Odontogenic ameloblast-associated (ODAM) is inactivated in toothless/enamelless placental mammals and toothed whales.
The gene for odontogenic ameloblast-associated (ODAM) is a member of the secretory calcium-binding phosphoprotein gene family. ODAM is primarily expressed in dental tissues including the enamel organ and the junctional epithelium, and may also have pleiotropic functions that are unrelated to teeth. Here, we leverage the power of natural selection to test competing hypotheses that ODAM is tooth-specific versus pleiotropic. Specifically, we compiled and screened complete protein-coding sequences, plus sequences for flanking intronic regions, for ODAM in 165 placental mammals to determine if this gene contains inactivating mutations in lineages that either lack teeth (baleen whales, pangolins, anteaters) or lack enamel on their teeth (aardvarks, sloths, armadillos), as would be expected if the only essential functions of ODAM are related to tooth development and the adhesion of the gingival junctional epithelium to the enamel tooth surface. We discovered inactivating mutations in all species of placental mammals that either lack teeth or lack enamel on their teeth. A surprising result is that ODAM is also inactivated in a few additional lineages including all toothed whales that were examined. We hypothesize that ODAM inactivation is related to the simplified outer enamel surface of toothed whales. An alternate hypothesis is that ODAM inactivation in toothed whales may be related to altered antimicrobial functions of the junctional epithelium in aquatic habitats. Selection analyses on ODAM sequences revealed that the composite dN/dS value for pseudogenic branches is close to 1.0 as expected for a neutrally evolving pseudogene. DN/dS values on transitional branches were used to estimate ODAM inactivation times. In the case of pangolins, ODAM was inactivated ~ 65 million years ago, which is older than the oldest pangolin fossil (Eomanis, 47 Ma) and suggests an even more ancient loss or simplification of teeth in this lineage. Our results validate the hypothesis that the only essential functions of ODAM that are maintained by natural selection are related to tooth development and/or the maintenance of a healthy junctional epithelium that attaches to the enamel surface of teeth.


Osteoporosis Management.
The clinical update serves as a brief review of recently published, high-impact, and potentially practice changing journal articles summarized for our readers. Topics include menopause, sexual dysfunction, breast health, contraception, osteoporosis, and cardiovascular disease. In this clinical update, we selected recent publications relevant to osteoporosis management. We highlight articles on the safety of long-term use of denosumab and bisphosphonates, fracture risk after discontinuing menopausal hormone therapy, calcium intake and cardiovascular risk, as well as the value of repeat dual X-ray absorptiometry scanning to monitor those on osteoporosis treatment.


Unanswered prayers: religiosity and the god-serving bias.
Two self-report experiments examined how religiosity affects attributions made for a target person's death. Online adults (Study 1, N = 427) and undergraduate students (Study 2, N = 326) read about Chris who had a heart attack, used religious or health behaviors, and lived or died. Participants made attributions to Chris and God (both studies), and reported their emotions (Study 2). Participants made more attributions to Chris when he lived than when he died, but only when he used health behaviors. The highly religious made more attributions to God, but not when Chris used religious behaviors and died (the God-serving bias); they reported the most positive emotions when Chris lived after using religious behaviors (the Hallelujah effect). Directions for future research in terms of implicit religious beliefs and normative evaluations of religion are discussed.


Hartree-Fock orbitals significantly improve the reaction barrier heights predicted by semilocal density functionals.
Semilocal density functional theory predictions for the barrier heights of representative hydrogen transfer, heavy-atom transfer, and nucleophilic substitution reactions are significantly improved in non-self-consistent calculations using Hartree-Fock orbitals. Orbitals from hybrid calculations yield related improvements. These results provide insight into compensating for one-electron self-interaction error in semilocal density functional theory.


2-Methyl-3-buten-2-ol (MBO) synthase expression in Nostoc punctiforme leads to over production of phytols.
Phytol is a diterpene alcohol of medicinal importance and it also has potential to be used as biofuel. We found over production of phytol in Nostoc punctiforme by expressing a 2-Methyl-3-buten-2-ol (MBO) synthase gene. MBO synthase catalyzes the conversion of dimethylallyl pyrophosphate (DMAPP) into MBO, a volatile hemiterpene alcohol, in Pinus sabiniana. The result of enhanced phytol production in N. punctiforme, instead of MBO, could be explained by one of the 2 models: either the presence of a native prenyltransferase enzyme with a broad substrate specificity, or appropriation of a MBO synthase metabolic intermediate by a native geranyl diphosphate (GDP) synthase. In this work, an expression vector with an indigenous petE promoter for gene expression in the cyanobacterium N. punctiforme was constructed and MBO synthase gene expression was successfully shown using reverse transcriptase (RT)-PCR and SDS-PAGE. Gas chromatography--mass spectrophotometry (GC-MS) was performed to confirm phytol production from the transgenic N. punctiforme strains. We conclude that the expression of MBO synthase in N. punctiforme leads to overproduction of an economically important compound, phytol. This study provides insights about metabolic channeling of isoprenoids in cyanobacteria and also illustrates the challenges of bioengineering non-native hosts to produce economically important compounds.


Expanding the known repertoire of virulence factors produced by Bacillus cereus through early secretome profiling in three redox conditions.
The pathogen Bacillus cereus causes diarrheal disease in humans. In the small intestine, B. cereus has to deal with anaerobiosis, low oxidoreduction potential, and carbohydrate limitation conditions. To gain insight into the virulence potential of low density B. cereus cells in such an environment, we cultured bacteria in low and high oxidoreduction potential anoxic conditions and in fully oxic conditions and compared their full secretomes. A unique pattern of proteins assigned to virulence factors was revealed. Among the 57 virulence-related factors, 31 were found for the first time in the B. cereus secretome. The putative fourth component of hemolysin BL (HblB'), enterotoxin FM, hemolysin II, and three new putative conserved enterotoxins were uncovered. Cross-comparison of the relative abundance of secreted proteins reveals that a restricted set comprising 19 proteins showed significant changes in response to redox condition changes. We complemented these results with transcriptomics data and confirmed the cytotoxicity of the B. cereus secretome toward Caco-2 human epithelial cells. Our data suggest that (i) the redox-dependent regulatory pathway may modulate the expression of a subset of virulence factors to ensure an appropriate response in a specific redox environment, and (ii) an early growth phase-dependent pathway could regulate the expression of several virulence factors, allowing B. cereus to infect a host whatever the redox conditions. This early growth phase-dependent pathway may function, at least partially, independently of the pleiotropic virulence gene regulator PlcR and may therefore be more specific to the B. cereus group.


Antithyroid drug therapy for Graves' hyperthyroidism: is long-term administration of a small maintenance dose necessary?
This retrospective study serves as an inquiry into the common practice of long-term administration of small maintenance doses of either methyl-mercaptoimidazole (MMI) or propylthiouracil (PTU) to Graves' hyperthyroid patients who became euthyroid with primary large doses of the same drugs. One hundred and two patients with Graves' hyperthyroidism treated with antithyroid drug (ATD) were studied. Sixty-one were treated with conventional long term therapy and 41 were treated with short-term therapy. Small maintenance doses of ATDs were not administered to the short-term therapy patients. The duration of long-term therapy was 28.6 +/- 20.2 months (from 12 to 48 months) and that of short-term therapy was 8.4 +/- 1.8 months (from 5 to 11). Post therapy and follow-up observation continued for 19.0 +/- 2.7 months (16-25 months) in both long-term and short-term patients. Of the 61 long-term therapy patients, 20 were relapsed and 41 (67.2%) continue to remain in remission. So too, of the 41 short-term therapy patients, 14 relapsed and 27 (65.9%) still remain in remission. There was no statistical difference between the long-term and short-term therapy group in age, sex, duration of symptoms before diagnosis, antithyroid antibodies, radioactive iodine uptake, free thyroid hormone levels or goiter size before treatment or in TBII levels at cessation of ATD. It is concluded that 'short-term ATD therapy' without a maintenance dose is sufficient and saves several months of the patient's and clinician's time.


The kinetics of competing multiple-barrier unimolecular dissociations of o-, m-, and p-chlorotoluene radical cations.
The kinetics of competing multiple-barrier unimolecular dissociations of o-, m-, and p-chlorotoluene radical cations to C7H7(+) (benzyl and tropylium) are studied by ab initio/Rice-Ramsperger-Kassel-Marcus (RRKM) calculations. This system presents a very intriguing kinetic example in which the conventional approach assuming a single-barrier or a double-well potential surface with one transition state cannot predict or explain the outcome. The molecular parameters obtained at the SCF level of theory with the DZP basis set are utilized for the evaluation of microcanonical RRKM rate constants with no adjustable parameters. First-principles calculations provide the microscopic details of the reaction kinetics along the two competing multiple-barrier reaction pathways: the rate-energy curves for all elementary steps; temporal variations of the reactants, the reaction intermediates, and the products; and the product yield as a function of energy. The rate constant for each channel is calculated as a function of the internal energy at 0 K. After the thermal correction, the calculated rate-energy curves for the benzyl channel agree well with the photoelectron photoion coincidence data obtained at room temperature for all three isomers. Close agreement between experiments and theory suggests that first-principles calculations taking the full sequence of kinetic steps into account offer a useful kinetic model capable of correctly predicting the outcome of competing multiple-barrier reactions. The slowest process is identified as [1,2] and [1,3] alpha-H migration at the entrance to the tropylium and benzyl channel, respectively. However, the overall rate is determined not by the slowest process, but by the combination of the slowest rate and the net flux toward the product, which is multiplicatively reduced with an increasing number of reaction intermediates. The product yield calculation confirms the benzyl cation as the predominant product. For all isomers, the thermodynamically most stable tropylium ion is produced much less than expected because a large fraction of flux coming into the tropylium channel goes back to the benzyl channel. The benzyl channel is kinetically favored because it involves a lower entrance barrier with fewer rearrangements than the tropylium channel.


