Suicidal Ideation in Adolescence: A Perspective View on the Role of the Ventromedial Prefrontal Cortex.
Suicide in adolescence is a worldwide issue, and it continues to present a serious problem in terms of its prevention. Among the various aspects of suicide, a very interesting area of research is represented by suicidal ideation. Recently, neuroimaging-based methods have made it possible to study the cognitive processes involved in several social situations and clinical conditions. This theoretical perspective article with an interdisciplinary approach integrates evidence from developmental psychology and social neuroscience with the aim of investigating the role of the brain area responsible for regulating negative emotions during the cognitive processes of suicidal ideation: the ventromedial prefrontal cortex. By highlighting the role of brain areas in the few studies published so far, it is possible to develop perspectives of considerable impact. Studying and understanding the role of brain areas involved in suicidal thoughts in adolescents could facilitate the creation of new perspectives on prevention programs and interventions.


A cross sectional survey of attitudes, awareness and uptake of the parental pertussis booster vaccine as part of a cocooning strategy, Victoria, Australia.
The Victorian Government Department of Health funded a diphtheria, tetanus and acellular pertussis vaccine for parents of infants from June 2009 to June 2012 as part of a cocooning strategy for the control of pertussis. The aim of this study was to assess parents' attitudes and awareness of the vaccination program, and to estimate vaccine uptake. A cross-sectional survey of 253 families with a child born in the first quarter of 2010 residing within five metropolitan and four rural local government areas in Victoria was conducted. Univariate analyses were performed to describe the relationship between demographic variables, knowledge and awareness of the disease, the vaccine program and vaccine uptake. Multivariate analyses examining predictors for awareness of the vaccine program and for the uptake of vaccination were also conducted. One hundred and five families were surveyed (response rate 43%). Of these, 93% indicated that they had heard of 'pertussis' or 'whooping cough' and 75% of mothers and 69% of fathers were aware the pertussis vaccine was available and funded for new parents. Overall, 70% of mothers and 53% of fathers were vaccinated following their child's birth, with metropolitan fathers less likely to be vaccinated as rural fathers (RR=0.6, p=0.002). Being a younger mother (p=0.02) or father (p=0.047), and being an Australian-born father (RR=1.9, p=0.03) were found to predict uptake of the vaccine in parents. Parents indicated a reasonable level of knowledge of pertussis and a willingness to be vaccinated to protect their child. However, vaccine uptake estimates indicated further opportunity for program improvement. Future cocooning strategies would benefit from specifically targeting fathers and metropolitan maternity hospitals to increase vaccine uptake. Wider promotion of the availability of vaccine providers may increase uptake to maximise the success of cocooning programs. Further investigation of the effectiveness of the cocooning strategy in decreasing infant morbidity and mortality is required.


[Expression of TLR9 in human nasal epithelial cells].
To analyze expression of TLR9 in human nasal epithelial cells by semi-quantitative reverse transcription-polymerase chain reaction, immunohistochemistry and flow cytometry. Human primary nasal epithelial cells (HNECs) were cultured, and then analyze the expression of TLR9 in primary cultured HNECs measured by semi-quantitative RT-PCR and immunohistochemistry and flow cytometry. Primary cultured HNECs were observed by 400 x optical microscopes. Round or irregular cells stick to the bottom of cell culture plates. RT-PCR showed that mRNA expressions of TLR9 were found in primary nasal epithelial cells by 1% agarose gel electrophoresis. Interestingly, by analyzing with gray level of GAPDH, expression of TLR9 mRNA in HNECs was higher than positive control PBMCs. TLR9 is expressed by HNECs. Expression of TLR9 mRNA in nasal epithelial cells is higher than in PBMCs.


An efficient, scarless, selection-free technology for phage engineering.
Most recently developed phage engineering technologies are based on the CRISPR-Cas system. Here, we present a non-CRISPR-based method for genetically engineering the Escherichia coli phages T5, T7, P1, and λ by adapting the pORTMAGE technology, which was developed for engineering bacterial genomes. The technology comprises E. coli harbouring a plasmid encoding a potent recombinase and a gene transiently silencing a repair system. Oligonucleotides with the desired phage mutation are electroporated into E. coli followed by infection of the target bacteriophage. The high efficiency of this technology, which yields 1-14% of desired recombinants, allows low-throughput screening for the desired mutant. We have demonstrated the use of this technology for single-base substitutions, for deletions of 50-201 bases, for insertions of 20 bases, and for four different phages. The technology may also be readily modified for use across many additional bacterial and phage strains.[Figure: see text].


Troxerutin attenuates cognitive decline in the hippocampus of male diabetic rats by inhibiting NADPH oxidase and activating the Nrf2/ARE signaling pathway.
Diabetes‑associated cognitive decline is a recently identified a potential complication of diabetes. The present study was designed to examine the effects of troxerutin, a potent antioxidant, on cognitive function in rats with streptozotocin‑induced diabetes and to further explore the potential underlying mechanisms. Cognitive functions were investigated by the Morris water maze test. The malondialdehyde (MDA) level and superoxide dismutase (SOD) activity in the hippocampus were assessed as the parameters of oxidative stress. Subunits of the NADPH oxidase (NOX) expression and nuclear factor erythroid 2‑related factor 2/antioxidant responsive element (Nrf2/ARE) signaling pathway were detected to explore the potential underlying mechanisms. The water maze test revealed that troxerutin significantly improved cognitive impairment in diabetic rats. Troxerutin treatment attenuated oxidative stress in the hippocampus of diabetic rats, as evidenced by the decreased MDA level and the increased SOD activity. Moreover, troxerutin activated the Nrf2/ARE signaling pathway via Nrf2 nuclear translocation in the cells in the hippocampus of diabetic rats. Troxerutin elevated the expression levels of the antioxidant enzymes, heme oxygenase‑1 (HO‑1) and NAD(P)H:quinone oxidoreductase (NQO1), and decreased the expression levels of the NOX subunits, gp91phox, p47phox and p22phox. On the whole, these findings demonstrate that troxerutin exerts neuroprotective effects against diabetes‑associated cognitive decline by suppressing oxidative stress in the hippocampus of rats with streptozotocin‑induced diabetes. Troxerutin may thus prove to be a potential therapeutic medicine for the treatment of diabetes‑associated cognitive decline.


Mus81, Rhp51(Rad51), and Rqh1 form an epistatic pathway required for the S-phase DNA damage checkpoint.
The S-phase DNA damage checkpoint slows the rate of DNA synthesis in response to damage during replication. In the fission yeast Schizosaccharomyces pombe, Cds1, the S-phase-specific checkpoint effector kinase, is required for checkpoint signaling and replication slowing; upon treatment with the alkylating agent methyl methane sulfonate, cds1Delta mutants display a complete checkpoint defect. We have identified proteins downstream of Cds1 required for checkpoint-dependant slowing, including the structure-specific endonuclease Mus81 and the helicase Rqh1, which are implicated in replication fork stability and the negative regulation of recombination. Removing Rhp51, the Rad51 recombinase homologue, suppresses the slowing defect of rqh1Delta mutants, but not that of mus81Delta mutant, defining an epistatic pathway in which mus81 is epistatic to rhp51 and rhp51 is epistatic to rqh1. We propose that restraining recombination is required for the slowing of replication in response to DNA damage.


