0.68). In conclusion, the serum level of laminin may have a diagnostic value in lung cancer patients. However, its predictive and prognostic roles were not observed.


[Neurosis-like tics in children].
The author examined 115 children from 4-14 years who suffered from ticose hyperkinesis. The specific traits of the background (somatical diseases, organic brain diseases, mental disorders, the MBD syndrome permitted to eliminate 4 groups of patients. On the basis of the achieved results the author comes to the conclusion that in the pathogenesis of a pseudoneurotic tic an important role is being played by a premorbid insufficiency of the motor analyzer. Comprehensive treatment is being recommended, with a consideration of the background against which the hyperkinetical syndrome arises.


A comparison of evaluative indices of quality of life and cognitive function in hemodialysis patients.
In the setting of end-stage renal disease, the reproducibility and responsiveness of three health-related quality-of-life instruments were evaluated. The Time Trade Off instrument (TTO) is a generic instrument used to evaluate the utility of a health state. The Hemodialysis Quality-of-Life questionnaire (HQL) is a disease-specific instrument. A series of function-specific tests evaluated neurocognitive function. The TTO and HQL instruments are patient centric in that patient values define the health status while the neurocognitive function tests reflect the values of healthcare professionals. Forty-seven chronic hemodialysis patients participated. Those with adequate dialysis, defined as a Kt/V (a measure of small solute removal during hemodialysis) above 1.0 were maintained at the level for two administrations of the three instruments separated by six to eight weeks. The test-retest intraclass correlation coefficient exceeded 0.90 for all five domains of the HQL questionnaire and exceeded 0.70 for nine neurocognitive function tests. Patients with inadequate dialysis (Kt/V less than 0.8) had Kt/V increased to above 1.0. The TTO was not responsive. For the HQL questionnaire, an item was considered responsive if a 1-point improvement, on a 7-point Likert type scale, occurred significantly more often among those with an improvement in hemodialysis treatment compared to those without improvement. Only one item had such a change and therefore the HQL cannot be considered responsive.(ABSTRACT TRUNCATED AT 250 WORDS)


White-tailed deer (Odocoileus virginianus) as a potential sentinel for human Lyme disease in Indiana.
We assessed the potential of white-tailed deer (WTD) (Odocoileus virginianus) to be a sentinel for human cases of Lyme disease (LD) in Indiana using location data from a 3-year survey of approximately 3400 hunted deer with associated tick Ixodes scapularis and Borrelia burgdorferi (Bb) data. Data on human LD cases at the county level were obtained from the Indiana Department of Health. All data were assigned to county centroids to match the resolution of the LD data before creating optimized trend surfaces for LD incidence, hunted deer count, Ixodes scapularis and Bb prevalence. To determine whether LD was spatially associated with the areas of high densities of deer, deer with Ixodes scapularis and deer with ticks infected with Bb, we used spatial analysis with distance indices (SADIE). The SADIE analysis found significant spatial association between LD and the distribution of three organismal predictor variables, that is, WTD, Ixodes ticks and Bb. Lyme disease incident rate varied between 0.08 cases per 10,000 habitants (Johnson county) and 5.9 cases per 10,000 habitants (Warren county). In conclusion, WTD can be used as an accurate and cost-effective sentinel for human LD. This method will permit public health workers to identify potentially endemic areas independently of human case reports.


Compressing a spinodal surface at fixed area: bijels in a centrifuge.
Bicontinuous interfacially jammed emulsion gels (bijels) are solid-stabilised emulsions with two inter-penetrating continuous phases. Employing the method of centrifugal compression we find that macroscopically the bijel yields at relatively low angular acceleration. Both continuous phases escape from the top of the structure, making any compression immediately irreversible. Microscopically, the bijel becomes anisotropic with the domains aligned perpendicular to the compression direction which inhibits further liquid expulsion; this contrasts strongly with the sedimentation behaviour of colloidal gels. The original structure can, however, be preserved close to the top of the sample and thus the change to an anisotropic structure suggests internal yielding. Any air bubbles trapped in the bijel are found to aid compression by forming channels aligned parallel to the compression direction which provide a route for liquid to escape.