Comprehensive Neurotoxicity of Lead Halide Perovskite Nanocrystals in Nematode Caenorhabditis elegans.
To date, all-inorganic lead halide perovskite quantum dots have emerged as promising materials for photonic, optoelectronic devices, and biological applications, especially in solar cells, raising numerous concerns about their biosafety. Most of the studies related to the toxicity of perovskite quantum dots (PeQDs) have focused on the potential risks of hybrid perovskites by using zebrafish or human cells. So far, the neurotoxic effects and fundamental mechanisms of PeQDs remain unknown. Herein, a comprehensive methodology is designed to investigate the neurotoxicity of PeQDs by using Caenorhabditis elegans as a model organism. The results show that the accumulation of PeQDs mainly focuses on the alimentary system and head region. Acute exposure to PeQDs results in a decrease in locomotor behaviors and pharyngeal pumping, whereas chronic exposure to PeQDs causes brood decline and shortens lifespan. In addition, some abnormal issues occur in the uterus during reproduction assays, such as vulva protrusion, impaired eggs left in the vulva, and egg hatching inside the mother. Excessive reactive oxygen species formation is also observed. The neurotoxicity of PeQDs is explained by gene expression. This study provides a complete insight into the neurotoxicity of PeQD and encourages the development of novel nontoxic PeQDs.


CLIC, a tool for expanding biological pathways based on co-expression across thousands of datasets.
In recent years, there has been a huge rise in the number of publicly available transcriptional profiling datasets. These massive compendia comprise billions of measurements and provide a special opportunity to predict the function of unstudied genes based on co-expression to well-studied pathways. Such analyses can be very challenging, however, since biological pathways are modular and may exhibit co-expression only in specific contexts. To overcome these challenges we introduce CLIC, CLustering by Inferred Co-expression. CLIC accepts as input a pathway consisting of two or more genes. It then uses a Bayesian partition model to simultaneously partition the input gene set into coherent co-expressed modules (CEMs), while assigning the posterior probability for each dataset in support of each CEM. CLIC then expands each CEM by scanning the transcriptome for additional co-expressed genes, quantified by an integrated log-likelihood ratio (LLR) score weighted for each dataset. As a byproduct, CLIC automatically learns the conditions (datasets) within which a CEM is operative. We implemented CLIC using a compendium of 1774 mouse microarray datasets (28628 microarrays) or 1887 human microarray datasets (45158 microarrays). CLIC analysis reveals that of 910 canonical biological pathways, 30% consist of strongly co-expressed gene modules for which new members are predicted. For example, CLIC predicts a functional connection between protein C7orf55 (FMC1) and the mitochondrial ATP synthase complex that we have experimentally validated. CLIC is freely available at www.gene-clic.org. We anticipate that CLIC will be valuable both for revealing new components of biological pathways as well as the conditions in which they are active.


Optimal Allocation of Node Capacity in Cascade-Robustness Networks.
The robustness of large scale critical infrastructures, which can be modeled as complex networks, is of great significance. One of the most important means to enhance robustness is to optimize the allocation of resources. Traditional allocation of resources is mainly based on the topology information, which is neither realistic nor systematic. In this paper, we try to build a framework for searching for the most favorable pattern of node capacity allocation to reduce the vulnerability to cascading failures at a low cost. A nonlinear and multi-objective optimization model is proposed and tackled using a particle swarm optimization algorithm (PSO). It is found that the network becomes more robust and economical when less capacity is left on the heavily loaded nodes and the optimized network performs better resisting noise. Our work is helpful in designing a robust economical network.


Methods to Study Epithelial Transport Protein Function and Expression in Native Intestine and Caco-2 Cells Grown in 3D.
The intestinal epithelium has important transport and barrier functions that play key roles in normal physiological functions of the body while providing a barrier to foreign particles. Impaired epithelial transport (ion, nutrient, or drugs) has been associated with many diseases and can have consequences that extend beyond the normal physiological functions of the transporters, such as by influencing epithelial integrity and the gut microbiome. Understanding the function and regulation of transport proteins is critical for the development of improved therapeutic interventions. The biggest challenge in the study of epithelial transport is developing a suitable model system that recapitulates important features of the native intestinal epithelial cells. Several in vitro cell culture models, such as Caco-2, T-84, and HT-29-Cl.19A cells are typically used in epithelial transport research. These cell lines represent a reductionist approach to modeling the epithelium and have been used in many mechanistic studies, including their examination of epithelial-microbial interactions. However, cell monolayers do not accurately reflect cell-cell interactions and the in vivo microenvironment. Cells grown in 3D have shown to be promising models for drug permeability studies. We show that Caco-2 cells in 3D can be used to study epithelial transporters. It is also important that studies in Caco-2 cells are complemented with other models to rule out cell specific effects and to take into account the complexity of the native intestine. Several methods have been previously used to assess the functionality of transporters, such as everted sac and uptake in isolated epithelial cells or in isolated plasma membrane vesicles. Taking into consideration the challenges in the field with respect to models and the measurement of transport function, we demonstrate here a protocol to grow Caco-2 cells in 3D and describe the use of an Ussing chamber as an effective approach to measure serotonin transport, such as in intact polarized intestinal epithelia.


An influent responsive control strategy with machine learning: Q-learning based optimization method for a biological phosphorus removal system.
Biological phosphorus removal (BPR) is an economical and sustainable processes for the removal of phosphorus (P) from wastewater, achieved by recirculating activated sludge through anaerobic and aerobic (An/Ae) processes. However, few studies have systematically analyzed the optimal hydraulic retention times (HRTs) in anaerobic and aerobic reactions, or whether these are the most appropriate control strategies. In this study, a novel optimization methodology using an improved Q-learning (QL) algorithm was developed, to optimize An/Ae HRTs in a BPR system. A framework for QL-based BPR control strategies was established and the improved Q function, Qt+1(st,st+1)=Qt(st,st+1)+k·[R(st,st+1)+γ·maxatQt(st,st+1)-Qt(st,st+1)] was derived. Based on the improved Q function and the state transition matrices obtained under different HRT step-lengths, the optimum combinations of HRTs in An/Ae processes in any BPR system could be obtained, in terms of the ordered pair combinations of the <current state-transition state>. Model verification was performed by applying six different influent chemical oxygen demand (COD) concentrations, varying from 150 to 600 mg L-1 and influent P concentrations, varying from 12 to 30 mg L-1. Superior and stable effluent qualities were observed with the optimal control strategies. This indicates that the proposed novel QL-based BPR model performed properly and the derived Q functions successfully realized real-time modelling, with stable optimal control strategies under fluctuant influent loads during wastewater treatment processes.


The role of regulatory B cells (Bregs) in the Tregs-amplifying effect of Sirolimus.
Sirolimus can significantly amplify regulatory T cells (Tregs) in vivo and in vitro, but the specific mechanism of this has not been well documented. The role of regulatory B cells (Bregs) in the Tregs-amplifying effect of Sirolimus was investigated in peripheral blood mononuclear cells (PBMCs) in vitro in this study. The results showed that the percentages of both CD19+CD24+CD38+TGF-β1+ Bregs and CD19+CD24+CD38+IL-10+ Bregs to B cells were elevated by Sirolimus in PBMCs including B cells. Sirolimus significantly enhances the cytokine production of transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) in PBMCs with B cells, and the enhancement significantly decreased in PBMCs without B cells. The percentage of CD4+CD25+Foxp3+ Tregs to T cells was also elevated by Sirolimus in PBMCs including B cells. The elevation of Tregs percentage decreased in PBMCs without B cells and recovered when additional TGF-β1 and IL-10 were added. The amplification of Tregs by Sirolimus was partially inhibited when either TGF-β1 or IL-10 was neutralized, and it even disappeared when these two cytokines were both neutralized. These results indicate that Sirolimus can amplify Bregs and Tregs in PBMCs in vitro, and Bregs may be the why Sirolimus amplifies Tregs.


Catalytic transformation of persistent contaminants using a new composite material based on nanosized zero-valent iron.
A new composite material based on deposition of nanosized zerovalent iron (nZVI) particles and cyanocobalamine (vitamin B12) on a diatomite matrix is presented, for catalytic transformation of organic contaminants in water. Cyanocobalamine is known to be an effective electron mediator, having strong synergistic effects with nZVI for reductive dehalogenation reactions. This composite material also improves the reducing capacity of nZVI by preventing agglomeration of iron nanoparticles, thus increasing their active surface area. The porous structure of the diatomite matrix allows high hydraulic conductivity, which favors channeling of contaminated water to the reactive surface of the composite material resulting in faster rates of remediation. The composite material rapidly degrades or transforms completely a large spectrum of water contaminants, including halogenated solvents like TCE, PCE, and cis-DCE, pesticides like alachlor, atrazine and bromacyl, and common ions like nitrate, within minutes to hours. A field experiment where contaminated groundwater containing a mixture of industrial and agricultural persistent pollutants was conducted together with a set of laboratory experiments using individual contaminant solutions to analyze chemical transformations under controlled conditions.


[Immunohistochemical demonstration of carcinoembryonic antigen and ultrastructural features of endometrial adenocarcinoma].
Determination of carcinoembryonic antigen levels in plasma (45 cases) and the immunohistochemical demonstration of tumor CEA (37 cases) were carried out in patients with endometrial adenocarcinoma. Twenty four out of 37 were also studied with the electron microscope. The plasma CEA level prior to therapy was significantly elevated (greater than 5.0ng/ml) in only one case (1/45:2.2%) of endometrial adenocarcinoma. CEA levels were more consistently elevated (4/17:23.5%) in patients with cervical adenocarcinoma. Immunoperoxidase staining of CEA (PAP method) was carried out using formalin-fixed paraffin embedded sections of 37 tumors. Tissue CEA activities were found in 9 out of 37 endometrial adenocarcinomas (24.3%) and 19 of 23 cervical adenocarcinomas (82.6%). Immunoreactive CEA was present in a high concentration on the cell surface of endometrial glands and less dense in their cytoplasm. In 9 of CEA positive endometrial carcinoma tissues, squamous metaplastic lesions were found in 4 cases and mucinous metaplasia in one case which were all CEA positive. With regard to the histopathological grade, CEA positive specimens were categorized G1 (4) and G2 (5) and all of the G3 were CEA negative. Seven of 9 cases of CEA positive specimens were examined under the electron microscope. There was no definite tendency in their ultrastructural characteristics, but all of the specimens examined revealed abundant cytoplasmic organelles suggestive of intracytoplasmic differentiation analogous to those of endometrial cells in proliferative phase. Moreover, fine structures of squamous and mucinous metaplastic cells were also described in detail.