Improving Preschoolers' Comprehension of Sex Abuse Prevention Concepts Through Video Repetition.
Because of their ease of administration and acceptance among parents, sex abuse prevention videotapes remain widely used. However, such video-based programs have shown limited effectiveness among preschool-aged children, the group most vulnerable to abuse. This study sought to determine whether having preschoolers review those video segments they did not comprehend initially, would increase their comprehension of sex abuse prevention concepts. Children who reviewed the concepts learned significantly more than children who viewed the segment once, even though an adult co-viewer explained the content to them. This efficient and simple method of enhancing young children's comprehension holds great promise for improving video-based sex abuse prevention efforts.


Parasites of orangutans (primates: ponginae): An overview.
Wild orangutan populations exist in an increasingly fragile state. As numbers continue to decline and populations became fragmented, the overall health of remaining individuals becomes increasingly at risk. Parasitic infections can have a serious impact on the health of wild orangutans, and can be fatal. It has been reported that rehabilitated individuals demonstrate a higher prevalence of parasitic diseases, and it is possible that they may spread these infections to wild orangutans upon reintroduction. In order to ensure the success of reintroduction and conservation efforts, it is crucial to understand the potential risks by fully understanding what parasites they have been reported to be infected with. Using this knowledge, future conservation strategies can be adapted to minimize the risk and prevalence of parasite transmission in the remaining orangutan populations. There is still limited information available on orangutan parasites, with several still not identified to the species level. Based on comprehensive literature review, we found 51 parasite taxa known to infect wild, semi-wild, and captive orangutans, including newly reported species. Here, we summarize methods used to identify parasites and draw conclusions relative to their reported prevalence. We also recommend fecal sample preservation and analytical methods to obtain best result in the future.


Steric stabilisers govern the colloidal and chemical stability but not in vitro cellular toxicity of linoleoylethanolamide cubosomes.
Linoleoylethanolamide (LEA) is an endogenous lipid with remarkable neuromodulatory properties. However, its therapeutic potential is limited by rapid clearance in vivo, targetability and solubility. This study aimed to formulate LEA into liquid crystalline nanoparticles (cubosomes) as a strategy to address the aforementioned challenges. The influence of three different steric stabilisers: Tween 80 and Pluronic F68, both of which have the potential to interact with receptors expressed at the blood-brain barrier and Pluronic F127 as a control, on colloidal stability, internal structure, chemical stability and cytotoxicity of the dispersions were investigated. We found that for effective stabilization of LEA dispersions, a higher concentration of Tween 80 was required compared to Pluronics. Freshly prepared dispersions showed mean particle size of <250 nm and low PDIs (<0.2), with an Im3m type cubic structure but with different lattice parameters. Upon storage at ambient temperature for a week, increased mean particle size and PDI, with a significant reduction in the concentration of LEA was observed in Tween 80-stabilised dispersions. Greater than 80% cell viability was observed at concentrations of up to 20 μg/mL LEA in the presence of all three stabilisers. Collectively, our results suggest that the stabiliser type influences colloidal and chemical stability but not cytotoxicity of LEA cubosomes. This study highlights the potential of endogenous bioactive lipids to be utilized as core cubosome forming lipids with the view to improving their solubility, rapid clearance and targetability to enable delivery of these bioactive molecules to the brain.


Routine HLA sequence-specific-oligonucleotide typing and confirming sequence-based typing of a prospective bone marrow donor identified a novel B*27 allele, HLA-B*2734.
In this study, we report the identification of a new human leukocyte antigen-B allele in a sample that was tested in our routine typing for volunteer bone marrow donors. This novel allele officially named B*2734 was found in a female donor of Caucasoid origin (laboratory code 158567). The search for unrelated bone marrow donors was initiated by the Aktion Knochenmarkspende Bayern. In comparison with the closest related allele B*2707, B*2734 differs at two nucleotide positions, all located in exon 3, at position 412, 'A' in B*2707 is replaced by 'G' and at position 486, 'G' is replaced by 'A' in the novel allele. The single nucleotide polymorphism at position 412 results in an amino acid substitution at codon 138. The amino acid asparagine is changed to aspartic acid in B*2734 allele. The second nucleotide exchange is a silent mutation and codon 163 remains unaffected as ACG-->ACA, still codes for alanine.


Physiological and morphological responses induced by α-particle radiation on Arabidopsis thaliana embryos.
Alpha (α)-particle radiation has been thoroughly studied in the occupational and residential environments, but biological mechanisms induced by α-particle radiation on plants are not clearly understood. In this study, radiation effects were examined using different total doses (1, 10, 100 Gy, respectively) of 241Am, α-particle on Arabidopsis embryos. No significant difference in the germination percentage was observed between the 3 levels of doses and the control. Germination speed and root length were increased by treatment with the 1-Gy dose of a-particles, and decreased by treatment with 10- and 100-Gy doses. Moreover, the bending degree of roots increased with radiation dose, and the roots showed an "S" shape when treated with the 100-Gy dose. Root bending under the 100-Gy dose was inhibited by scavengers of reactive oxygen species (ROS). Root gravitropism and root length may respond to the consistency of ROS induced by irradiation. Further analysis of the physiological effects revealed that an increase in a-particle radiation intensity enhanced the activity of catalase and the content of malondialdehyde, but superoxide dismutase activity was reduced by treatment with 100-Gy radiation of a-particles, suggesting that the high linear energy transfer of a-particles may cause a relatively high level of membrane lipid preoxidation and high accumulation of ROS. ROS showed both physiological and morphological responses following exposure to α-particle radiation in Arabidopsis embryos.


[Job stressors and satisfaction in the nursing staff of a critical unit].
The objectives of our study were: to identify the stressor agents of the nursing staff according to the sociodemographical and professional characteristics; to know if the frequency of exposure to job stressors is modified based on sociodemographical characteristics; and to know if there is a relationship between job stress and satisfaction. The study sample was made up of 71 nurses (N) and 48 nursing assistants (NA). Information was collected with a self-administrated questionnaire. Satisfaction was assessed with the Warr, Cook and Wall survey and job stressors with the <<Nursing Stress Scale.>> Demographic and professional variables were collected. The percentage of responses was 88.2%. Mean stress in SD was significantly higher than in the NA, 38 (10.7) and 27.9 (9.2) respectively; p < 0.001. The stressor mean is higher based on age and type of contract in both categories. We have not found any differences in relationship to satisfaction. Both categories identified as main stressors those related with the patient's suffering, death and job excess. 1) The most frequently identified job stressors in both categories are those related with patient suffering, death and job excess. 2) The Ns have a significantly greater exposure to job stressors. 3) Young age and insecurity in the job increase exposure to job stressors. 4) We have not found any relationship between the job stressors and satisfaction.