Distancing, self-esteem, and subjective well-being in head and neck cancer.
Distancing (i.e. construing oneself as dissimilar to a negatively-stereotyped group) preserves self-esteem and may benefit other domains of subjective well-being. Head and neck cancer (HNC) is stigmatized because major risk factors include avoidable lifestyle variables (smoking, alcohol consumption, and human papilloma virus). Because the benefits of coping efforts, such as distancing, are most evident when people are under stress, we hypothesize that the psychosocial benefits of distancing will be most pronounced when cancer and its treatment interfere substantially with participation in valued activities and interests (i.e. high illness intrusiveness). To test whether distancing preserves self-esteem and other domains of subjective well-being (SWB) in HNC, especially when illness intrusiveness is high. Five hundred and twenty-two HNC outpatients completed a semantic-differential measure of perceived similarity to the 'cancer patient' and measures of illness intrusiveness, self-esteem, depressive symptoms, and psychological well-being in structured interviews. Evaluations of the 'cancer patient' reflected cancer stereotypes. A statistically significant interaction supported the central hypothesis: When people held negative stereotypes, those who construed themselves as similar to the 'cancer patient' reported lower self-esteem than those who construed themselves as dissimilar. Distancing did not benefit other SWB variables. Some results were counter-intuitive: e.g. Emotional distress increased with increasing illness intrusiveness when people did not hold negative cancer stereotypes, but when they held highly negative stereotypes, distress decreased with increasing illness intrusiveness. Overall, distancing preserved self-esteem in people with HNC and was associated with benefits in other SWB domains.


A multifaceted rehabilitation program for women with cancer.
A multifaceted rehabilitation program for women diagnosed with cancer includes a personal fitness plan, aerobic exercise classes, journaling, and a six-day environmental wilderness experience. The program's purpose is for participants to learn how to cope with uncertainties in life and to promote a wellness concept for living with cancer. This is achieved through successfully meeting the challenges of the program. A descriptive study, using journal entries of the pilot group's 12 women with breast cancer, provides insight into participants' views of the program. Their responses described: personal growth through succeeding at new and difficult experiences; normalization engendered by communicating with others having cancer; exhilaration at focusing on challenging events external to personal health problems; and courage that overrode their fears of facing what seemed impossible.


Lung function in lambs with diaphragmatic hernia after reversible fetal tracheal occlusion.
Short-duration resuscitation (< or =4 hours) of lambs with diaphragmatic hernia treated in utero with tracheal occlusion have shown improved lung function compared with untreated diaphragmatic hernia. This may be a transient phenomenon in the treated diaphragmatic hernia lambs because of surfactant deficiency. Our objective was to analyze the effect of fetal tracheal occlusion with or without release of the occlusion 1 week before delivery on pulmonary function during a longer period of resuscitation (8 hours) in the diaphragmatic hernia lamb model. Four groups were compared: diaphragmatic hernia (n = 5), diaphragmatic hernia and tracheal occlusion until delivery (n = 5), diaphragmatic hernia and tracheal occlusion with release of the occlusion 1 week before delivery (n = 5), and normal controls (n = 4). Despite persistently decreased surfactant levels, diaphragmatic hernia lambs treated with tracheal occlusion had normal-sized lungs with marked improvement in lung function and gas exchange over 8 hours when compared with untreated lambs with diaphragmatic hernia. Release of the tracheal occlusion 1 week before delivery added no benefit. It appears that surfactant-independent mechanisms such as pulmonary growth and structural changes are of foremost importance in relating to improved compliance, oxygenation, and ventilation of diaphragmatic hernia lambs treated with tracheal occlusion.


Dexamethasone stimulation of fetal rat lung antioxidant enzyme activity in parallel with surfactant stimulation.
It has recently been determined that fetal lung antioxidant enzyme activity markedly increases late in gestation. A test was made of whether this normal late-in-gestation change in O2-protective enzymes would be responsive to the maturing effect of hormonal (glucocorticoid) treatment. Pregnant rats received 0.2 mg/kg of dexamethasone (or saline) at 48 and 24 hours prior to delivery of their fetuses on gestational days 19, 20, 21, and 22 (newborn). Lung disaturated phosphatidylcholine showed an expected response to prenatal dexamethasone exposure with significant elevations of surfactant lipid at gestational days 20 and 21. A similar effect of prenatal dexamethasone treatment on the lung antioxidant defensive system was found. Superoxide dismutase, catalase, and glutathione peroxidase--enzymes protective against hyperoxia-induced lung injury--showed an accelerated pattern of maturation with significant increases in the dexamethasone-treated fetal lungs compared with control fetal lung enzyme levels at gestational days 20 and 21. The results suggest that prenatal dexamethasone treatment may have dual benefits when used in impending premature deliveries--that is, it may stimulate maturation of both the surfactant system and also the antioxidant enzyme system, and this maturation can help protect the premature newborn's lungs from the toxic complications of hyperoxic therapy that may be required because of immaturity.