Mcl-1 inhibitor suppresses tumor growth of esophageal squamous cell carcinoma in a mouse model.
Esophageal squamous cell carcinoma (ESCC) has a high morbidity in China, accounting for 90% of all esophageal carcinoma cases. Hence, identifying drug targets for prevention and treatment of ESCC is essential. Due to its critical role in the regulation of cell apoptosis, Mcl-1 holds great potential as a target for treatment against ESCC. In current study, we used a 4-nitroquinoline-1-oxide (4-NQO)-induced ESCC mouse model of test whether A-1210477, a Mcl-1 small molecular inhibitor, could repress ESCC development. We showed that A-1210477 treatment decreased ESCC formation and animal weight loss in a dose dependent manner. We detected decreased cellular proliferation in A-1210477-treated ESCC tissue by Ki67 expression. Moreover, A-1210477 treatment increased the number of apoptotic cells in ESCC tissues. Our study clearly demonstrates the contribution of Mcl-1 to ESCC development through promoting cell proliferation and inhibition of apoptosis, and provides a strong evidence for further evaluation of A-1210477 for treating ESCC.


Cordyceps sinensis aqueous extract regulates the adaptive immunity of mice subjected to 60 Co γ irradiation.
Cordyceps sinensis (CS) is a traditional Chinese medicine that is known for treating various diseases, and particularly for exerting therapeutic effects in immune disorders. The adaptive immunoregulatory effects of CS aqueous extract (CSAE) on γ-irradiated mice have not been reported previously. The study aimed to evaluate the therapeutic effects of CSAE in mice immunosuppressed by irradiation. We observed that CSAE administration significantly increased body weight and spleen index, as well as the number of white blood cells, lymphocytes, and platelets in peripheral blood, T and B lymphocytes in spleen tissue, and total serum immunoglobulins in irradiated mice, whereas total serum pro-inflammatory cytokine levels were decreased. Collectively, CSAE maintained the structural integrity of spleen tissue and repaired its damage in irradiated mice as shown by hematoxylin and eosin staining, and decreased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive splenocytes. Mechanistically, CSAE upregulated Bcl-2, and downregulated Bax and cleaved caspase-3 in spleen of irradiated mice. However, there were no significant differences in red blood cells and neutrophils in different groups. The results revealed that CSAE had protective effects against irradiation-induced immunosuppression, which was likely associated with an antiapoptotic effect and the regulation of adaptive immunity.


A Deep Quality Monitoring Network for Quality-Related Incipient Faults.
Although quality-related process monitoring has achieved the great progress, scarce works consider the detection of quality-related incipient faults. Partial least square (PLS) and its variants only focus on faults with larger magnitudes. In this article, a deep quality monitoring network (DQMNet) for quality-related incipient fault detection is developed. DQMNet includes the feature input layer, feature extraction layers, and the output layer. In the feature input layer, collected variables are divided according to quality variables, and then, features are extracted, respectively, through base detectors. For the feature extraction layers, singular values (SVs) of sliding-window patches and principal component analysis (PCA) are adopted to mine the hidden information layer by layer. For the output layer, statistics are constructed from quality-related/unrelated feature matrix through Bayesian inference. The superiority of DQMNet is demonstrated by a numerical simulation and the benchmark data of Tennessee Eastman process (TEP).


Proton decoupling and recoupling under double-nutation irradiation in solid-state NMR.
The effect of (1)H decoupling in magic-angle spinning solid-state NMR is studied under radiofrequency irradiation causing simultaneous nutations around a pair of orthogonal axes. Double-nutation with an arbitrary pair of nutation frequencies is implemented through modulation of the amplitude, phase, and frequency of the transmitting pulses. Similarity and difference of double-nutation decoupling and two-pulse phase-modulation decoupling schemes [A. E. Bennett, C. M. Rienstra, M. Auger, K. V. Lakshmi, and R. G. Griffin, J. Chem. Phys. 103, 6951-6958 (1995) and I. Scholz, P. Hodgkinson, B. H. Meier, and M. Ernst, J. Chem. Phys. 130, 114510 (2009)] are discussed. The structure of recoupling bands caused by interference of the (1)H spin nutation with sample spinning is studied by both experiments and numerical simulations.


Endoscopic screening for premalignant changes 25 years after gastrectomy: results of a five-year prospective study.
Sixty-three partial gastrectomy patients an average 20 years after surgery were reviewed by endoscopy and biopsy in 1977. No cases of invasive carcinoma were found. The patients were then divided into two groups. Those with moderate epithelial dysplasia (13 patients) were reviewed at 6-12 monthly intervals. One patient developed severe dysplasia but none developed an invasive carcinoma. The remaining patients with either no or mild dysplasia were offered endoscopy after 5 years and 24 agreed. Of the 12 patients with no dysplasia at the outset: 5 still had no dysplasia 5 years later, 3 had mild dysplasia and 4 now had moderate dysplasia. There were 12 with mild dysplasia at the first endoscopy, 9 remained unchanged at the review and 3 had moderate dysplasia. If dysplastic changes in gastric mucosa are pre-malignant, progression to invasive carcinoma would appear to be slow. Even 25 years after gastrectomy only a modest deterioration in the grade of dysplasia was found and no invasive cancer.


Whole-body thallium imaging in coronary artery disease.
The aim of this study was to evaluate the incidence, type, and severity of asymptomatic leg perfusion abnormalities in 116 male patients with proven coronary artery disease (CAD) who performed near-maximal treadmill test. Interextremity asymmetry was observed in 60% of patients, but the incidence of this sign increased with age (from 35% below forty-five years of age to 72% over sixty-one years). Asymmetry was very marked or marked in 61% of all segments and moderate in 39% of them. A significant decrease in fractional uptake was observed in 21% of patients with CAD and in 25% of those with interextremity asymmetry. Myocardial ischemia, which was defined by reversible defects on myocardial tomoscintigraphy, was three times more frequent in patients with interextremity asymmetry than in patients with normal results from exercise whole-body thallium scintigraphy. This observation, combined with type, extent, and location of asymmetry, is highly suggestive of silent peripheral arterial disease in most cases. Whole-body scan could easily be performed following an exercise myocardial thallium scan so as to provide information on multifocal atherosclerosis in patients with CAD or multiple and severe vascular risk factors. The prognostic value of these silent peripheral muscle perfusion abnormalities remains to be established.


Orange-Light-Induced Photochemistry Gated by pH and Confined Environments.
We introduce a new photochemically active compound, i.e., pyridinepyrene (PyPy), entailing a pH-active moiety that effects a significant halochromic shift into orange-light (λ = 590 nm) activatable photoreactivity while concomitantly exerting control over its reaction pathways. With blue light (λ = 450 nm) in neutral to basic pH, a [2 + 2] photocycloaddition can be triggered to form a cyclobutene ring in a reversible fashion. If the pH is decreased to acidic conditions, resulting in a halochromic absorption shift, photocycloaddition on the small-molecule level is blocked due to repulsive interactions and exclusive trans-cis isomerization is observed. Through implementation of PyPy into the confined environment of a single-chain nanoparticle (SCNP) design, one can overcome the repulsive forces and exploit the halochromic shift for orange light (λ = 590 nm)-induced cycloaddition and formation of macromolecular three-dimensional (3D) architectures.


Granulocyte transfusion – when and how should it be used?
There are no randomized controlled trials proving the clinical benefit of granulocyte transfusions. However, clinical experience and a number of case studies suggest that granulocyte transfusions may be life-saving in certain situations. In our opinion granulocyte transfusions should be considered for patients with profound neutropenia and severe, life-threatening infection not responding to antibiotic or antifungal therapy. Since the clinical effect seems to be dose-dependent, the granulocyte concentrate should contain a large number of cells, which usually means that the donor should be mobilized with steroids and G-CSF. Regular blood donors as well as relatives to the patient can be used for granulocyte donations with apheresis technique after information of the process. Granulocyte transfusion should be given daily as long as the indication remains. The clinical efficacy of the transfusions should be evaluated daily.


The integration of physiologically-targeted skin care in the management of atopic dermatitis: focus on the use of a cleanser and moisturizer system incorporating a ceramide precursor, filaggrin degradation products, and specific "skin-barrier-friendly" excipients.
Atopic dermatitis (AD) may be considered the "poster disease" for exemplifying the significance of abnormalities of the epidermal barrier that occur predominantly within the stratum corneum (SC) and upper epidermis. Specifically, impairments of the SC permeability barrier, antimicrobial barrier, and immunologic barrier contribute markedly to the fundamental pathophysiology of AD. The multiple clinical sequelae associated with epidermal barrier impairments inherent to AD include dry skin, pruritus, increased skin sensitivity to irritants and allergens, eczematous skin changes, staphylococcal skin and anterior nares colonization, and increase in some cutaneous infections (ie, molluscum contagiosum). This article addresses the pathophysiology of AD with clinically relevant correlations, and discusses the scientific basis of a specially designed cleanser and moisturizer system that incorporates ceramide technology and filaggrin degradation products along with other "barrier-friendly" excipients.


Vertebrobasilar insufficiency revealed by xenon-133 inhalation SPECT.
A study of cerebral and cerebellar blood flow reactivity to acetazolamide by xenon-133-inhalation single photon emission computed tomography (133Xe SPECT) was carried out in a patient with bouts of transient basilar ischemia, whose neurological examination, computed tomographic scan, and auditory evoked potentials were normal. Though the patient was symptom-free at the time of the study, 133Xe SPECT demonstrated vertebrobasilar insufficiency by showing an impaired vasodilatory response in both the occipital lobes and the right cerebellar hemisphere. Three weeks later, the patient suffered an extensive stroke in these same areas. We therefore suggest that this method could be of great value in the assessment of vertebrobasilar insufficiency.


Neuroprotective effects of α-iso-cubebene against glutamate-induced damage in the HT22 hippocampal neuronal cell line.
Since oxidative stress is critically involved in excitotoxic damage, we sought to determine whether the activation of the transcription factors, cAMP-responsive element binding protein (CREB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2, also known as NFE2L2), by α-iso-cubebene is involved in its protective effects against glutamate-induced neuronal cell death. Pre-treatment with α-iso-cubebene significantly attenuated glutamate-induced cytotoxicity in mouse hippocampus-derived neuronal cells. α-iso-cubebene also reduced the glutamate-induced generation of reactive oxygen species and calcium influx, thus preventing apoptotic cell death. α-iso-cubebene inhibited glutamate-induced mitochondrial membrane depolarization and, consequently, inhibited the release of the apoptosis-inducing factor from the mitochondria. Immunoblot anlaysis revealed that the phosphorylation of extracellular signal-regulated kinase (ERK) by glutamate was reduced in the presence of α-iso-cubebene. α-iso-cubebene activated protein kinase A (PKA), CREB and Nrf2, which mediate the expression of the antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1), involved in neuroprotection. In addition, α-iso-cubebene induced the expression of antioxidant responsive element and CRE transcriptional activity, thus conferring neuroprotection against glutamate-induced oxidative injury. α-iso-cubebene also induced the expression of Nrf2-dependent genes encoding HO-1 and NQO1. Furthermore, the knockdown of CREB and Nrf2 by small interfering RNA attenuated the neuroprotective effects of α-iso-cubebene. Taken together, our results indicate that α-iso-cubebene protects HT22 cells from glutamate-induced oxidative damage through the activation of Nrf2/HO-1/NQO-1, as well as through the PKA and CREB signaling pathways.