Critical residues at the Ly49 natural killer receptor's homodimer interface determine functional recognition of m157, a mouse cytomegalovirus MHC class I-like protein.
NK cell function is regulated by Ly49 receptors in mice and killer cell Ig-like receptors in humans. Although inhibitory Ly49 and killer cell Ig-like receptors predominantly ligate classical MHC class I molecules, recent studies suggest that their activating counterparts recognize infection. The quintessential example is resistance to the mouse CMV in C57BL/6 mice, which depends on the functional recognition of m157, a mouse CMV-encoded MHC class I-like molecule, by Ly49H, an activating NK cell receptor. We have taken advantage of the natural variation in closely related members of the Ly49C-like receptors and the availability of Ly49 crystal structures to understand the molecular determinants of the Ly49H-m157 interaction and to identify amino acid residues discriminating between m157 binding and nonbinding receptors. Using a site-directed mutagenesis approach, we have targeted residues conserved in receptors binding to m157 (Ly49H and Ly49I(129)) but different from receptors lacking m157 recognition (Ly49C, Ly49I(B6), and Ly49U). Wild-type and mutant receptors were transfected into reporter cells, and physical binding as well as functional activation by m157 was studied. Our findings suggested that the Ly49 MHC class I contact "site 2," I226, may not be involved in m157 binding. In contrast, residue Y146 and G151, mapping at the receptor homodimer interface, are likely critical for functional recognition of the m157 glycoprotein. Our combined functional and three-dimensional modeling approach suggested that the architecture of the Ly49H dimer is crucial to accessing m157, but not MHC class I. These results link Ly49 homodimerization variability to the direct recognition of pathogen products.


The future for clinical scientists in laboratory medicine.
Clinical science in the UK has been presented with a range of opportunities and new initiatives in recent years. This review summarizes the contribution of clinical scientists to the changing face of laboratory medicine, and describes some recent UK Government initiatives to modernize the scientific service and develop the people who work in it. Recent changes in the regulation of professional practice and the need for maintenance of professional competence are also discussed.


Mobile physician reporting of clinically significant events-a novel way to improve handoff communication and supervision of resident on call activities.
Reporting of clinically significant events represents an important mechanism by which patient safety problems may be identified and corrected. However, time pressure and cumbersome report entry procedures have discouraged the full participation of physicians. To improve the process, our internal medicine training program developed an easy-to-use mobile platform that combines the reporting process with patient sign-out. Between August 25, 2011, and January 25, 2012, our trainees entered clinically significant events into i-touch/i-phone/i-pad based devices functioning in wireless-synchrony with our desktop application. Events were collected into daily reports that were sent from the handoff system to program leaders and attending physicians to plan for rounds and to correct safety problems. Using the mobile module, residents entered 31 reportable events per month versus the 12 events per month that were reported via desktop during a previous 6-month study period. Advances in information technology now permit clinically significant events that take place during "off hours" to be identified and reported (via handoff) to next providers and to supervisors via collated reports. This information permits hospital leaders to correct safety issues quickly and effectively, while attending physicians are able to use information gleaned from the reports to optimize rounding plans and to provide additional oversight of trainee on call patient management decisions.


Induction of pulmonary indoleamine 2,3-dioxygenase by intraperitoneal injection of bacterial lipopolysaccharide.
Indoleamine 2,3-dioxygenase [indoleamine: oxygen 2,3-oxidoreductase (decyclizing)] activity in the supernatant fraction (30,000 X g, 30 min) of the mice lung homogenate increased approximately 30- to 50-fold after an intraperitoneal administration of bacterial lipopolysaccharide. In all other tissues tested, no significant increase in enzyme activity was observed. The effect appeared to be specific for the lipopolysaccharide fraction because glycogen and zymosan were almost ineffective under the same experimental conditions. In the lung, the enzyme activity increased almost linearly during the first 24 hr after a single injection of the lipopolysaccharide fraction (20 microgram per mouse). The enzyme activity started to decrease after 48 hr and reached a normal value after about 6 days. The increase in enzyme activity was completely abolished by cycloheximide or actinomycin D. Other enzymes in the lung such as beta-glucuronidase, acid phosphatase, and monoamine oxidase did not change significantly with this treatment.


Ectoine degradation pathway in halotolerant methylotrophs.
Microorganisms living in saline environments are forced to regulate turgor via the synthesis of organic osmoprotective compounds. Microbial adaptation to fluctuations in external salinity includes degradation of compatible solutes. Here we have examined the biochemical pathway of degradation of the cyclic imino acid ectoine, the major osmoprotector in halotolerant methane-utilizing bacteria. The BLAST search of the genes involved in ectoine degradation in the halotolerant methanotroph Methylotuvimicrobium alcaliphilum 20Z was performed with the reference sequences of Halomonas elongata. The genes for the key enzymes of the pathway were disrupted by insertion mutagenesis and the cellular metabolites in the methanol extracts of mutant cells were analyzed by HPLC. The doeA gene from Mm. alcaliphilum 20Z was heterologously expressed in Escherichia coli to identify the product of ectoine hydrolysis catalyzed by ectoine hydrolase DoeA. We have shown that the halotolerant methanotroph Mm. alcaliphilum 20Z possesses the doeBDAC gene cluster coding for putative ectoine hydrolase (DoeA), Nα-acetyl-L-2,4-diaminobutyrate deacetylase (DoeB), diaminobutyrate transaminase (DoeD) and aspartate-semialdehyde dehydrogenase (DoeC). The deletion of the doeA gene resulted in accumulation of the higher level of ectoine compared to the wild type strain. Nγ-acetyl-L-2,4-diaminobutyrate (Nγ-acetyl-DAB), a substrate for ectoine synthase, was found in the cytoplasm of the wild type strain. Nα-acetyl-L-2,4-diaminobutyrate (Nα-acetyl-DAB), a substrate for the DoeB enzyme, appeared in the cells as a result of exposure of the doeB mutant to low osmotic pressure. The genes for the enzymes involved in ectoine degradation were found in all aerobic methylotrophs capable of ectoine biosynthesis. These results provide the first evidence for the in vivo operation of the ectoine degradation pathway in methanotrophs and thus expand our understanding of the regulation mechanisms of bacterial osmoadaptation. During adaptation to the changes in external osmolarity, halophilic and halotolerant methylotrophs cleave ectoine, thereby entering the carbon and nitrogen of the compatible solute to the central metabolic pathways. The biochemical route of ectoine degradation in the halotolerant methanotroph Mm. alcaliphilum 20Z is similar to that in heterotrophic halophiles. We have shown that ectoine hydrolase DoeA in this methanotroph hydrolyzes ectoine with the formation of the only isomer: Nα-acetyl-DAB. All aerobic methylotrophs capable of ectoine biosynthesis harbor the genetic determinants for ectoine degradation.


Effect of Porosity and Concentration Polarization on Electrolyte Diffusive Transport Parameters through Ceramic Membranes with Similar Nanopore Size.
Diffusive transport through nanoporous alumina membranes (NPAMs) produced by the two-step anodization method, with similar pore size but different porosity, is studied by analyzing membrane potential measured with NaCl solutions at different concentrations. Donnan exclusion of co-ions at the solution/membrane interface seem to exert a certain control on the diffusive transport of ions through NPAMs with low porosity, which might be reduced by coating the membrane surface with appropriated materials, as it is the case of SiO₂. Our results also show the effect of concentration polarization at the membrane surface on ionic transport numbers (or diffusion coefficients) for low-porosity and high electrolyte affinity membranes, which could mask values of those characteristic electrochemical parameters.