Ca2+/calmodulin-dependent transcriptional activation of delta-opioid receptor gene expression induced by membrane depolarization in NG108-15 cells.
Regulation of gene expression is one of the mechanisms by which neuronal activity elicits long-term changes in neuronal phenotype and function. Although activity-dependent induction of immediate-early genes has been extensively studied, much less is known about the late-response genes. We have investigated the activity-dependent regulation of delta-opioid receptor (DOR) mRNA levels in NG108-15 cells. Transsynaptic activation was mimicked by depolarization with 55 mM KCl or veratridine. Both treatments lead to a time-dependent increase of DOR mRNA levels. Ca2+ entry through L-type voltage-dependent Ca2+ channels activated by depolarization appears to be involved, because L-type channel blockers reduced the induction of DOR expression. Ca2+ binding to calmodulin is the next step in the signal transduction pathway, because a calmodulin antagonist, W7, reduced the effect of veratridine. A selective inhibitor of calmodulin kinases (KN-62) and cyclosporin, an inhibitor of calcineurin, also antagonized the depolarization-induced increase in DOR mRNA levels, which indicates that both calcium/calmodulin-dependent enzymes are involved in the activity-dependent induction of DOR gene expression. Induction of DOR gene expression by an activity-dependent increase in intracellular Ca2+ concentration may serve as a feedback regulatory mechanism because activation of DOR leads to hyperpolarization and lower excitability of neurons.


Flow cytometry analysis of the effect of allopurinol and the dinitroaniline compound (Chloralin) on the viability and proliferation of Leishmania infantum promastigotes.
Leishmaniasis is a major parasitic disease in the tropical regions. However, Leishmania infantum has recently emerged as a very important cause of opportunistic infections for individuals positive for human immunodeficiency virus (HIV). However, there is a lack of in vitro tests for assessing the effect of anti-parasitic drugs on the viability and proliferation of Leishmania infantum. The aim of this study is to assess the efficacy of anti-parasitic drugs like allopurinol and Chloralin on the viability and proliferation of L. infantum promastigotes by utilizing two complementary flow cytometric approaches after exposure of the promastigotes to various concentrations of the drugs. The density of the cultures in the presence and absence of allopurinol was determined by haemocytometer enumeration. The two flow cytometric approaches used to monitor the drug effect were: (i) a quantitative method to measure cell division using 5-,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) staining and (ii) evaluation of cell viability by dual-staining with the membrane-permeable nuclear stain, SBRY-14 and propidium iodide. It was found that concentrations of allopurinol above 50 microg/ml yielded a clear decrease in the proliferation rate of the promastigotes. However, the viability results showed that about 46.8% of the promastigotes incubated in the presence of 800 microg/ml of allopurinol were still alive after 96 hours. In sharp contrast, more than 90% of promastigotes treated with Chloralin 10 microM (2.7 microg/ml) were dead after 48 hours of treatment. These flow cytometric findings suggest that allopurinol has a leishmaniostatic effect while the dinitroaniline compound (Chloralin) has a leishmaniocidal effect against promastigotes. The flow cytometric data on proliferation and viability were consistent with results obtained from haemocytometer counts and allowed us to develop a model for assessing in vitro the effects of medicaments like allopurinol and chloralin on L. infantum promastigotes on a cellular level.


Fluorescence resonance energy transfer on the voltage-dependent sodium channel. Spatial relationship and site coupling between the batrachotoxin and Leiurus quinquestriatus quinquestriatus alpha-scorpion toxin receptors.
A fluorescent N- methylanthraniloyl derivative of the potent depolarizing agent batrachotoxin has been used to probe the structural and conformational properties of the neurotoxin receptor site on the voltage-dependent sodium channel. Batrachotoxin A 20-alpha-N- methylanthranilate (BTX-NMA) retains high affinity for its receptor site on the synaptosomal sodium channel with a Kd between 78 and 91 nM and an average site capacity of 2 pmol/mg of synaptosomal protein in the presence of Leiurus quinquestriatus quinquestriatus alpha-scorpion toxin. The fluorescence emission of BTX-NMA upon binding to synaptosomes indicates a hydrophobic environment. Toxin V from L. quinquestriatus, an allosteric activator, effects a 20-nm red shift in the spectrum of bound BTX-NMA and a 4-fold enhancement in the fluorescence quantum yield disclosing a conformational change into a hydrophilic environment. Fluorescence resonance energy transfer measurements show that the distance separating the receptor sites is 37 +/- 10 A. Thus, the binding of alpha-scorpion toxin must involve conformational changes that extend over large distances from the batrachotoxin-binding locus. This information together with the distance measurements between the tetrodotoxin and alpha-scorpion toxin receptors and the conformational transition associated with this distance upon batrachotoxin addition indicate a conformationally flexible channel with coupling of sites through the polyatomic framework of individual subunits or through extensive alterations in subunit/subunit interactions.


Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice.
Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10'-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9',10'-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)-promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-κB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress-mediated unfolded protein response (ER(UPR)), through decreasing ER(UPR)-mediated protein kinase RNA-activated like kinase-eukaryotic initiation factor 2α activation, and inositol requiring 1α-X-box-binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, β-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression.