Involvement of mu- and delta-opioid receptors in the effects of systemic and locally perfused morphine on extracellular levels of dopamine, DOPAC and HVA in the nucleus accumbens of the halothane-anaesthetized rat.
The effects of systemic and intra-accumbens infusion of morphine on the extracellular level of dopamine (DA) and its metabolites, DOPAC and HVA, were investigated in the nucleus accumbens (NAcc) of halothane-anaesthetized rats using in vivo microdialysis. Morphine in a dose of 1 or 5 mg/kg i.v. produced a significant increase (60-100% of baseline levels) in the extracellular level of DA for at least 3 h. Morphine at 5, but not 1 mg/kg, produced a small (10-15%) but significant reduction in the level of DOPAC when compared with saline in the first h following injection. Pretreatment with the preferential mu-opioid receptor antagonist naloxone in a dose of 1 or 3 mg/kg i.p. significantly blocked the morphine-induced changes in the extracellular levels of DA and DOPAC. Pretreatment with the selective delta-opioid receptor antagonist, naltrindole, at 1 mg/kg i.p. blocked only the morphine-induced decrease in DA metabolism. Furthermore, in the presence of naltrindole, systemic morphine induced a large and long-lasting increase in the level of DOPAC and HVA, which was significantly higher than in rats receiving combinations of saline/water + saline, saline/water + morphine and naltrindole + saline. When applied directly into the NAcc, morphine at concentrations of 125, 250 and 500 ng infused over 10 min produced a dose-related increase in the extracellular level of accumbens DA with either no effect or a small reduction in the level of DOPAC and HVA. The effects of intra-accumbens morphine on DA levels were significantly blocked by pretreatment with i.p. naltrindole but not naloxone. These results indicate that, while systemic morphine probably increases DA via activation of mu-opioid receptors, local perfusion of morphine increases DA in the NAcc via activation of delta-opioid receptors located in the NAcc. Furthermore, under the conditions of the study, it appears that activation of mu- and delta-opioid receptors by morphine respectively increases and decreases DA metabolism.


Estimated health benefits, costs and cost-effectiveness of eliminating dietary industrial trans fatty acids in Kenya: cost-effectiveness analysis.
To model the potential health gains and cost-effectiveness of a mandatory limit of industrial trans fatty acids (iTFA) in Kenyan foods. Multiple cohort proportional multistate life table model, incorporating existing data from the Global Burden of Disease study, pooled analyses of observational studies and peer-reviewed evidence of healthcare and policy implementation costs. Kenya. Adults aged ≥20 years at baseline (n=50 million). A mandatory iTFA limit (≤2% of all fats) in the Kenyan food supply compared with a base case scenario of maintaining current trans fat intake. Averted ischaemic heart disease (IHD) events and deaths, health-adjusted life years; healthcare costs; policy implementation costs; net costs; and incremental cost-effectiveness ratio. Over the first 10 years, the intervention was estimated to prevent ~1900 (95% uncertainty interval (UI): 1714; 2148) IHD deaths and ~17 000 (95% UI: 15 475; 19 551) IHD events, and to save ~US$50 million (95% UI: 44; 56). The corresponding estimates over the lifespan of the model population were ~49 000 (95% UI: 43 775; 55 326) IHD deaths prevented, ~113 000 (95% UI: 100 104; 127 969) IHD events prevented and some ~US$300 million (256; 331) saved. Policy implementation costs were estimated as ~US$9 million over the first 10 years and ~US$20 million over the population lifetime. The intervention was estimated to be cost saving regardless of the time horizon. Findings were robust across multiple sensitivity analyses. Findings support policy action for a mandatory iTFA limit as a cost-saving strategy to avert IHD events and deaths in Kenya.


EVOLUTIONARY ADAPTATION TO TEMPERATURE II. THERMAL NICHES OF EXPERIMENTAL LINES OF ESCHERICHIA COLI.
Groups of replicated lines of the bacterium Escherichia coli were propagated for 2,000 generations at constant 32, 37, or 42°C, or in an environment that alternated between 32 and 42°C. Here, we examine the performance of each group across a temperature range of 12-44°C measuring the temperatures over which each line can maintain itself in serial dilution culture (the thermal niche). Thermal niche was not affected by selection history: average lower and upper limits remained about 19 and 42°C for all groups. In addition, no significant differences among groups were observed in rate of extinction at more extreme temperatures. Within the thermal niche, we measured the mean fitness of the evolved groups relative to their common ancestor. Increases in mean fitness were temperature specific, with the largest increase for each group occurring near its selected temperature. Thus, the temperature at which mean fitness relative to the ancestor was greatest (the thermal optimum) diverged by about 10°C for the groups selected at constant 32°C versus constant 42°C. Tradeoffs in relative fitness (decrements relative to the ancestor elsewhere within the thermal niche) did not necessarily accompany fitness improvements, although tradeoffs were observed for a few of the lines. We conclude that adaptation in this system was quite temperature specific, but substantial divergence among groups in thermal optima had little effect on the limits of their thermal niches and did not necessarily involve tradeoffs in fitness at other temperatures.


Interpolation of diabatic potential-energy surfaces: quantum dynamics on ab initio surfaces.
A method for constructing diabatic potential-energy matrices from ab initio quantum chemistry data is described and tested for use in exact quantum reactive scattering. The method is a refinement of that presented in a previous paper, in that it accounts for the presence of the nonremovable derivative coupling. The accuracy of quantum dynamics on this type of diabatic potential is tested by comparison with an analytic model and for an ab initio description of the two lowest-energy states of H3.


Alcohol Consumption and Cardiovascular Disease: A Mendelian Randomization Study.
The causal role of alcohol consumption for cardiovascular disease remains unclear. We used Mendelian randomization (MR) to predict the effect of alcohol consumption on 8 cardiovascular diseases. Up to 94 single-nucleotide polymorphisms were used as instrumental variables for alcohol consumption. Genetic association estimates for cardiovascular diseases were obtained from large-scale consortia and UK Biobank. Analyses were conducted using the inverse variance-weighted, weighted median, MR-PRESSO, MR-Egger, and multivariable MR methods. Genetically predicted alcohol consumption was consistently associated with stroke and peripheral artery disease across the different analyses. The odds ratios (ORs) per 1-SD increase of log-transformed alcoholic drinks per week were 1.27 ([95% CI, 1.12-1.45] P=2.87×10-4) for stroke and 3.05 ([95% CI, 1.92-4.85] P=2.30×10-6) for peripheral artery disease in the inverse variance-weighted analysis. There was some evidence for positive associations of genetically predicted alcohol consumption with coronary artery disease (OR, 1.16 [95% CI, 1.00-1.36]; P=0.052), atrial fibrillation (OR, 1.17 [95% CI, 1.00-1.37]; P=0.050), and abdominal aortic aneurysm (OR, 2.60 [95% CI, 1.15-5.89]; P=0.022) in the inverse variance-weighted analysis. These associations were somewhat attenuated in multivariable MR analysis adjusted for smoking initiation. There was no evidence of associations of genetically predicted alcohol consumption with heart failure (OR, 1.00 [95% CI, 0.68-1.47]; P=0.996), venous thromboembolism (OR, 1.04 [95% CI, 0.77-1.39]; P=0.810), and aortic valve stenosis (OR, 1.03 [95% CI, 0.56-1.90]; P=0.926). This study provides evidence of a causal relationship between higher alcohol consumption and increased risk of stroke and peripheral artery disease. The causal role of alcohol consumption for other cardiovascular diseases requires further research.


Mutation of a single TMVI residue, Phe(282), in the beta(2)-adrenergic receptor results in structurally distinct activated receptor conformations.
We showed previously that Phe(303) in transmembrane segment (TM) VI of the alpha(1B)-adrenergic receptor (alpha(1B)-AR), a residue conserved in many G protein-coupled receptors (GPCRs), is critically involved in coupling agonist binding with TM helical movement and G protein activation. Here the equivalent residue, Phe(282), in the beta(2)-AR was evaluated by mutation to glycine, asparagine, alanine, or leucine. Except for F282N, which exhibits attenuated basal and maximal isoproterenol stimulation, the Phe(282) mutants display varying degrees of constitutive activity (F282L > F282A > F282G), and as shown by the results of substituted cysteine accessibility method (SCAM) studies, induce movement of endogenous cysteine(s) into the water-accessible ligand-binding pocket. For F282A, movement is confined to Cys(285) in TMVI, whereas F282L induces movement of both Cys(285) in TMVI and Cys(327) in TMVII. Further, engineered cysteine-sensor studies indicate that F282L causes movement of TMVI, both above and below an apparent kink-inducing TMVI proline (Pro(288)), whereas that due to F282A is confined to the domain below Pro(288). A plausible interpretation of these data is that receptor activation involves rigid body movement of TMVI which, because of its Pro(288)-induced kink, acts as a pivot to transduce and amplify the agonist-induced conformational change in the upper domain, to a change in the lower domain required for productive receptor-G protein coupling.


Losartan affects glomerular AKT and mTOR phosphorylation in an experimental model of type 1 diabetic nephropathy.
The AKT-mTOR pathway is activated in diabetic nephropathy. Renin-angiotensin system modulators exert beneficial effects on the diabetic kidney. We explored the action of losartan on AKT-mTOR phosphorylation in glomeruli and podocytes. Diabetes mellitus was induced to Sprague-Dawley rats by streptozotocin. Five months later, the rats were commenced on losartan and euthanized 2 months later. Kidneys were processed for immunofluorescence studies. Glomeruli were isolated for Western blot analysis. Diabetes increased activated forms of AKT and mTOR both in glomeruli and podocytes. In diabetic rats, losartan decreased phosphorylated/activated forms of AKT (Thr308) and mTOR (Ser2448) in glomeruli but decreased only activated mTOR in podocytes. However, in both glomeruli and podocytes of healthy animals, an inverse pattern was evident. In conclusion, a new body of evidence indicates the differential activation of AKT-mTOR in glomeruli and podocytes of healthy and diabetic animals in response to losartan.