Localized Normal Coordinates in Accurate Vibrational Structure Calculations: Benchmarks for Small Molecules.
The impact of localized CH-stretching normal coordinates in comparison to canonical normal coordinates on the performance of accurate vibrational structure calculations has been studied for simple molecules of up to eight atoms. Two aspects have been considered in detail, (a) the (pre)screening of coupling terms within an n-mode expansion of the multidimensional potential energy surface and (b) the demands in vibrational configuration interaction calculations (VCI). All calculations have been performed in a realistic setup, and the effect of any approximation has been measured in deviations of the final VCI frequencies, which allows for a direct comparison with experimental data.


Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans.
A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.


Cerebrovascular events associated with infusion through arterially malpositioned triple-lumen catheter: report of three cases and review of literature.
Analysis of 10 adult patients treated from January 1998 to November 2004 for arterial misplacement of triple-lumen catheter (TLC) during internal jugular vein cannulation was performed. Three cases that developed neurologic symptoms occurring in the context of infusion through a TLC that was arterially malpositioned are presented, along with the review of literature. In 7 patients, the diagnosis of arterial misplacement was suspected by the color or flow characteristics of blood and confirmed by a combination of blood gas analysis, connecting catheter to transducer, and/or chest film. In the remaining 3 patients, intraarterial misplacement was not suspected. In these patients, the initial review of chest films by qualified physicians prior to starting infusion failed to detect malposition of the catheter. Retrospectively, subtle clues suggestive of arterially placed TLCs were found. All 3 patients developed neurologic symptoms. Initiation of neurologic workup delayed a correct diagnosis by 6 to >48 hours. A volumetric pump was used for infusion in all patients. Of the 3 patients with neurologic symptoms, 1 recovered completely, 1 became comatose, and 1 partially improved. Based on our observations and review of literature, we conclude that cursory examination of chest films to verify proper positioning of central venous catheter attempted through the internal jugular vein may fail to detect arterial malposition. Infusion by volumetric pump precludes backflow of blood in the intravenous tubing as an indicator. Neurologic symptoms concurrent with the infusion of fluids and medication should raise suspicion of accidental arterial infusion.


Regulatory volume increase in nematocytes isolated from acontia of Aiptasia diaphana (Cnidaria, Anthozoa).
Nematocytes, Cnidarians stinging cells used primarily in capturing prey or in turning away predators, can regulate their volume under 35% hyposmotic shock showing regulatory volume decrease (RVD). In this study, for the first time, we investigate the capability of nematocytes to regulate their volume under hypertonic conditions, through regulatory volume increase (RVI). The experiments were carried out in acontial nematocytes of Aiptasia diaphana (Cnidaria: Anthozoa) isolated by the chemical method of applying 605 mM SCN-. Channel inhibitors, as amiloride, Gd3+, NPPB, DIDS, bumetanide and ion substitution have been employed to assess the role of ions in such volume regulation mechanisms. Our results suggest that nematocytes are able to perform RVI. The regulatory volume recovery process after hypertonic stimulation involves Na+ conductance and Na+/K+/2Cl- cotransport but not Cl- conductive pathways. Further studies will be necessary to better define such mechanisms and RVI control signalling, taking into account that the nematocyte is known to be a very primitive eukaryotic cell.


[Application of inhaled nitric oxide in extreme preterm neonates with with BPD].
Prolonged inhaled nitric oxide (iNO) from birth in preterm neonates with BPD improves endogenous surfactant function as well as lung growth, angiogenesis, and alveologenesis. As a result there is a reduction in the frequency of the "new" form of BPD in neonates under 28 weeks of gestation and birth weight under 1000 gr. Delivery of inhaled nitric oxide is a new method of prevention of chronic lung disease. According to a large number of randomized trials iNO in premature neonates reduces pulmonary morbidity and leads to a reduction of the mortality in this population of patients. This new therapy does not have serious side effects.


Improvement of image classification using wavelet coefficients with structured-based neural network.
Image classification is a challenging problem in organizing a large image database. However, an effective method for such an objective is still under investigation. A method based on wavelet analysis to extract features for image classification is presented in this paper. After an image is decomposed by wavelet, the statistics of its features can be obtained by the distribution of histograms of wavelet coefficients, which are respectively projected onto two orthogonal axes, i.e., x and y directions. Therefore, the nodes of tree representation of images can be represented by the distribution. The high level features are described in low dimensional space including 16 attributes so that the computational complexity is significantly decreased. 2,800 images derived from seven categories are used in experiments. Half of the images were used for training neural network and the other images used for testing. The features extracted by wavelet analysis and the conventional features are used in the experiments to prove the efficacy of the proposed method. The classification rate on the training data set with wavelet analysis is up to 91%, and the classification rate on the testing data set reaches 89%. Experimental results show that our proposed approach for image classification is more effective.


An mt(+) gamete-specific nuclease that targets mt(-) chloroplasts during sexual reproduction in C. reinhardtii.
Although the active digestion of mating-type minus (mt-) chloroplast DNA (cpDNA) in young zygotes is considered to be the basis for the uniparental inheritance of cpDNA in Chlamydomonas reinhardtii, little is known about the underlying molecular mechanism. One model of active digestion proposes that nucleases are either synthesized or activated to digest mt- cpDNA. We used a native-PAGE/in gelo assay to investigate nuclease activities in chloroplasts from young zygotes, and identified a novel Ca(2+)-dependent nuclease activity. The timing of activation (approximately 60-90 min after mating) and the localization of the nuclease activity (in mt- chloroplasts) coincided with the active digestion of mt- cpDNA. Furthermore, the activity of the nuclease was coregulated with the maturation of mating-type plus (mt+) gametes, which would enable the efficient digestion of mt- cpDNA. Based on these observations, we propose that the nuclease (designated as Mt(+)-specific DNase, MDN) is a developmentally controlled nuclease that is activated in mt+ gametes and participates in the destruction of mt- cpDNA in young zygotes, thereby ensuring uniparental inheritance of chloroplast traits.


PMF scoring revisited.
Knowledge-based scoring functions have become accepted choices for fast scoring putative protein-ligand complexes according to their binding affinities. Since their introduction 5 years ago, the knowledge base of protein-ligand complexes has grown to the point were rederiving potentials of mean force becomes meaningful for statistical reasons. Revisiting potential of mean force (PMF) scoring (J. Med. Chem. 1999, 42, 791), we present an updated PMF04 scoring function that is based on 7152 protein-ligand complexes from the PDB. This constitutes an increase of about 10-fold compared to the knowledge base of the original PMF99 score (697 complexes). Because of the increased statistical basis of the PMF04 score, potentials for metal ions have been derived for the first time. In addition, potentials for halogens have reached statistical significance and are included also. Comparison of scoring accuracies between PMF99 and PMF04 shows an increased performance of the new score for many well-established test sets. Extending the testing of PMF scoring to the recently introduced PDBbind database containing the large number of 800 protein-ligand complexes illustrates the current limits of the approach.