Molecular characterization of two cDNAs from Sinapis alba L. expressed specifically at an early stage of tapetum development.
Flower formation in the long-day plant Sinapis alba is strictly dependent on an inductive light treatment. Differential screening of an apex cDNA library prepared 10 days after flower induction against cDNAs from vegetative apices has identified two cDNA clones, pSFD10.35 and pSFD10.44, which represent transcripts expressed transiently between day 10 and day 20 after induction and which disappear before flowers reach maturity. The corresponding full-length cDNAs which were isolated, Satap35 and Satap44, display 86% overall sequence identity. These cDNAs encode polypeptides with predicted molecular weights of 12.7 and 12.4 kDa, and isoelectric points of 10.4 and 7.5, respectively. The N-terminal portions of the open reading frames have characteristics of signal sequences. In situ hybridization reveals that both transcripts are localized exclusively in the tapetal cell layer of the anthers. Maximal expression is observed in flower buds of approximately 1.5 mm length (tetrad stage). Southern blot analysis demonstrates the presence of additional, closely related genes in the Sinapis genome, as well as the occurrence of homologous genes in Arabidopsis thaliana, Brassica napus and Nicotiana tabacum.


Palladium(ii) complexes of N,N-diphenylacetamide based thio/selenoethers and flower shaped Pd16S7 and prismatic Pd17Se15 nano-particles tailored as catalysts for C-C and C-O coupling.
2-Bromo-N,N-diphenylacetamide (P1) prepared by reacting diphenylamine with α-bromoacetyl bromide, on treatment with Na2S and Na2Se generated in situ, has resulted in thio and selenoether ligands, L1 ((Ph2NCOCH2)2S) and L2 ((Ph2NCOCH2)2Se), respectively. Reacting these ligands with Na2PdCl4 in ethanol at room temperature resulted in their complexes [Pd(L1/L2)2Cl2] (C1/C2). P1, L1, L2, C1 and C2 were characterized by 1H, 13C{1H} and 77Se{1H} NMR spectroscopy, IR spectroscopy and High resolution mass spectrometry (HR-MS). Single crystal structures of all the five compounds were determined by X-ray diffraction. In both C1 and C2 the geometry of Pd is nearly square planar. Flower shaped Pd16S7 (size 26-50 nm) and prismatic Pd17Se15 NPs (size 20-55 nm) were synthesized by a single source precursor route (thermolysis at ∼280 °C in trioctylphosphine) from air and moisture insensitive C1 and C2, respectively. These shapes of the two nanophases were unknown hitherto. They were characterized by powder X-ray diffraction (PXRD), SEM-EDX and HR-TEM and found to show good catalytic activity for Suzuki-Miyaura (Pd loading 0.5 mol%; yield up to 96%) and C-O (Pd loading 0.5 mol%; yield up to 96%) coupling reactions (at 100 °C) of aryl bromides with phenylboronic acid and phenol, respectively. The complexes C1 and C2 were found very efficient for Suzuki-Miyaura and C-O coupling as revealed by their optimum loading of 0.0001-0.01 and 0.1 mol% of Pd, respectively, for the two reactions. The reuse of the complexes or NPs as a catalyst is demonstrated.


Antibiotic Therapy and Risk of Early-Onset Colorectal Cancer: A National Case-Control Study.
Antibiotic use has emerged as a risk factor for colorectal neoplasia and is hypothesized as a contributor to the rising incidence of colorectal cancer under age 50 years or early-onset colorectal cancer (EOCRC). However, the impact of antibiotic use and risk of EOCRC is unknown. We conducted a population-based case-control study of CRC among individuals aged ≥18 years in the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) cohort (2006-2016). The primary outcome was EOCRC. A secondary outcome was CRC at any age. Incident CRC was pathologically confirmed, and for each, up to 5 population-based controls were matched on age, sex, county of residence, and calendar year. We assessed prescriptions until 6 months before CRC diagnosis. Conditional logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). We identified 54,804 cases of CRC (2,557 EOCRCs) and 261,089 controls. Compared with none, previous antibiotic use was not associated with EOCRC risk after adjustment for potential confounders (aOR 1.06, 95% CI: 0.96, 1.17) with similarly null findings when stratified by anatomic tumor site. In contrast, previous antibiotic use was weakly associated with elevated risk for CRC at any age (aOR 1.05, 95% CI: 1.02, 1.07). A potential but modest link between broad-spectrum antibiotic use and EOCRC was observed (aOR 1.13, 95% CI: 1.02, 1.26). We found no conclusive evidence that antibiotics are associated with EOCRC risk. Although antibiotic use was weakly associated with risk of CRC at any age, the magnitude of association was modest, and the study period was relatively short.