Mitochondria-targeting ratiometric fluorescent probe for γ-glutamyltranspeptidase and its application to colon cancer.
A mitochondria-targeting ratiometric probe was designed for γ-glutamyltranspeptidase (γGT). Mechanistic study by HPLC and an inhibitor assay showed that the probe underwent γGT-mediated amide-to-amine transformation and induced a ratiometric fluorescence response in cellular mitochondria. Further application was successful for the detection of cancerous colons in mice.


Environmental Protection through waste management, Implications for staff development.
Increasing public concern is focusing on healthcare providers as a primary source of medical waste. As nurses practice in expanded roles in a variety of settings, attention must be paid to teaching them how to be ecologically responsible by assessing the environmental impact of the services they provide and providing ways to reduce the volume of waste.


Progression of Blood Flow Restricted Resistance Training in Older Adults at Risk of Mobility Limitations.
Blood flow restriction (BFR) resistance training leads to increased muscle mass and strength but the progression leading to adaptations may be different as strength gains are often to a lesser magnitude than high-load (HL) training. The impact of training loads and repetitions on older adults' muscle mass and strength following BFR or HL training was evaluated. Twenty-one older adults (67-90 years) classified as being at risk of mobility limitations were randomly assigned to HL (n = 11) or BFR (n = 10) knee extension (KE) and flexion (KF) training twice per week for 12 weeks. Strength was measured with 10-repetition maximum (10-RM) tests and isometric contractions. Cross-sectional area (CSA) of the quadriceps and hamstrings was measured. HL and BFR interventions increased 10-RM KF and isometric strength (P < 0.05) and hamstrings CSA increased an average of 4.8 ± 5.9% after HL and BFR training (time main effect P < 0.01). There were no differences between the training groups (time x group interactions P > 0.05). The rate of progression of KF training load and repetitions was comparable (time × group interactions of each variable P > 0.05). The groups averaged an increase of 0.50 ± 25 kg⋅week-1 and 1.8 ± 0.1.7 repetitions⋅week-1 of training (time main effects P < 0.05). The HL training group experienced greater improvements in KE 10-RM strength than the BFR group (60.7 ± 36.0% vs. 35.3 ± 25.5%; P = 0.03). In both groups, isometric KE strength increased 17.3 ± 18.5% (P = 0.001) and there were no differences between groups (P = 0.24). Quadriceps CSA increased (time main effect P < 0.01) and to similar magnitudes (time x group interaction P = 0.62) following HL (6.5 ± 3.1%) and BFR training (7.8 ± 8.2%). The HL group experienced accelerated progression of load when compared to BFR (0.90 ± 0.60 kg⋅week-1 vs. 30 ± 0.21 kg⋅week-1; P = 0.006) but was not different when expressed in relative terms. BFR training progressed at a rate of 3.6 ± 1.3 repetitions⋅week-1 while the HL group progressed at 2.2 ± 0.43 repetitions⋅week-1 (P = 0.003). HL training led to greater increases in KE 10-RM and it may be attributed to the greater load and/or faster rate of progression of the load throughout the 12-week training period and the specificity of the testing modality. Incorporating systematic load progression throughout BFR training periods should be employed to lead to maximal strength gains.


Oral administration of natural polyphenol-loaded natural polysaccharide-cloaked lipidic nanocarriers to improve efficacy against small-cell lung cancer.
Oral administration shows good tolerance in patients. Botanic anticancer drugs without serious side effects have attracted increased attention worldwide. However, oral delivery of natural anticancer drugs faces great challenges due to low solubility, gastrointestinal side effects, first-pass effects, and P-glycoprotein efflux. Here, we loaded the natural polyphenol curcumin (Cc) into natural polysaccharide-cloaked lipidic nanocarriers (Cc@CLNs) to improve the efficacy in small-cell lung cancer (SCLC) associated with oral administration. Compared to other nanoformulations, Cc@CLNs have advantages of simple operation, easy scale-up, low cost, and high safety. Cc@CLNs improve bioavailability by inducing synergistic effects (efficient cell membrane penetration, inherent muco-adhesiveness, resistance to pepsin and trypsin degradation, promoted dissolution, enhanced epithelia/M cellular uptake and inhibition of efflux transporters) and countering the tendency of nanocarriers to aggregate and fuse, which limit lipid-based nanosystems. In this study, we first evaluated the oral bioavailability of Cc@CLNs in rats and their efficacy in H446 tumor-bearing mice. The oral bioavailability increased by 8.94-fold, and the tumor growth inhibition rate doubled compared to that achieved with free Cc. We investigated the action of Cc against SCLC stem cells, and Cc@CLNs greatly enhanced this action. The expression of CD133 and ABCG2 in the Cc@CLNs group decreased by 38.05% and 32.57%, respectively, compared to the respective expression levels in the control.


Long-term functional and psychological recovery in a population of acute respiratory distress syndrome patients treated with VV-ECMO and in their caregivers.
Acute respiratory distress syndrome (ARDS) survivors are affected with long-term physical/mental impairments, with improvements limited mostly to the first year after intensive care (ICU) discharge. Furthermore, caregivers of ICU patients exhibit psychological problems after family-member recovery. We evaluated the long-term physical and mental recovery of ARDS survivors treated with veno-venous extracorporeal membrane oxygenation (VV-ECMO), and the long-term psychological impact on their caregivers. Single-center prospective evaluation of a retrospective cohort of 75 ARDS patients treated with VV-ECMO during a seven-year period (25.10.2009-11.08.2016). Primary outcomes were the 36-Item Short-Form Health-Survey (SF-36, patients only), and risks of depression, anxiety or post-traumatic stress disorder (PTSD), both for patients and their caregivers. We investigated correlations between outcomes and population characteristics. Of 50 ICU-survivors, seven died later and five were not contactable. Among 38 living patients, 33 participated (87%, 31 with their caregiver) with 2.7 years of median follow-up. Physical and mental SF-36 component scores were 42 (inter-quartile range, IQR:22) and 52 (IQR:18.5), respectively. The worst domains of the SF-36 were physical-role limitations (25, IQR:100) and general-health perception (56, IQR:42.5). Psychological tests highlighted high risk of depression (39-42%, patients; 39-52%, caregivers), anxiety (42%, patients; 39%, caregivers), and PTSD (47%, patients; 61%, caregivers). Patient depression or anxiety scores were correlated to age and to the outcome reported by caregivers. At almost three-year follow-up, ARDS survivors treated with VV-ECMO showed reduced health-related quality-of-life and high risk of psychological impairment, in particular PTSD. Caregivers of this population were at high psychological risk as well.


Anti-inflammatory and antinociceptive activities of Seseli L. species (Apiaceae) growing in Turkey.
The ethyl acetate and methanol (80%) extracts obtained from 10 Seseli L. species (Apiaceae) growing in Turkey, Seseli andronakii Woron., Seseli campestre Besser, Seseli gummiferum Pall. ex Sm. subsp. corymbosum (Boiss. and Heldr.) P.H. Davis, Seseli gummiferum Pall. ex Sm. subsp. gummiferum, Seseli hartvigii Parolly and Nordt, Seseli libanotis (L.) W. Koch, Seseli petraeum M. Bieb., Seseli peucedanoides (Bieb.) Koso-Pol., Seseli resinosum Freyn and Sint., Seseli tortuosum L. were evaluated for their in vivo anti-inflammatory and antinociceptive activities. For the preliminary screening of anti-inflammatory activity, carrageenan-induced hind paw edema and for the antinociceptive activity, p-benzoquinone-induced abdominal constriction test were used. Among the plant extracts, the ethyl acetate extracts from Seseli andronakii, Seseli campestre, Seseli gummiferum subsp. corymbosum, Seseli petraeum, Seseli resinosum and Seseli tortuosum showed 30.1, 32.3, 36.9, 39.8, 35.1, 37.6% inhibition in p-benzoquinone-induced abdominal constriction test, respectively. The ethyl acetate extracts of Seseli gummiferum subsp. corymbosum, Seseli petraeum, Seseli resinosum and Seseli tortuosum also exhibited notable inhibition, ranging between 24.5-29.7, 28.1-33.3, 17.4-27.5 and 27.9-31.3%, respectively, in carrageenan-induced hind paw edema model at 100 mg/kg dose without inducing any gastric damage, quite comparable to indomethacin (41.8-44.8% inhibition) as a reference sample. During the acute toxicity evaluation, neither death nor gastric bleeding was observed for any of the plant extracts. Results have supported the traditional use of some Seseli species against inflammatory disorders. Further studies are warranted to define and isolate the active anti-inflammatory and antinociceptive components from the active species which may yield safe and effective agents to be used in current treatments.


Evidence that two sizes of ventromedial hypothalamic neurones project to the mesencephalic central grey matter in rats.
The spatial spread of the extracellular antidromic action potentials was measured in eighty-three neurones in the ventromedial nucleus region of the female rat hypothalamus following electrical stimulation of the mesencephalic central grey matter. The positive-negative configuration of the antidromic action potentials across the extracellular field suggested that the potentials were generated predominantly by neuronal soma with simple geometries. When represented by the distance travelled by the electrode, at which peak-to-peak spike amplitude exceeded the half maximum value, the spatial spread of the extracellular field ranged from 25 to 174 micron. The frequency distribution for the field size was distinctively bimodal and could be divided into large and small groups at 85 micron. Antidromic action potentials with larger extracellular fields had significantly larger maximum spike amplitude and shorter duration, indicating that differences in field size were associated with neuronal size. At least 55% of the central grey projection of the ventromedial nucleus originated from small neurones. Taking into account the sampling bias, a much greater proportion of the central grey projection may arise from small neurones. The lack of a systematic difference in the antidromic spike latencies between large and small cells indicated that axonal thickness is not the major factor in determining the latency of the responses of the ventromedial hypothalamic neurones to stimulation of the central grey matter.