Generalized Fast Discharges Along the Genetic Generalized Epilepsy Spectrum: Clinical and Prognostic Significance.
To investigate the electroclinical characteristics and the prognostic impact of generalized fast discharges in a large cohort of genetic generalized epilepsy (GGE) patients studied with 24-h prolonged ambulatory electroencephalography (paEEG). This retrospective multicenter cohort study included 202 GGE patients. The occurrence of generalized paroxysmal fast activity (GPFA) and generalized polyspike train (GPT) was reviewed. GGE patients were classified as having idiopathic generalized epilepsy (IGE) or another GGE syndrome (namely perioral myoclonia with absences, eyelid myoclonia with absences, epilepsy with myoclonic absences, generalized epilepsy with febrile seizures plus, or GGE without a specific epilepsy syndrome) according to recent classification proposals. GPFA/GPT was found in overall 25 (12.4%) patients, though it was significantly less frequent in IGE compared with other GGE syndromes (9.3 vs. 25%, p = 0.007). GPFA/GPT was found independently of seizure type experienced during history, the presence of mild intellectual disability/borderline intellectual functioning, or EEG features. At multivariable analysis, GPFA/GPT was significantly associated with drug resistance (p = 0.04) and with a higher number of antiseizure medications (ASMs) at the time of paEEG (p < 0.001) and at the last medical observation (p < 0.001). Similarly, GPFA/GPT, frequent/abundant generalized spike-wave discharges during sleep, and a higher number of seizure types during history were the only factors independently associated with a lower chance of achieving 2-year seizure remission at the last medical observation. Additionally, a greater number of GPFA/GPT discharges significantly discriminated between patients who achieved 2-year seizure remission at the last medical observation and those who did not (area under the curve = 0.77, 95% confidence interval 0.57-0.97, p = 0.02). We found that generalized fast discharges were more common than expected in GGE patients when considering the entire GGE spectrum. In addition, our study highlighted that GPFA/GPT could be found along the entire GGE continuum, though their occurrence was more common in less benign GGE syndromes. Finally, we confirmed that GPFA/GPT was associated with difficult-to-treat GGE, as evidenced by the multivariable analysis and the higher ASM load during history.


[Labor management using epidural anesthesia in a gravida patient with high spinal injury].
Since autonomic hyperreflexia (AH) is a serious complication during labor in a gravida with spinal cord injury, anesthetic measures should be taken for the suppression of AH even in a sensory-loss condition. Several reports have described various methods for the suppression of AH, in which epidural anesthesia has been advocated as a useful means for the prevention or amelioration of AH. However, it is difficult to evaluate the efficacy of epidural anesthesia due to the lack of sensory and motor functions. We report a primipara who had spinal cord injury below the T 3 level at the age of 17 due to a traffic accident and underwent successful vaginal delivery twice under epidural anesthesia at the ages of 30 and 32. For the first delivery, we placed two epidural catheters. We controlled the rate and the content of epidural infusion through the two different injection sites so as to meet delivery process. For the second delivery we did epidural anesthesia in the same way. Tubal-ligation was also performed under epidural anesthesia after the second delivery. No major obstetric complication including AH occurred in either of delivery. The woman with high spinal injury could have two healthy children without major complications during labor by the cooperation of gynecologists and anesthesiologists.


[Response of photosynthetic characteristics of peanut seedlings leaves to low light].
To investigate the effects of shading and light recovery on the photosynthetic characteristics of peanut seedlings leaves, different shading treatments including no shading, 27% shading, 43% shading, and 77% shading were performed with black sunshade net at the seedling stage of two peanut cultivars Fenghua 1 and Fenghua 2, with related parameters determined. It was shown that with the increase of shading degree, the leaf chlorophyll content, actual PSII photochemical efficiency under irradiance (phi(PS II)), and maximum PS II photochemical efficiency (Fv/Fm) of test cultivars increased, while the Chl a/b ratio and photosynthetic rate (Pn) decreased. On the first day after light recovery, the Pn and stomatal conductance (Gs) decreased while the intercellular CO2 concentration (Ci) increased with increasing shading degree when measured under high light, but the Pn increased and the Gs and Ci decreased with increasing shading degree when measured under low light. The ratio of Pn measured under low light to that measured under high light increased significantly. With increasing shading degree, the light compensation point, light saturation point, CO2 compensation point, CO2 saturation point, and carboxylation efficiency decreased, while the apparent quantum yield increased. After the removal of shading, the Pn, phi(PS II), and Fv/Fm under natural light decreased immediately, but increased gradually 3-5 days after. 15 days after light recovery, the Pn, phi(PS II) and Fv/Fm in treatment 27% shading recovered to the level of no shading. As for the other treatments, the restored extent differed with shading degree and test variety. In the same treatments, the leaf chlorophyll content, Pn and phi(PS II) of Fenghua 1 were higher than those of Fenghua 2. The results demonstrated that shading at seedling stage improved the capabilities of test varieties in using low light, but reduced the capabilities in using high light.


MicroRNA-138 suppresses proliferation, invasion and glycolysis in malignant melanoma cells by targeting HIF-1α.
MicroRNAs (miRs) may induce mRNA degradation or inhibit protein translation by directly binding to the 3'-untranslational region of target mRNAs. It has been reported that miR-138 is downregulated in malignant melanoma (MM) cells. However, the role of miR-138 in MM cell proliferation, invasion and energy metabolism remains unknown. These were investigated using reverse transcription-quantitative polymerase chain reaction was used to evaluate the expression of miR-138 and the mRNA expression of hypoxia-inducible factor-1α (HIF-1α), as HIF-1α serves a crucial role in glycolysis, which is important for tumor growth. In addition, western blot analysis was used to detected the protein expression of HIF-1α, while MTT and Transwell assays evaluated cell proliferation and invasion, respectively. Furthermore, glucose consumption and lactic acid production were assessed. These tests were conducted using the normal human melanocyte cell line HM and the MM cell line WM451, which was transfected variously with scramble miR mimics, miR-138 mimics, miR-138 inhibitor, non-specific small interfering (si)RNA, HIF-1α siRNA, or co-transfected with miR-138 mimics and pc-DNA3.1(+)-HIF-1α plasmid. The results showed that miR-138 was significantly downregulated in MM WM451 cells compared to a normal melanocyte cell line HM. Overexpression of miR-138 significantly inhibited the proliferation and invasion of WM451 cells. These effects were similar to those induced by the siRNA-mediated knockdown of HIF-1α, a direct target of miR-138. Further investigation found that miR-138 negatively regulated the protein expression of HIF-1α in WM451 cells. Moreover, upregulation of miR-138 notably inhibited the glycolysis level, as demonstrated by reduced glucose consumption and lactic acid production, which could be reversed by the overexpression of HIF-1α. In summary, the present study demonstrated that miR-138 is able to inhibit proliferation, invasion and glycolysis in MM cells, potentially by directly targeting HIF-1α.


Family history of alcoholism and the stability of personality in young adulthood.
The authors examined the magnitude and durability of personality differences related to family history of alcoholism (FH) and the development of alcohol use disorders (AUDs) in late adolescence and early adulthood. Data were taken from a longitudinal sample (N = 487; approximately half FH-positive [+]) who completed the Eysenck Personality Questionnaire (H. J. Eysenck & S. B. G. Eysenck, 1975) at 3 points spanning 11 years (participants were 18 years old at baseline). Hierarchical linear analyses showed that FH+ participants had higher levels of neuroticism and psychoticism over the study period, independent of AUD. Despite relatively large mean decreases in neuroticism (as well as extraversion), the magnitude of the between-groups differences found at age 18 were maintained over the next decade. These changes thus reflect stable underlying differences in personality and not artifacts of higher rates of AUDs in FH+ individuals, recently living in an alcoholic home, vulnerability to the developmental challenge of leaving home, and/or a developmental lag.