Treating depressed and anxious smokers in smoking cessation programs.
Cigarette smoking is the leading cause of preventable death in the United States. In addition, smoking rates among depressed and anxious smokers are higher than in the population at large. Furthermore, treating depressed and anxious smokers effectively is particularly challenging because of their significant negative affect, dysfunctional emotional regulation, severe withdrawal symptoms, and numerous institutional barriers to successful treatment. Previous reviews in this area have typically focused on depression or anxiety disorders, whereas this review focuses on both disorders. This article presents a brief review of the literature on treating depressed and anxious smokers in smoking cessation programs. We also discuss treatment issues, challenges, and guidelines regarding effective interventions for depressed and anxious smokers who wish to stop smoking. The potential benefits for better health and improved functioning are quite large. Moreover, the merit of pursuing evidence-based interventions with these comorbid populations of depressed and anxious smokers-including practical, multidisciplinary, and cost-effective smoking cessation programs-is compelling. A sensible time for an aggressive approach to this health promotion effort is now.


Melasma: an Up-to-Date Comprehensive Review.
Melasma is a common acquired condition of symmetric hyperpigmentation, typically occurring on the face, with higher prevalence in females and darker skin types. Multiple etiologies, including light exposure, hormonal influences, and family history, have been implicated in the pathogenesis of this disorder. Overall prevalence ranges widely at 1-50%, since values are typically calculated within a specific ethnic population within a geographic region. Histologically, melasma can display increased epidermal and/or dermal pigmentation, enlarged melanocytes, increased melanosomes, solar elastosis, dermal blood vessels, and, occasionally, perivascular lymphohistiocytic infiltrates. Various topical, oral, and procedural therapies have been successfully used to treat melasma. Traditional topical therapies including hydroquinone, tretinoin, corticosteroids, and triple combination creams; however, other synthetic and natural topical compounds have also shown varying efficacies. Promising oral therapies for melasma include tranexamic acid, Polypodium leucotomos, and glutathione. Procedures, including chemical peels, microneedling, radiofrequency, and lasers, are also often used as primary or adjunctive treatments for melasma. Notably, combination therapies within or across treatment modalities generally result in better efficacies than monotherapies. This review serves as a comprehensive update on the current understanding of the epidemiology, pathogenesis, clinical and histologic features of melasma, as well as treatments for this common, yet therapeutically challenging, condition.


The cured immune phenotype achieved by treatment of visceral leishmaniasis in the BALB/c mouse with a nonionic surfactant vesicular formulation of sodium stibogluconate does not protect against reinfection.
Single-dose treatment with sodium stibogluconate solution (SSG) and treatment with a nonionic surfactant vesicular formulation of sodium stibogluconate (SSG-NIV) were compared for the ability to protect BALB/c mice against infection with Leishmania donovani. Prophylactic treatment with SSG-NIV protected against infection, although its effects were time and organ dependent; protection was not obtained with SSG. Protection against reinfection with L. donovani was observed only in mice cured by treatment with SSG-NIV. However, this protective effect was probably due to the presence of residual drug rather than an immune effect, since prophylactic SSG-NIV treatment gave similar results. Transfer of enriched spleen T-cell populations from L. donovani-infected mice or from infected SSG-NIV-treated mice gave no protection against L. donovani infection in the recipients. T cells from infected mice, but not from infected SSG-NIV-treated mice, were infectious to recipients. SSG-NIV treatment was equally effective against visceral leishmaniasis in immunocompetent and SCID mice, whereas SSG treatment was less effective in the latter. The results of this study suggest that the high antileishmanial activity of SSG-NIV is due to favorable modification of SSG delivery and does not require a fully functional immune response. Cure of visceral leishmaniasis by SSG-NIV treatment in the BALB/c mouse did not protect against reinfection.


Wavelet methods for inverting the Radon transform with noisy data.
Because the Radon transform is a smoothing transform, any noise in the Radon data becomes magnified when the inverse Radon transform is applied. Among the methods used to deal with this problem is the wavelet-vaguelette decomposition (WVD) coupled with wavelet shrinkage, as introduced by Donoho (1995). We extend several results of Donoho and others here. First, we introduce a new sufficient condition on wavelets to generate a WVD. For a general homogeneous operator, whose class includes the Radon transform, we show that a variant of Donoho's method for solving inverse problems can be derived as the exact minimizer of a variational problem that uses a Besov norm as the smoothing functional. We give a new proof of the rate of convergence of wavelet shrinkage that allows us to estimate rather sharply the best shrinkage parameter needed to recover an image from noise-corrupted data. We conduct tomographic reconstruction computations that support the hypothesis that near-optimal shrinkage parameters can be derived if one can estimate only two Besov-space parameters about an image f. Both theoretical and experimental results indicate that our choice of shrinkage parameters yields uniformly better results than Kolaczyk's (1996) variant of Donoho's method and the classical filtered backprojection method.


Intrinsic conformational preferences of the Hoechst dye family and their influence of DNA binding.
Quantum mechanical calculations have been used to investigate the molecular conformation of the Hoechst family of DNA-binding dyestuffs. Compounds in which the phenolic substituent adopts either a meta or para position were studied. Two different environments have been considered, which are the gas phase and aqueous solution; the conformation in aqueous solution has been modeled through a self-consistent reaction field strategy. The results clearly indicate that Hoechst dyes do not adopt a planar conformation and that the degree of planarity is controlled by the external environment. A comparison with experimental data reveals that the conformation of Hoechst dyes in the gas phase is similar to that observed in DNA complexes by X-ray crystallography. In aqueous solution, the conformation deviates from planarity more than in the gas phase, since non-bonded interactions with the solvent offset the loss of conjugative interactions. The role of the drug conformation in the binding mechanism with DNA is discussed.