TEsoNet: knowledge transfer in surgical phase recognition from laparoscopic sleeve gastrectomy to the laparoscopic part of Ivor-Lewis esophagectomy.
Surgical phase recognition using computer vision presents an essential requirement for artificial intelligence-assisted analysis of surgical workflow. Its performance is heavily dependent on large amounts of annotated video data, which remain a limited resource, especially concerning highly specialized procedures. Knowledge transfer from common to more complex procedures can promote data efficiency. Phase recognition models trained on large, readily available datasets may be extrapolated and transferred to smaller datasets of different procedures to improve generalizability. The conditions under which transfer learning is appropriate and feasible remain to be established. We defined ten operative phases for the laparoscopic part of Ivor-Lewis Esophagectomy through expert consensus. A dataset of 40 videos was annotated accordingly. The knowledge transfer capability of an established model architecture for phase recognition (CNN + LSTM) was adapted to generate a "Transferal Esophagectomy Network" (TEsoNet) for co-training and transfer learning from laparoscopic Sleeve Gastrectomy to the laparoscopic part of Ivor-Lewis Esophagectomy, exploring different training set compositions and training weights. The explored model architecture is capable of accurate phase detection in complex procedures, such as Esophagectomy, even with low quantities of training data. Knowledge transfer between two upper gastrointestinal procedures is feasible and achieves reasonable accuracy with respect to operative phases with high procedural overlap. Robust phase recognition models can achieve reasonable yet phase-specific accuracy through transfer learning and co-training between two related procedures, even when exposed to small amounts of training data of the target procedure. Further exploration is required to determine appropriate data amounts, key characteristics of the training procedure and temporal annotation methods required for successful transferal phase recognition. Transfer learning across different procedures addressing small datasets may increase data efficiency. Finally, to enable the surgical application of AI for intraoperative risk mitigation, coverage of rare, specialized procedures needs to be explored.


Nicotinic receptor expression following nicotine exposure via maternal milk.
Studies have shown nicotine is excreted into maternal milk, so that suckling offspring would be a target of the drug during the pre-weaning period. Since nicotine exposure leads to an upregulation of neuronal nicotinic receptors, this study examines the hypothesis that nicotine delivered via maternal milk is capable of altering neuronal nicotinic receptor regulation in the drug-exposed rat pups. The present study showed that postnatal nicotine exposure via maternal milk was sufficient to induce an upregulation in brain nicotinic receptors similar to that seen in adults that smoke. Such exposure may result in altered neuronal development and synaptic activity and structure, potentially leading to long-term behavioral, learning, and memory deficits.


Congenital tuberculosis with candidal sepsis in a neonate.
About 300 cases of congenital tuberculosis have been reported in the world literature, nevertheless rarely with nonspecific clinical manifestations. Here, we report the case of a premature infant with congenital tuberculosis and septicemia due to Candida krusei, who was treated successfully.


The burden of hepatitis C virus in the world, China, India, and the United States from 1990 to 2019.
Hepatitis C virus infection can lead to an enormous health burden worldwide. Investigating the changes in HCV-related burden between different countries could provide inferences for disease management. Hence, we aim to explore the temporal tendency of the disease burden associated with HCV infection in China, India, the United States, and the world. Detailed data on the total burden of disease related to HCV infection were collected from the Global Burden of Disease (GBD) 2019 database. Joinpoint regression models were used to simulate the optimal joinpoints of annual percent changes (APCs). Further analysis of the age composition of each index over time and the relationship between ASRs and the socio-demographic Index (SDI) were explored. Finally, three factors (population growth, population aging, and age-specific changes) were deconstructed for the changes in the number of incidences, deaths, and DALYs. It was estimated that 6.2 million new HCV infections, 0.54 million HCV-related deaths, and 15.3 million DALYs worldwide in 2019, with an increase of 25.4, 59.1, and 43.6%, respectively, from 1990, are mainly due to population growth and aging. China experienced a sharp drop in age-standardized rates in 2019, the United States showed an upward trend, and India exhibited a fluctuating tendency in the burden of disease. The incidence was increasing in all locations recently. HCV remains a global health concern despite tremendous progress being made. The disease burden in China improved significantly, while the burden in the United States was deteriorating, with new infections increasing recently, suggesting more targeted interventions to be established to realize the 2030 elimination goals.


Enhanced expression and solubility of main protease (Mpro) of SARS-CoV-2 from E. coli.
The main protease (Mpro) of SARS-CoV-2 is a essential enzyme that facilitates viral transcription and replication. Furthermore, the conservation of Mpro across different variants and its non-overlapping nature with human proteases make it an appealing target for therapeutic interventions against SARS-CoV-2. Multiple inhibitors specifically target Mpro to mitigate the infection caused by SARS-CoV-2. In the current study, successful cloning and expression of SARS-CoV-2 Mpro were achieved using two E. coli hosts, namely BL21-DE3 and BL21-DE3-RIL. By optimizing the conditions for induction, the expression of Mpro in the soluble fraction of E. coli was improved. Subsequently, Mpro was purified using affinity chromatography, yielding significantly higher quantities from the BL21-DE3-RIL strain compared to the BL21-DE3 strain, with the former producing nearly twice as much as the latter. The purified Mpro was further characterized by mass spectrometry, fluorescence spectroscopy and circular dichroism (CD). Through fluorescence quenching studies, it was discovered that both GC376 and chitosan, which are inhibitors of Mpro, induced structural changes in the purified Mpro protein. This indicates that the protein retained its functional activity even after being expressed in a bacterial host. Further, FRET-based assay highlighted that the enzymatic activity of Mpro was significantly reduced in presence of both GC376 and chitosan. Consequently, the utilization of optimal conditions and the BL21-DE3-RIL bacterial host facilitates the cost-effective production of Mpro on a large scale, enabling high yields. This production approach can be applied for the screening of potent therapeutic drugs, making it a valuable resource for drug development endeavors.


Healthy food choice education for undergraduate university students: a quasi-experimental design.
A healthy diet is necessary in every period of life to protect health and prevent diseases. The main purpose of nutrition education is to convey the importance of adequate-balanced nutrition and healthy food choice in maintaining health. This study was conducted to determine the food choice behaviors of the students who took (n=95) and did not take (n=145) the "Healthy Food Choice" course at Cukurova University. The "Healthy Food Choice" course was given as an elective in the fall semester of the 2021-2022 academic year. The data were collected between April and June 2022 through a demographic questionnaire, the healthy food choice test, and the perceived stress scale (PSS). Sensory appeal and health were found to be the most important determinants, while familiarity and ethical concern were the least important factors in the food choice of the students who took the course. In the control group, sensory appeal and price were the most important determinants, while ethical concern and weight control were the least important factors. Health, natural content, and weight control were more effective in food choices of the students who took the healthy food choice course compared to the controls (p<0.05). Also, PSS score was associated with the importance of the food price positively in the case group and negatively associated with natural content in the controls. Furthermore, the present study showed that BMI was positively associated with weight control and familiarity in the HFC group and negatively associated with natural content in the control group. Giving the HFC course to university students showed positive results in terms of food choice behaviors.


Angiotensin-estrogen interaction in female brain reduces drinking and pressor responses.
Water intake fluctuates over the estrous cycle in rats, with daily intake lowest on the day of estrus. Since estrogen levels are highest preceding estrus and since the brain integrates thirst behavior, a possible central action of estrogen on fluid regulatory mechanisms was investigated in adult male and ovariectomized female rats. Ad libitum drinking was not changed the day of intracerebroventricular injection of estradiol benzoate (EB) but was significantly depressed the following day in females only. Drinking induced by intracerebroventricular angiotensin but not carbachol or cellular dehydration was also depressed in females the day after central EB treatment; again, no change occurred in males. To determine whether central EB depressed other centrally mediated responses to angiotensin, pressor responses to intracerebroventricular injections of angiotensin, carbachol, and hypertonic NaCl were also assessed. Only angiotensin-induced pressor responses in females were attenuated by central EB treatment, with a time course similar to that observed for the depression of drinking. We conclude that central regulatory responses to angiotensin are modulated by estrogen in female but not male brains.


Hepatitis C virus nonstructural protein NS3 binds to Sm-D1, a small nuclear ribonucleoprotein associated with autoimmune disease.
Hepatitis C virus (HCV) causes a persistent infection, chronic hepatitis, and leads to hepatocellular carcinoma. Nonstructural protein 3 (NS3) of HCV possesses protease, nucleoside triphosphatase, and helicase activities. Using the yeast two hybrid assay, we identified Sm-D1, a host protein that binds to NS3. Sm-D1 is a component of small nuclear ribonucleoprotein (snRNP) complexes which are associated with autoimmune disease. Sm-D1 has Gly-Arg (GR) repeats at the C terminus, which contains dimethylarginine modified by post-translational modification and may constitute an immunoreactive determinant. Deletion mutants revealed that the C-terminal region of Sm-D1 containing the GR repeats was the binding region for NS3, and the expression feature of Sm-D1 was affected by co-expression of NS3. Immunostaining assay demonstrated that NS3 was also present in the nucleus of cells overexpressing Sm-D1, although it was usually found in cytoplasm. The localization of NS3 could change following interaction with Sm-D1 and affect the function of Sm-D1.


Visualization of elusive structures using intracardiac echocardiography: insights from electrophysiology.
Electrophysiological mapping and ablation techniques are increasingly used to diagnose and treat many types of supraventricular and ventricular tachycardias. These procedures require an intimate knowledge of intracardiac anatomy and their use has led to a renewed interest in visualization of specific structures. This has required collaborative efforts from imaging as well as electrophysiology experts. Classical imaging techniques may be unable to visualize structures involved in arrhythmia mechanisms and therapy. Novel methods, such as intracardiac echocardiography and three-dimensional echocardiography, have been refined and these technological improvements have opened new perspectives for more effective and accurate imaging during electrophysiology procedures. Concurrently, visualization of these structures noticeably improved our ability to identify intracardiac structures. The aim of this review is to provide electrophysiologists with an overview of recent insights into the structure of the heart obtained with intracardiac echocardiography and to indicate to the echo-specialist which structures are potentially important for the electrophysiologist.


Functional assessment of human femoral arteries after cryopreservation.
An established method for the cryopreservation of human femoral arteries for subsequent transplantation as allografts has been studied with particular attention to preservation of smooth muscle and endothelium. Human femoral arteries (HFAs) were harvested from multi-organ donors. Two groups were established; a control group of unfrozen HFAs and a group of cryopreserved HFAs. Cryopreservation was performed using RPMI solution containing dimethyl sulfoxide and the rate of cooling was 1 degrees C/min to -40 degrees C and faster thereafter until -150 degrees C was reached. The contraction and relaxation responses of unfrozen and frozen/thawed arteries were assessed by measurement of the isometric force generated by the HFAs in an organ bath. After thawing (warming was at 15 degrees C/min) the maximal contractile response to noradrenaline was 43% of the response of unfrozen HFAs. The endothelium-independent response to sodium nitroprusside was not altered, whereas the endothelium-dependent relaxation response to acetylcholine was slightly altered. The cryopreservation method used provided limited preservation of the contractility of human femoral arteries, and good preservation of both endothelium-independent and endothelium-dependent relaxation responses.