Bioinformatic Identification of Potential RNA Alterations on the Atrial Fibrillation Remodeling from Human Pulmonary Veins.
Atrial fibrillation (AF) is the most frequent persistent arrhythmia. Many genes have been reported as a genetic background for AF. However, most transcriptome analyses of AF are limited to the atrial samples and have not been evaluated by multiple cardiac regions. In this study, we analyzed the expression levels of protein-coding and long noncoding RNAs (lncRNAs) in six cardiac regions by RNA-seq. Samples were donated from six subjects with or without persistent AF for left atria, left atrial appendages, right atria, sinoatrial nodes, left ventricles, right ventricles, and pulmonary veins (PVs), and additional four right atrial appendages samples were collected from patients undergoing mitral valve replacement. In total, 23 AF samples were compared to 23 non-AF samples. Surprisingly, the most influenced heart region in gene expression by AF was the PV, not the atria. The ion channel-related gene set was significantly enriched upon analysis of these significant genes. In addition, some significant genes are cancer-related lncRNAs in PV in AF. A co-expression network analysis could detect the functional gene clusters. In particular, the cancer-related lncRNA, such as SAMMSON and FOXCUT, belong to the gene network with the cancer-related transcription factor FOXC1. Thus, they may also play an aggravating role in the pathogenesis of AF, similar to carcinogenesis. In the least, this study suggests that (1) RNA alteration is most intense in PVs and (2) post-transcriptional gene regulation by lncRNA may contribute to the progression of AF. Through the screening analysis across the six cardiac regions, the possibility that the PV region can play a role other than paroxysmal triggering in the pathogenesis of AF was demonstrated for the first time. Future research with an increase in the number of PV samples will lead to a novel understanding of the pathophysiology of AF.


Inhibition of ergosterol biosynthesis is not accompanied by a change in fatty acid composition in Saccharomyces cerevisiae treated with the antifungal agent 6-amino-2-n-pentylthiobenzothiazole.
The antifungal agent 6-amino-2-n-pentylthiobenzothiazole at a concentration of 40 microM lowered the specific growth rate of exponentially growing cultures of Saccharomyces cerevisiae by 36%. Treatment with 6-amino-2-n-pentylthiobenzothiazole inhibited the biosynthesis of ergosterol and caused an accumulation of the methylated sterol precursors ergosta-5,7-dienol and squalene, but had no significant effect on the composition and the rate of biosynthesis of fatty acids. The results indicate that neither the inhibition of ergosterol biosynthesis, nor the slowing-down of culture growth by this antifungal agent, led to a compensatory alteration in the pattern of fatty-acyl chains in membrane lipids. This finding contradicts the accepted wisdom for the action of a number of antifungal agents.


Epizootic of vesicular disease in pigs caused by coxsackievirus B4 in the Soviet Union in 1975.
Swine vesicular disease virus (SVDV) emerged around 1960 from a human enterovirus ancestor, coxsackievirus B5 (CVB5), and caused a series of epizootics in Europe and Asia. We characterized a coxsackievirus B4 strain that caused an epizootic involving 24 488 pigs in the Soviet Union in 1975. Phylogenetic evidence suggested that the swine virus emerged from a human ancestor between 1945 and 1975, almost simultaneously with the transfer of CVB5.


XAFS spectroscopy in catalysis research: AXAFS and shape resonances.
Two new techniques in X-ray absorption spectroscopy (XAS) have recently been developed which provide previously unobtainable information on supported noble metal catalysts. Atomic X-ray absorption fine structure (AXAFS) provides direct information on the average changes in interatomic potential of the metal particles induced by metal-support effects. Changes in the interatomic potential can now be directly related to changes in catalytic reactivity. Analysis of shape resonances near the X-ray absorption edge provides information on the changes in the nature of the bonding of adsorbates (like hydrogen) to the metal cluster as induced by the properties of the support. The strong decrease in activity of supported platinum clusters for neo-pentane hydrogenolysis with increasing alkalinity of the support can be ascribed to a decrease in ionization potential of the metal particles directly influenced by the alkalinity of the support.


Connecting the food and agriculture sector to nutrition interventions for improved health outcomes.
To achieve the Sustainable Development Goal of zero hunger, multi-sectoral strategies to improve nutrition are necessary. Building towards this goal, the food and agriculture sector must be considered when designing nutritional interventions. Nevertheless, most frameworks designed to guide nutritional interventions do not adequately capture opportunities for integrating nutrition interventions within the food and agriculture sector. This paper aims to highlight how deeply connected the food and agriculture sector is to underlying causes of malnutrition and identify opportunities to better integrate the food and agriculture sector and nutrition in low and middle income countries. In particular, this paper: (1) expands on the UNICEF conceptual framework for undernutrition to integrate the food and agriculture sector and nutrition outcomes, (2) identifies how nutritional outcomes and agriculture are linked in six important ways by defining evidence-based food and agriculture system components within these pathways: as a source of food, as a source of income, through food prices, women's empowerment, women's utilization of time, and women's health and nutritional status, and (3) shows that the food and agriculture sector facilitates interventions through production, processing and consumption, as well as through farmer practices and behavior. Current frameworks used to guide nutrition interventions are designed from a health sector paradigm, leaving agricultural aspects not sufficiently leveraged. This paper concludes by proposing intervention opportunities to rectify the missed opportunities generated by this approach. Program design should consider the ways that the food and agriculture sector is linked to other critical sectors to comprehensively address malnutrition. This framework is designed to help the user to begin to identify intervention sites that may be considered when planning and implementing multi-sectoral nutrition programs. The online version contains supplementary material available at 10.1007/s12571-022-01262-3.


Peripheral neutrophil inclusions in amiodarone treated patients.
In 14 patients receiving chronic amiodarone therapy the appearance of multilamellar inclusion bodies in peripheral blood neutrophils was related to both plasma concentrations of amiodarone and its desethyl metabolite and unwanted effects of the drug. Seven of the patients had well defined inclusion bodies. In this group mean amiodarone and desethylamiodarone concentrations were significantly higher than in the remaining seven patients and all but one had unwanted effects of the drug. Of the seven patients without inclusion bodies only one, with high plasma amiodarone and desethylamiodarone concentrations, had unwanted effects of the drug. It is concluded that the appearance of multilamellar bodies in the blood neutrophils of amiodarone-treated patients may help to distinguish those patients at risk of long-term amiodarone toxicity.


Prevention of ventricular fibrillation in experimental myocardial infarction.
The fall in the ventricular fibrillation threshold during the first half an hour following ligation of the descending branch of the left coronary artery in dog was not influenced by the i.v. injection of trimecain (Mesokain Spofa). On the other hand, an i.v. injection of methypranol (Trimepranol Spofa) given prior to ligation increased the level of ventricular fibrillation threshold 3 to 4 times compared to control value before occlusion in all 10 studied dogs. Depression of the beta-blocking adrenergic activity may thus prevent the occurrence of ventricular fibrillation in acute myocardial ischaemia.