Antioxidant and anti-apoptotic effects of cannabidiol in model of ischemic stroke in rats.
One of the main non-psychoactive phytocannabinoids of cannabis is cannabidiol (CBD), which has attracted much attention for its neuroprotective roles. The present study was designed to assess whether pretreatment of CBD can attenuate two of the destructive processes of cerebral ischemia, including oxidative stress and cell death. The male rats were randomly divided into 6 main groups (control, MCAO, vehicle, and CBD-treated groups). Using stereotaxic surgery, a cannula was inserted into the right lateral ventricle of the rat brain. CBD was injected at doses of 50, 100 and 200 ng/rat for five consecutive days. After pretreatment, middle cerebral artery (MCA) was blocked for 60 min using the intraluminal filament technique. 24 h after reperfusion, each main group was considered for measurement of infarct volume, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), p53 gene expression, pathological alterations, and expression of Bax, Bcl-2, cytochrome C, and caspase-3 proteins. The results revealed that CBD at dose of 100 ng/rat reduced the infarction volume and MDA level in cortical and striatal areas of rat brain compared with vehicle group. In addition, the CBD at dose of 100 ng/rat elevated the activity of SOD enzyme in cortex and striatum. The increase in the activity of CAT was also seen at dose of 100 ng/rat in cortex. Furthermore, the Bcl-2/Bax ratio was significantly diminished by the dose of 100 ng/rat CBD in cortex. Moreover, a decrease in expression of cytosolic cytochrome C was observed by CBD at doses of 100 and 200 ng/rat in cortex. CBD at doses 100 and 200 ng/rat also reduced the expression of caspase-3 in cortical and striatal areas, respectively. P53 was downregulated following administration of CBD at dose of 100 ng/rat. Moreover, histological analysis showed the decrease in the percentage of pyknotic neurons in 100 and 200 ng/rat CBD-received groups. CBD played the anti-apoptosis and anti-oxidant roles in cerebral ischemia by affecting the pathways of intrinsic apoptosis, endogenous antioxidant enzymes, and lipid peroxidation.


Malaria control in East Africa: the Kampala Conference and the Pare-Taveta Scheme: a meeting of common and high ground.
The 1950 Malaria Conference in Equatorial Africa, held in Kampala, Uganda, has been remembered primarily for its decision to control malaria '...by modern methods as soon as feasible, whatever the original degree of endemicity, and without awaiting the outcome of further experiments.' This decision was far from conclusive and, indeed, reflects only one side of the argument which brought two groups of malariologists into direct opposition on the wisdom of malaria control in equatorial Africa, using modern methods such as DDT. Through an examination of the unpublished verbatim transcript of the Kampala Conference, we are able to document the 'furious debates' which took place at Kampala in 1950. We highlight, in particular, the adamant concerns expressed by some of the delegates that intervention in areas of high malaria transmission might lead to a loss of naturally acquired immunity which, in turn, could give rise to a resurgence of malaria, should the control strategies fail to be sustained. As we show, this concern had been expressed by a number of malariologists working in East Africa in the first half of the twentieth century, but it was only with the advent of DDT, as a residual insecticide, that the implications of wide-spread control, in the absence of any knowledge of the long-term consequences, became a serious possibility. While the Kampala Conference gave the 'go ahead' to control malaria in Africa without awaiting the outcome of 'further experiments', a number of participants insisted that a field trial should be set up to evaluate the impact of malaria on areas of high transmission both before and after spraying: to this end, a field trial in Pare-Taveta was carried out in 1954-59. In this paper we look at the Kampala Conference for its scientific debates and the Pare-Taveta Scheme for its field applications. In the final part of the paper, we address a number of questions raised at Kampala which have, once more, become contentious issues, following the recent successful trials of ITBNs. We believe that an understanding of the historical foundations of these issues should provide an important component of the new WHO campaign to Roll Back Malaria.