Langat flavivirus protease NS3 binds caspase-8 and induces apoptosis.
The flavivirus NS3 protein plays an important role in the cleavage and processing of the viral polyprotein and in the synthesis of the viral RNA. NS3 recruits NS2B and NS5 proteins to form complexes possessing protease and replicase activities through protease and nucleoside triphosphatase/helicase domains. We have found that NS3 also induces apoptosis. Expression of the Langat (LGT) virus NS3 protein resulted in a cleavage of cellular DNA and reduced the viability of cells. Coexpression of NS3 with apoptotic inhibitors (CrmA and P35) and addition of caspase peptide substrates (Z-VAD-FMK and Z-IETD-FMK) to NS3-transfected cells blocked NS3-induced apoptosis. In cotransfection experiments, NS3 bound to caspase-8 and enhanced caspase-8-mediated apoptosis. NS3 and caspase-8 colocalized in the cytoplasm of transfected cells. Deletion analysis demonstrated that at least two regions of NS3 contribute to its apoptotic activities. The protease and helicase domains are each able to bind to caspase-8, while the protease domain alone induces apoptosis. The protease domain and tetrahelix region of the helicase domain are required for NS3 to augment caspase-8-mediated apoptosis. Thus, the LGT virus NS3 protein is a multifunctional protein that binds to caspase-8 and induces apoptosis.


Bioactive phenols from the leaves of Baccaurea ramiflora.
Two new phenols, 6'- O-vanilloylisotachioside ( 1) and 6'- O-vanilloyltachioside ( 2), together with nine known compounds, were isolated from the leaves of Baccaurea ramiflora (Euphorbiaceae). The structures of the new compounds were elucidated mainly by analysis of physical and spectroscopic data. Compounds 1 - 10 were tested for antioxidant activities by using MTT and DPPH assays. Seven compounds, 1, 2, and 4 - 8, revealed potent antioxidant activities against H (2)O (2)-induced impairment in PC12 cells, and exhibited significant DPPH radical-scavenging activities with IC (50) values of 86.9, 142.9, 15.2, 37.6, 35.9, 30.2, and 79.8 microM, respectively.


[The COP-BLAM therapy for malignant lymphoma].
COP-BLAM therapy, which has recently been reported to be useful in the treatment of malignant lymphoma, was performed on 36 patients, and the results and adverse effects of treatment were evaluated. Complete remission (CR) and partial remission (PR), was obtained in 32 (88.9%) and in 4 (11.1%) out of the 36 patients, respectively. So the effective ratio was 100%. Analyzing results according to staging classification, CR was obtained in all of those in stages I and II, and in 84% of those in stages III and IV. The four patients with recurrent disease after CHOP therapy exhibited a CR ratio of 50% indicating that therapy is effective in recurrent cases. Adverse effects observed among the patients included leukocytopenia under 1,000/microliters (5.6%), thrombocytopenia under 5 x 10(4)/microliters (2.8%), gastrointestinal symptoms (25%), peripheral neuropathy (8.3%) and alopecia (27.3%). The efficacy of COP-BLAM therapy appears to be satisfactory with malignant lymphoma, and all adverse effects were of mild degree. In addition, it may be effective in the treatment of recurrent cases which remitted after CHOP and other therapies.


Insights into the Molybdenum/Copper Heterometallic Cluster Assembly in the Orange Protein: Probing Intermolecular Interactions with an Artificial Metal-Binding ATCUN Tag.
Orange protein (ORP) is a small bacterial protein, of unknown function, that contains a unique molybdenum/copper heterometallic cluster, [S2MoVIS2CuIS2MoVIS2]3- (Mo/Cu), non-covalently bound. The native cluster can be reconstituted in a protein-assisted mode by the addition of CuII plus tetrathiomolybdate to apo-ORP under controlled conditions. In the work described herein, we artificially inserted the ATCUN ("amino terminus Cu and Ni") motif in the Desulfovibrio gigas ORP (Ala1Ser2His3 followed by the native amino acid residues; modified protein abbreviated as ORP*) to increase our understanding of the Mo/Cu cluster assembly in ORP. The apo-ORP* binds CuII in a 1:1 ratio to yield CuII-ORP*, as clearly demonstrated by EPR (g||,⊥ = 2.183, 2.042 and ACu||,⊥ = 207 × 10-4 cm-1, 19 × 10-4 cm-1) and UV-visible spectroscopies (typical d-d transition bands at 520 nm, ε = 90 M-1 cm-1). The 1H NMR spectrum shows that His3 and His53 are significantly affected upon the addition of the CuII. The X-ray structure shows that these two residues are very far apart (Cα-Cα ≈ 27.9 Å), leading us to suggest that the metal-induced NMR perturbations are due to the interaction of two protein molecules with a single metal ion. Docking analysis supports the metal-mediated dimer formation. The subsequent tetrathiomolybdate binding, to yield the native Mo/Cu cluster, occurs only upon addition of dithiothreitol, as shown by UV-visible and NMR spectroscopies. Additionally, 1H NMR of AgI-ORP* (AgI used as a surrogate of CuI) showed that AgI strongly binds to a native methionine sulfur atom rather than to the ATCUN site, suggesting that CuII and CuI have two different binding sites in ORP*. A detailed mechanism for the formation of the Mo/Cu cluster is discussed, suggesting that CuII is reduced to CuI and transferred from the ATCUN motif to the methionine site; finally, CuI is transferred to the cluster-binding region, upon the interaction of two protein molecules. This result may suggest that copper trafficking is triggered by redox-dependent coordination properties of copper in a trafficking pathway.


Methylene Blue Prevents Retinal Damage Caused by Perinatal Asphyxia in the Rat.
Perinatal asphyxia (PA) is responsible for a large proportion of neonatal deaths and numerous neurological sequelae, including visual dysfunction and blindness. In PA, the retina is exposed to ischemia/reoxygenation, which results in nitric oxide (NO) overproduction and neurotoxicity. We hypothesized that methylene blue (MB), a guanylyl cyclase inhibitor, and free-radical scavenger currently used in the clinic, may block this pathway and prevent PA-induced retinal degeneration. Male rat pups were subjected to an experimental model of PA. Four groups were studied: normally delivered (CTL), normally delivered treated with 2 mg Kg-1 MB (MB), exposed to PA for 20 min at 37°C (PA), and exposed to PA and, then, treated with MB (PA-MB). Scotopic electroretinography performed 45 days after birth showed that PA animals had significant defects in the a- and b-waves and oscillatory potentials (OP). The same animals presented a significant increase in the thickness of the inner retina and a large number of TUNEL-positive cells. All these physiological and morphological parameters were significantly prevented by the treatment with MB. Gene expression analysis demonstrated significant increases in iNOS, MMP9, and VEGF in the eyes of PA animals, which were prevented by MB treatment. In conclusion, MB regulates key players of inflammation, matrix remodeling, gliosis, and angiogenesis in the eye and could be used as a treatment to prevent the deleterious visual consequences of PA. Given its safety profile and low cost, MB may be used clinically in places where alternative treatments may be unavailable.


Failure to detect a DNA repair-related defect in the transfection of ataxia-telangiectasia cells by enzymatically restricted plasmid.
We have transfected two SV40-transformed human fibroblast cell lines with plasmids in which double-strand breaks have been introduced by restriction enzymes, within or near the selected gene. Restriction of pSV2gpt with KpnI, as previously shown by Cox et al. (1986), reduced the frequency of transfection more in the ionizing radiation-sensitive ataxia-telangiectasia line AT5BIVA than in the resistant line MRC5V1. When the related plasmid pSV2neo was restricted with SmaI, the reduction in transfection was less in the ataxia-telangiectasia than in the normal cell line. Under our conditions, the apparent defect in transfection of AT5BIVA by pSV2gpt appears to be a result of the unusual sensitivity of the repair-deficient recipient to the selective agent. Loss of potential transfectants is exacerbated when transient gene expression is reduced by restriction of the plasmid. We suggest that a reduction in yield of transfectants with restricted plasmid in ataxia-telangiectasia cells cannot readily be used as evidence of a defect in DNA repair. Our results are also relevant to standard transfection experiments, since they emphasize the importance of optimizing selection when transient expression may be reduced, to ensure that potential transfectants are not killed by the selection regime.


Emergent behavior in strongly correlated electron systems.
I describe early work on strongly correlated electron systems (SCES) from the perspective of a theoretical physicist who, while a participant in their reductionist top-down beginnings, is now part of the paradigm change to a bottom-up 'emergent' approach with its focus on using phenomenology to find the organizing principles responsible for their emergent behavior disclosed by experiment-and only then constructing microscopic models that incorporate these. After considering the organizing principles responsible for the emergence of plasmons, quasiparticles, and conventional superconductivity in SCES, I consider their application to three of SCES's sister systems, the helium liquids, nuclei, and the nuclear matter found in neutron stars. I note some recent applications of the random phase approximation and examine briefly the role that paradigm change is playing in two central problems in our field: understanding the emergence and subsequent behavior of heavy electrons in Kondo lattice materials; and finding the mechanism for the unconventional superconductivity found in heavy electron, organic, cuprate, and iron-based materials.


Primary ovarian pregnancy after the empty follicle syndrome: a case report.
A 32-year-old nulligravida woman underwent in vitro fertilization treatment because of 6 years of unexplained infertility. On the day of ovum pick-up, no eggs were retrieved and the patient was diagnosed to have empty follicle syndrome. Six weeks later, she presented with left lower abdominal pain and mild vaginal bleeding. Laboratory tests and diagnostic laparoscopy revealed left ovarian pregnancy. Left oophorectomy was performed and the histopathological examination confirmed the diagnosis.


[The mechanisms of chronic kidney damage in renal transplant and their possible reversibility].
Chronic allograft dysfunction (CAD) represents the main cause of delayed graft loss. Several mechanisms, immunological and not, are involved in the pathogenesis of CAD, some of which are modifiable. Suboptimal immunosuppression may induce subclinical acute rejections, identifiable by histology and influencing graft survival. Typical transplant recipients' comorbidities such as hypertension, diabetes and dyslipidemia accelerate CAD progression. Calcineurin inhibitors, which are known to be nephrotoxic, play a key role in the onset of CAD through several mechanisms. Therapeutic interventions to stop or at least slow down CAD progression involve all these modifiable factors by means of comorbidity correction, tailored immunosuppression and, in some cases, withdrawal of calcineurin inhibitors.