Antibacterial Hydrogel as a Self-Drug-Delivery System Derived from Zn(II)-bis-imidazole/NSAID-Based Organic-Inorganic Hybrids.
A skin wound is prone to bacterial infection and growth. An antibacterial topical hydrogel that can act as a self-drug-delivery (SDD) system is reported here. Two bidentate ligands (L2/L1) derived from imidazole/benzimidazole derivatives when reacted with Zn(NO3)2 and a series of nonsteroidal-anti-inflammatory drugs (NSAIDs) produced crystalline products, which were characterized by single-crystal X-ray diffraction (SXRD). Simple mixing of the ingredients of the crystalline products (stoichiometry guided by the corresponding crystal structure) produced an aqueous gel (DMSO/water) when the bidentate ligand was water-insoluble L2, whereas water-soluble L1 readily produced hydrogels under similar conditions. Dynamic rheology and scanning electron microscopy (SEM) were employed to characterize the gels. Zone inhibition diameters, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and hemolysis data suggested that among the hydrogelators, L1MEC derived from L1, meclofenac and Zn(NO3)2, was found to be the best against the Gram-negative bacteria Escherichia coli. The corresponding hydrogel L1MEC_HG and a piece of a dried cloth bandage coated with the hydrogel also showed appreciable activity against E. coli. The antibacterial property of L1MEC_HG against E. coli, thus demonstrated, is relevant in developing an antibacterial SDD system because E. coli is reported to be present in infected wounds.


A new digital case-based educational program Orthogeriatrics TeleECHO, a strategy to improve the care of fragility fracture patients.
Participation in Orthogeriatrics TeleECHO was associated with improvement in physicians' knowledge and self-confidence in managing elderly patients with fractures. To develop and conduct an interactive case-based virtual TeleECHO program to expand the knowledge of healthcare professionals in the field of orthogeriatrics. The project included twelve 90-min sessions for physicians and healthcare managers. Each session was based on real clinical cases discussed by the multidisciplinary group of faculty. The efficacy of the project was assessed using questionnaires. The attendance of individual sessions ranged from 129 to 224 with the total number of participants 829; 25% of participants were from remote rural regions. A survey conducted at the beginning of the project showed insufficient knowledge and ability to apply the concepts of orthogeriatrics. A final questionnaire showed that 74% of respondents participated in most sessions, with 94% wishing to continue participating in further sessions. There was a statistically significant overall improvement in confidence of caring for fragility fracture patients with an effect size of 0.75 (p<0.001). The proportion of responders who were able to apply their new knowledge in clinical practice shortly after TeleECHO showed a substantial increase (p<0.0001). The Orthogeriatrics TeleECHO program was effective in changing perceptions and self-confidence of the participants, and applying knowledge acquired to patient care. This model of learning could be applied in other countries in other languages to improve post-fracture care worldwide.


Dystroglycan and protein O-mannosyltransferases 1 and 2 are required to maintain integrity of Drosophila larval muscles.
In vertebrates, mutations in Protein O-mannosyltransferase1 (POMT1) or POMT2 are associated with muscular dystrophy due to a requirement for O-linked mannose glycans on the Dystroglycan (Dg) protein. In this study we examine larval body wall muscles of Drosophila mutant for Dg, or RNA interference knockdown for Dg and find defects in muscle attachment, altered muscle contraction, and a change in muscle membrane resistance. To determine if POMTs are required for Dg function in Drosophila, we examine larvae mutant for genes encoding POMT1 or POMT2. Larvae mutant for either POMT, or doubly mutant for both, show muscle attachment and muscle contraction phenotypes identical to those associated with reduced Dg function, consistent with a requirement for O-linked mannose on Drosophila Dg. Together these data establish a central role for Dg in maintaining integrity in Drosophila larval muscles and demonstrate the importance of glycosylation to Dg function in Drosophila. This study opens the possibility of using Drosophila to investigate muscular dystrophy.


Landau-Kleffner syndrome: a clinical and EEG study of five cases.
In five children with normal initial psychomotor development, a Landau-Kleffner syndrome appeared at age 3-7 years. No neuroanatomic lesions were noted. Aphasia and hyperkinesia were isolated in three patients and associated with global regression of higher cortical functions in one patient. Massive intellectual deterioration and psychotic behavior were associated with transient aphasia in one patient. The epilepsy (focal motor and generalized tonic-clonic seizures, subclinical EEG focal seizures during sleep, and atypical absences) always regressed spontaneously or with antiepileptic drug (AED) treatment. The EEG in waking patients showed focal and generalized spike-wave discharges on a normal background rhythm. Discharge topography and pattern changed frequently. During sleep, discharges always increased. At some time during syndrome development, all patients had bilateral spike-waves for greater than 85% of the sleep period, while at other times the discharges were discontinuous or continuous but focal or unilaterally hemispheric. Discharge topography and abundance changed from night to night. The abnormal EEG and the impaired higher functions developed and regressed together, but not with strict temporal correlation. Our own experience suggests that the Landau-Kleffner syndrome and epilepsy with continuous spike-wave activity in slow-wave sleep cannot be clearly differentiated. They may be different points on the spectrum of a single syndrome.


Effects of lymphokine-activated killer cells and interleukin-2 on the ascites formation and the survival time of nude mice bearing human ovarian cancer cells.
The effect of intraperitoneal instillations of interleukin-2 (IL-2) and/or lymphokine-activated killer (LAK) cells on the ascites formation and the survival time was examined using nude mice as a model, with malignant ascites produced by intraperitoneal inoculation of human ovarian cancer cells derived from ascites of a patient with serous cystadenocarcinoma of the ovary. Twenty-eight days after tumor inoculation, all nude mice in the untreated group and in the group treated with spleen cells alone formed ascites. Two of ten nude mice treated with IL-2 alone after tumor inoculation survived without forming ascites during the experimental period. On the other hand, all nude mice treated with LAK cells alone had formed ascites 14 days after tumor inoculation. When LAK cells and IL-2 were combined, five of ten mice survived without forming ascites during the experimental period. The survival time of the group treated with IL-2 alone was significantly prolonged compared to the groups that received medium alone, spleen cells alone and LAK cells alone. When administration of LAK cells was followed by IL-2, the survival time was further prolonged.


Brain size and limits to adult neurogenesis.
The walls of the cerebral ventricles in the developing embryo harbor the primary neural stem cells from which most neurons and glia derive. In many vertebrates, neurogenesis continues postnatally and into adulthood in this region. Adult neurogenesis at the ventricle has been most extensively studied in organisms with small brains, such as reptiles, birds, and rodents. In reptiles and birds, these progenitor cells give rise to young neurons that migrate into many regions of the forebrain. Neurogenesis in adult rodents is also relatively widespread along the lateral ventricles, but migration is largely restricted to the rostral migratory stream into the olfactory bulb. Recent work indicates that the wall of the lateral ventricle is highly regionalized, with progenitor cells giving rise to different types of neurons depending on their location. In species with larger brains, young neurons born in these spatially specified domains become dramatically separated from potential final destinations. Here we hypothesize that the increase in size and topographical complexity (e.g., intervening white matter tracts) in larger brains may severely limit the long-term contribution of new neurons born close to, or in, the ventricular wall. We compare the process of adult neuronal birth, migration, and integration across species with different brain sizes, and discuss how early regional specification of progenitor cells may interact with brain size and affect where and when new neurons are added.