Bach1 gene ablation reduces steatohepatitis in mouse MCD diet model.
Bach1 is a transcriptional repressor of heme oxygenase-1 (HO-1, a.k.a. HSP-32), which is an inducible enzyme and has anti-oxidation/anti-inflammatory properties shown in various models of organ injuries. Since oxidative stress plays a pivotal role in the pathogenesis of nonalcoholic steatohepatitis (NASH), HO-1 induction would be expected to prevent the development of NASH. In this study, we investigated the influence of Bach1 ablation in mice on the progression of NASH in methionine-choline deficient (MCD) diet model. Bach1 ablation resulted in significant induction of HO-1 mRNA and its activity in the liver. When fed MCD diet, Bach1(-/-) mice exhibited negligible hepatic steatosis compared to pronounced steatohepatitis in wild type mice with 6-fold increase in hepatic triglyceride content. Whereas feeding of MCD diet decreased mRNA expressions of peroxisome proliferator-activated receptor (PPAR) α and microsomal triglyceride transfer protein (MTP) in wild type mice, there were no change in Bach1(-/-) mice. In addition, hepatic concentration of malondialdehyde (MDA), a biomarker for oxidative stress as well as plasma alanine aminotransferase (ALT) was significantly lower in Bach1(-/-) mice. These findings suggest that Bach1 ablation exerts hepatoprotective effect against steatohepatitis presumably via HO-1 induction and may be a potential therapeutic target.


Targeted expression of the dominant-negative FGFR4a in the eye using Xrx1A regulatory sequences interferes with normal retinal development.
Molecular analysis of vertebrate eye development has been hampered by the availability of sequences that can selectively direct gene expression in the developing eye. We report the characterization of the regulatory sequences of the Xenopus laevis Rx1A gene that can direct gene expression in the retinal progenitor cells. We have used these sequences to investigate the role of Fibroblast Growth Factor (FGF) signaling in the development of retinal cell types. FGFs are signaling molecules that are crucial for correct patterning of the embryo and that play important roles in the development of several embryonic tissues. FGFs and their receptors are expressed in the developing retina, and FGF receptor-mediated signaling has been implicated to have a role in the specification and survival of retinal cell types. We investigated the role of FGF signaling mediated by FGF receptor 4a in the development of retinal cell types in Xenopus laevis. For this purpose, we have made transgenic Xenopus tadpoles in which the dominant-negative FGFR4a (Delta FGFR4a) coding region was linked to the newly characterized regulatory sequences of the Xrx1A gene. We found that the expression of Delta FGFR4a in retinal progenitor cells results in abnormal retinal development. The retinas of transgenic animals expressing Delta FGFR4a show disorganized cell layering and specifically lack photoreceptor cells. These experiments show that FGFR4a-mediated FGF signaling is necessary for the correct specification of retinal cell types. Furthermore, they demonstrate that constructs using Xrx1A regulatory sequences are excellent tools with which to study the developmental processes involved in retinal formation.


Extreme value statistics for river quality simulations.
Various methods have been proposed to assess intermittent pollution loads and impacts on rivers in urban areas. Although the variables to describe the impact are mainly the same, the standards show significant differences in the assessment of permitted concentration level, duration and return period. The probability of an event is derived using either frequencies of occurrence or predefined extreme value distributions. Both methods have drawbacks. To bypass these, an a posteriori estimation of the statistical distribution of data based on the peak-over-threshold method is proposed. The method is exemplarily demonstrated using a semi-virtual case study.


Coordination of host and endosymbiont gene expression governs endosymbiont growth and elimination in the cereal weevil Sitophilus spp.
Insects living in nutritionally poor environments often establish long-term relationships with intracellular bacteria that supplement their diets and improve their adaptive and invasive powers. Even though these symbiotic associations have been extensively studied on physiological, ecological, and evolutionary levels, few studies have focused on the molecular dialogue between host and endosymbionts to identify genes and pathways involved in endosymbiosis control and dynamics throughout host development. We simultaneously analyzed host and endosymbiont gene expression during the life cycle of the cereal weevil Sitophilus oryzae, from larval stages to adults, with a particular emphasis on emerging adults where the endosymbiont Sodalis pierantonius experiences a contrasted growth-climax-elimination dynamics. We unraveled a constant arms race in which different biological functions are intertwined and coregulated across both partners. These include immunity, metabolism, metal control, apoptosis, and bacterial stress response. The study of these tightly regulated functions, which are at the center of symbiotic regulations, provides evidence on how hosts and bacteria finely tune their gene expression and respond to different physiological challenges constrained by insect development in a nutritionally limited ecological niche. Video Abstract.


Practical scale up synthesis of carboxylic acids and their bioisosteres 5-substituted-1H-tetrazoles catalyzed by a graphene oxide-based solid acid carbocatalyst.
Herein, catalytic application of a metal-free sulfonic acid functionalized reduced graphene oxide (SA-rGO) material is reported for the synthesis of both carboxylic acids and their bioisosteres, 5-substituted-1H-tetrazoles. SA-rGO as a catalytic material incorporates the intriguing properties of graphene oxide material with additional benefits of highly acidic sites due to sulfonic acid groups. The oxidation of aldehydes to carboxylic acids could be efficiently achieved using H2O2 as a green oxidant with high TOF values (9.06-9.89 h-1). The 5-substituted-1H-tetrazoles could also be effectively synthesized with high TOF values (12.08-16.96 h-1). The synthesis of 5-substituted-1H-tetrazoles was corroborated by single crystal X-ray analysis and computational calculations of the proposed reaction mechanism which correlated well with experimental findings. Both of the reactions could be performed efficiently at gram scale (10 g) using the SA-rGO catalyst. SA-rGO displays eminent reusability up to eight runs without significant decrease in its productivity. Thus, these features make SA-rGO riveting from an industrial perspective.