Evidence-based practice: use of the ventilator bundle to prevent ventilator-associated pneumonia.
To examine critical care nurses' knowledge about the use of the ventilator bundle to prevent ventilator-associated pneumonia. Published reports were reviewed for current evidence on the use of the ventilator bundle to prevent ventilator-associated pneumonia, and education sessions were held to present the findings to 61 nurses in coronary care and surgical intensive care units. Changes in the nurses' knowledge were evaluated by using a 10-item test, given both before and after the sessions. Changes in the nurses' practices related to ventilator-associated pneumonia, including elevation of the head of the bed to 30 degrees to 45 degrees , were observed in 99 intubated patients. After the education sessions, the nurses performed better on 8 of the 10 items tested (P from .03 to <.001). The areas of most significant improvement were elevation of the head of the bed (P < .001), charting of the elevation of the head of the bed (P= .009), oral care (P= .009), checking of the nasogastric tube for residual volume (P = .008), washing of hands before contact with patients (P < .001), and limiting the wearing of rings (P < .001) and nail polish (P = .04). Even after the education sessions, the nurses' compliance with hand-washing recommendations before contact with patients was low, though statistically some improvement was apparent. Contraindications to elevation of the head of the bed did not appear to affect the nurses' practices (P= .38). Education sessions designed to inform nurses about the ventilator bundle and its use to prevent ventilator-associated pneumonia have a significant effect on participants' knowledge and subsequent clinical practice.


Augmentation of delayed-type hypersensitivity by vesicular stomatitis virus infection in mice.
Effects of the infection with vesicular stomatitis virus (VSV) on delayed-type hypersensitivity (DTH) to heterologous erythrocytes were investigated in mice. Infection at the time of immunization resulted in production of high levels of DTH that were specific to the antigen used for immunization. The high level of DTH produced in VSV-infected mice could not be attributed to the nonspecific enhancement of the footpad swelling with the infection. Augmentation of DTH was observed in all strains of the mouse (CBA, BALB/c, C3H/He, and C57BL/6) used. The augmenting effect of VSV infection was not as apparent in adult thymectomized mice in which the level of VSV-replicating T cells was reduced. These results strongly suggest that DTH-mediating T cells are resistant to infection by VSV, and also that there are VSV-sensitive cells that may be engaged in the suppression of DTH. It seems improbable, however, that the cells sensitive to VSV infection represent the suppressor cells themselves, since the enhancing effect was not observed in mice in which the suppressor cells were induced by the administration of high doses of the antigen.


Electromagnetic spin-orbit interactions via scattering of subwavelength apertures.
Circularly polarized electric fields incident on subwavelength apertures produce near-field phase singularities with phase vorticity +/-1 depending on the polarization handedness. These near-field phase singularities combine with those associated with orbital angular momentum and result in polarization-dependent transmission. We produce arbitrary phase vorticity in the longitudinal component of scattered electric fields by varying the incident beam and aperture configuration.


Melanomagenesis: overcoming the barrier of melanocyte senescence.
Although melanoma ultimately progresses to a highly aggressive and metastatic disease that is typically resistant to currently available therapy, it often begins as a benign nevus consisting of a clonal population of hyperplastic melanocytes that cannot progress because they are locked in a state of cellular senescence. Once senescence is overcome, the nevus can exhibit dysplastic features and readily progress to more lethal stages. Recent advances have convincingly demonstrated that senescence represents a true barrier to the progression of many types of cancer, including melanoma. Thus, understanding the mechanism(s) by which melanoma evades senescence has become a priority in the melanoma research community. Senescence in most cells is regulated through some combination of activities within the RB and p53 pathways. However, differences discovered among various tumor types, some subtle and others quite profound, have revealed that senescence frequently operates in a context-dependent manner. Here we review what is known about melanocyte senescence, and how such knowledge may provide a much-needed edge in our struggles to contain or perhaps vanquish this often-fatal malignancy.


Laparoscopic resection of schwannoma in the hepatoduodenal ligament: a case report.
The occurrence of schwannomas in the hepatoduodenal ligament is rare, and its preoperative accurate diagnosis is difficult. Only few cases have been treated with laparoscopic surgery. A 54-year-old man visited our hospital following abnormal abdominal computed tomography findings. He had no complaints, and his laboratory investigations were normal. Abdominal contrast-enhanced computed tomography revealed a tumor with enhancement at the margin of the hepatoduodenal ligament. The abdominal magnetic resonance imaging findings of the tumor showed hypointensity on the T1-weighted images and mixed hypointensity and hyperintensity on the T2-weighted fat-suppression images. Positron emission tomography showed localized accumulation of fludeoxyglucose only in the hepatoduodenal ligament tumor. The patient underwent laparoscopic tumor resection for accurate diagnosis. Histopathologically, the tumor was mainly composed of spindle cells, which were strongly positive for S-100 protein on immunohistochemical staining. The patient was discharged without any postoperative complications on day 5. Complete tumor resection is essential for schwannomas to avoid recurrence. Laparoscopic surgery is useful for schwannomas occurring in the hepatoduodenal ligament and can be performed safely by devising an appropriate surgical method.


Practical approaches to resolving reactive metabolite liabilities in early discovery.
Idiosyncratic toxicity is one of the principal causes for withdrawal of marketed drugs after launch. Circumstantial evidence suggests that several drug-induced adverse effects are a result of transformation of a drug to electrophilic reactive metabolites (RMs) that can covalently bind to vital macromolecules in the body. Strategies have been implemented in early discovery to examine (and minimize) the formation of RMs. A common technique involves incubation of a new chemical entity with NADPH-supplemented human liver microsomes (HLMs) in the presence of soft nucleophilic trapping agents, such as glutathione (GSH) or N-acetylcysteine (NAC). Advances in mass spectrometry and the advent of very sensitive mass spectrometers ensure facile identification of the resulting GSH or NAC adducts of the reactive species. Detection of sulfhydryl conjugates in in vitro incubations, however, raise more questions regarding the path forward for RM-positive drug candidates. One approach that can assist in mitigating RM formation is assessment of their total body burden. Computation of dose using in vitro intrinsic clearance (Clint), potency data (Ceff) and the fractional contribution of RM pathway (frm), can provide an initial read of the daily burden of RM. This overview attempts to provide practical ways of assessing these factors and assist in putting the risk of RM formation into perspective.


Amount and type of physical activity as predictors of growth in executive functions, attentional control, and social self-control across 4 years of elementary school.
This paper used a nationally representative sample of children from the United States to examine the extent to which physical activity and sports participation may promote growth in children's executive functions (EFs), attention, and social self-control over time. Using data from the ECLS-K:2011 (N = 18,174), findings indicated that regular physical activity predicted growth in EFs and attention from 3rd to 4th grade (βs = 0.03-0.05) but not from kindergarten to 1st grade. After controlling for the frequency of physical activity, participation in group sports predicted increases in EFs, attention, and social self-control during both periods (βs = 0.02-0.04). Though modest in size, the findings suggest that encouraging children to engage in more frequent and more team-based activity will benefit the development of their EFs and related skills, and especially so for children in middle childhood.


Tumor necrosis factor/cachectin and interleukin-1 secretion by cord blood monocytes from premature and term neonates.
Blood monocytes produce two well-defined cytokines, tumor necrosis factor/cachectin (TNF) and Il-1, that have multiple immunologic and inflammatory functions. This study examined the secretion of these cytokines by cord blood monocytes from preterm and term neonates stimulated with or without lipopolysaccharide (LPS). Seventeen samples (eight preterm, nine term) were collected. Supernatants of monocytes were assayed for activities of IL-1 (mitogenesis for mouse thymocytes) and TNF (cytotoxicity for L929 cells). IL-1 and TNF activities were not significant in supernatants of unstimulated monocytes from either preterm or term infants. IL-1 secretion by LPS-stimulated monocytes from term and preterm neonates was comparable to IL-1 activity by monocytes from adults, but TNF activity by LPS-stimulated monocytes from preterm neonates was significantly less than that from monocytes of either term or adult groups (p less than 0.05). TNF activity in supernatants of LPS-stimulated monocytes was neutralized 100% by monoclonal antibody to TNF-alpha; IL-1 activity was neutralized 80% by polyclonal antiserum to IL-1-beta. Given the multifactorial biologic activities of TNF, the decreased secretion of TNF by monocytes from preterm neonates may be significant in describing mechanisms for the increased susceptibility of the preterm neonate to infection.


Gene rearrangements in the mitochondrial genome of Cynoglossus bilineatus (Pleuronectiformes: Cynoglossidae).
Cynoglossus bilineatus (Cynoglossidae, Soleoidei) is characterized by both eyes on the left side of the body and with a rounded snout and a short rostral hook. Here we first report the mitogenome of this tongue sole, which is 16,454 bp in length, and gene rearrangements have been observed. Particularly, the tRNA-Gln gene encoded by the light strand (L-strand) has translocated to the heavy strand (H-strand), along with the tRNA-Ile gene shuffling. In addition, the putative control region has translocated downstream to a position between the ND1 and tRNA-Gln genes, leaving a 26-bp intergenic spacer in its original position. However, the arrangement of the rest genes is identical to that of the typical teleost. This result could contribute to a better understanding the molecular mechanisms of gene rearrangement in fish mitogenome as well as phylogenetic study of Cynoglossidae and Pleuronectiformes.


[Development of a tissue-equivalent magnetic resonance imaging phantom using indigestible dextrin and soluble calcium].
In magnetic resonance imaging (MRI), the ideal phantom should have similar T1 and T2 values to those of organs of interest for measuring the change in signal intensity, contrast ratio and contrast noise ratio. There have been several reports to develop such a phantom using materials with limited availability or complex methods. In this study, we have developed a simple phantom using indigestible dextrin and soluble calcium at 1.5-tesla MRI. The T1 and T2 values have been reduced by dissolving indigestible dextrin and soluble calcium in distilled water. The similar T1 and T2 values to those of organs (i.e., kidney cortex, kidney medulla, liver, spleen, pancreas, bone marrow, uterus myometrium, uterus endometrium, uterus cervix, prostate, brain white matter, and brain gray matter) have been obtained by varying the concentration of indigestible dextrin and soluble calcium. This phantom is easy to develop and has a potential to increase the accuracy of MRI phantom experiments.


Fast optimal frictionless atom cooling in harmonic traps: shortcut to adiabaticity.
A method is proposed to cool down atoms in a harmonic trap without phase-space compression as in a perfectly slow adiabatic expansion, i.e., keeping the same populations of instantaneous levels in the initial and final traps, but in a much shorter time. This may require that the harmonic trap become transiently an expulsive parabolic potential. The cooling times achieved are shorter than those obtained using optimal-control bang-bang methods and real frequencies.