Modulational instability and breathing motion in the two-dimensional nonlinear Schrödinger equation with a one-dimensional harmonic potential.
Modulational instability and breathing motion are studied in the two-dimensional nonlinear Schrödinger (NLS) equation trapped by the one-dimensional harmonic potential. The trapping potential is uniform in the y direction and the wave function is confined in the x direction. A breathing motion appears when the initial condition is close to a stationary solution which is uniform in the y direction. The amplitude of the breathing motion is larger in the two-dimensional system than that in the corresponding one-dimensional system. Coupled equations of the one-dimensional NLS equation and two variational parameters are derived by the variational approximation to understand the amplification of the breathing motion qualitatively. On the other hand, there is a breathing solution in the x direction which is uniform in the y direction to the two-dimensional NLS equation. It is shown that the modulational instability along the y direction is suppressed when the breathing motion is sufficiently strong, even if the norm is above the critical value of the collapse.


Ethical issues in laparoscopic hysterectomy.
Hysterectomy is performed for a wide range of benign and malignant conditions, such as fibroids, menorrhagia and pelvic pain, and gynaecological malignancies. One in four women has a chance of undergoing hysterectomy in her lifetime. Conventionally abdominal hysterectomy is done through the open approach. However, many patients assume that the modern laparoscopic hysterectomy is superior to the standard approach. Laparoscopic surgical centres are mushrooming in major cities. This article presents ethical considerations involved in the decision-making process of choosing from the surgical options available.


Wenzhouxiangella Strain AB-CW3, a Proteolytic Bacterium From Hypersaline Soda Lakes That Preys on Cells of Gram-Positive Bacteria.
A new haloalkaliphilic species of Wenzhouxiangella, strain AB-CW3, was isolated from a system of hypersaline alkaline soda lakes in the Kulunda Steppe using cells of Staphylococcus aureus as growth substrate. AB-CW3's complete, circular genome was assembled from combined nanopore and Illumina sequencing and its proteome was determined for three different experimental conditions. AB-CW3 is an aerobic gammaproteobacterium feeding mainly on proteins and peptides. Unique among Wenzhouxiangella, it uses a flagellum for motility, fimbria for cell attachment and is capable of complete denitrification. AB-CW3 can use proteins derived from living or dead cells of Staphylococcus and other Gram-positive bacteria as the carbon and energy source. It encodes and expresses production of a novel Lantibiotic, a class of antimicrobial peptides which have so far only been found to be produced by Gram-positive bacteria. AB-CW3 likely excretes this peptide via a type I secretion system encoded upstream of the genes for production of the Lanthipeptide. Comparison of AB-CW3's genome to 18 other Wenzhouxiangella genomes from marine, hypersaline, and soda lake habitats indicated one or two transitions from marine to soda lake environments followed by a transition of W. marina back to the oceans. Only 19 genes appear to set haloalkaliphilic Wenzhouxiangella apart from their neutrophilic relatives. As strain AB-CW3 is only distantly related to other members of the genus, we propose to provisionally name it "Wenzhouxiangella alkaliphila".


[Survival of Trypanosoma cruzi in experimentally contaminated drinks].
Trypanosoma cruzi is the causative agent of Chagas disease, transmitted primarily by triatomine insects. However, in 2005, oral transmission was documented in countries where the disease is endemic for Chagas disease. This trend may also occur in Colombia, a situation that motivated epidemiological alerts and the necessity for exploring the risk level of oral, human-to-human infection by T. cruzi. Survival times were established for the T. cruzi strain DS using juices involved in the outbreak of Lebrija County (Cesar, Colombia) in 2008. Survival of the T. cruzi strain was evaluated as defined by vitality (forward movement) and viability (growth in isolation medium Novy, McNeal and Nicolle/liver infusion tryptose). This strain was molecularly characterized as TCLA, isolated from a patient associated with an outbreak in Aguachica County (Santander, very near Lebrija). Its survival was tested in tangerine juice, guava, soursop (guanábana), water and sugar water. The T. cruzi strain DS remained vital in mandarin at room temperature for 72 hr, at refrigerated temperatures for 36 hr;, the soursop (guanábana) for 48 hr at room temperature and 384 hr under refrigeration; and guava at both temperatures 24 hr. This strain was viable 2 and 24 hours post-infection in each of the other juices at the two temperature conditions. The DS T. cruzi strain survived in all drinks for more than 24 hours post-infection, with a survival time of 384 hr in the juice of soursop (guanábana) under refrigeration.