Instant MR labeling of stem cells using magnetoelectroporation.
For cellular MR imaging, conventional approaches to intracellular magnetic labeling of nonphagocytic cells rely on the use of secondary compounds such as transfection agents and prolonged incubation of cells. Magnetoelectroporation (MEP) was investigated as an alternative method to achieve instant (<1 s) endosomal labeling with the FDA-approved formulation Feridex, without the need for adjunct agents or initiating cell cultures. While MEP was harmful at higher voltages or pulse durations, the procedure could be properly calibrated using a pulse of 130 V and 17 ms. Labeling was demonstrated for stem cells from mice, rats, and humans; the uptake of iron was in the picogram range and comparable to values obtained using transfection agents. MEP-labeled stem cells exhibited an unaltered viability, proliferation, and mitochondrial metabolic rate. Labeled mesenchymal stem cells (MSCs) and neural stem cells (NSCs) differentiated into adipogenic, osteogenic, and neural lineages in an identical fashion as unlabeled cells, while containing Feridex particles as demonstrated by double immunofluorescent staining. MEP-labeled NSCs proliferated normally following intrastriatal transplantation and could be readily detected by MR imaging in vivo. As MEP circumvents the use of secondary agents, obviating the need for clinical approval, MEP labeling may be ideally suitable for bedside implementation.


Evaluation of a mosquito home system for controlling Aedes aegypti.
Dengue is a significant public health issue that is caused by Aedes spp. mosquitoes. The current vector control methods are unable to effectively reduce Aedes populations and thus fail to decrease dengue transmission. Hence, there is an urgent need for new tools and strategies to reduce dengue transmission in a wide range of settings. In this study, the Mosquito Home System (MHS) and Mosquito Home Aqua (MHAQ) formulations were assessed as commercial autodissemination traps in laboratory and small-scale field trials. Multiple series of laboratory and small-scale field trials were performed to assess the efficacy of MHS and MHAQ exposed to Ae. aegypti. In the laboratory trials, various parameters such as fecundity, fertility, wing size, oviposition preferences, residual effects, and MHAQ transference to other containers through controlled experiments were tested. For small-scale field trials, the efficacy of the MHS and MHAQ approaches was determined to ascertain whether wild mosquitoes could transfer the MHAQ formulation from MHS stations to ovitraps. The data revealed that Ae. aegypti was highly susceptible to low concentrations of MHAQ formulations and had a residual effect of up to 3 months, with MHAQ exposure affecting fecundity, fertility, and mosquito wing size. In the oviposition studies, gravid females strongly preferred the hay infusion compared to tap water and MHAQ during egg-laying in the laboratory. Nevertheless, the use of commercial MHAQ by MHS was highly attractive in field settings compared to conventional ovitraps among local Aedes spp. mosquitoes. In addition, MHAQ horizontal transfer activities in the laboratory and small-scale field trials were demonstrated through larval bioassays. These findings demonstrated the potential of MHAQ to be transferred to new containers in each study site. This study provided proof of principle for the autodissemination of MHAQ. Through further refinement, this technique and device could become an effective oviposition trap and offer an alternative preventive tool for vector control management.


Antidesma thwaitesianum Müll. Arg. Fruit Juice, Its Phytochemical Contents, Antimicrobial Activity, and Application in Chiffon Cake.
Antidesma thwaitesianum Müll. Arg. or Mao is well-known in Thailand for its use in soft drinks and wine. This study investigated the potential of its fruit juice as a food preservative based on its antimicrobial activity against food-borne pathogens and spoilage. The fruit juice had antibacterial activity against Bacillus cereus TISTR1527, Staphylococcus aureus TISTR2329, Listeria monocytogenes DMST17303, Pseudomonas aeruginosa TISTR357, Salmonella Typhimurium DMST562, and Escherichia coli TISTR074. The minimum inhibitory concentration ranged from 25 to 100 mg/ml. Of significance was that the juice had excellent antifungal activities against Aspergillus flavus TISTR3135 and Penicillium digitatum ATCC10030. Furthermore, the fruit juice increased the lag time of spore germination of P. digitatum. Analysis of the phytochemical contents of the juice showed that the total phenolic and flavonoid contents were 20.07 mg GAE/g and 3.57 mg QE/g, respectively. In antioxidant activity assay, the juice exhibited moderate DPPH and ABTS+ radical scavenging and ferric-reducing activities. The addition of 5% fruit juice extended the microbial shelf life of chiffon cake. The treated chiffon cake had a shelf-life of 7 days, compared to 3 days for the untreated control. These results support the possible use of Mao fruit juice as an antimicrobial agent and a natural food preservative.


High-efficiency non-mosaic CRISPR-mediated knock-in and indel mutation in F0 Xenopus.
The revolution in CRISPR-mediated genome editing has enabled the mutation and insertion of virtually any DNA sequence, particularly in cell culture where selection can be used to recover relatively rare homologous recombination events. The efficient use of this technology in animal models still presents a number of challenges, including the time to establish mutant lines, mosaic gene editing in founder animals, and low homologous recombination rates. Here we report a method for CRISPR-mediated genome editing in Xenopus oocytes with homology-directed repair (HDR) that provides efficient non-mosaic targeted insertion of small DNA fragments (40-50 nucleotides) in 4.4-25.7% of F0 tadpoles, with germline transmission. For both CRISPR/Cas9-mediated HDR gene editing and indel mutation, the gene-edited F0 embryos are uniformly heterozygous, consistent with a mutation in only the maternal genome. In addition to efficient tagging of proteins in vivo, this HDR methodology will allow researchers to create patient-specific mutations for human disease modeling in Xenopus.


Safe administration of bevacizumab combination chemotherapy for the patients with recurrent cervical cancer after pelvic radiotherapy: Two case reports.
In Japan, bevacizumab has not been proven either effective or safe for the treatment of recurrent cervical cancer. The present study reported two cases in which bevacizumab combination chemotherapy was safely administered for recurrent cervical cancer following pelvic radiotherapy. Case 1 was a 62-year-old woman with stage IIIB squamous cell carcinoma of the cervix who had received whole pelvic external beam radiotherapy (WPEBRT) at a dose of 50.4 Gy and high dose rate intra-cavitary brachytherapy at a dose of 24 Gy to the pelvis one year earlier. For recurrent cervical cancer, chemotherapy with paclitaxel, carboplatin and bevacizumab was administered for six cycles. Case 2 was a 52-year-old woman with stage IIB squamous cell carcinoma of the cervix who had received WPEBRT at a dose of 50.4 Gy to the pelvis 11 years earlier. For lymph node and liver metastases, chemotherapy with paclitaxel, cisplatin, and bevacizumab was administered for six cycles. Although grade 2 proteinuria was observed in one of these patients, there were no intestinal perforation, fistula, hypertension, proteinuria or thrombosis events, which are the characteristic adverse reactions associated with bevacizumab. Hematotoxicity was also manageable. Regarding the antitumor effect, case 1 demonstrated a complete response, whereas case 2 resulted in stable disease.


Reaching young women who sell sex: Methods and results of social mapping to describe and identify young women for DREAMS impact evaluation in Zimbabwe.
Young women (aged 15-24) who exchange sex for money or other support are among the highest risk groups for HIV acquisition, particularly in high prevalence settings. To prepare for introduction and evaluation of the DREAMS programme in Zimbabwe, which provides biomedical and social interventions to reduce adolescent girls' and young women's HIV vulnerability, we conducted a rapid needs assessment in 6 towns using a "social mapping" approach. In each site, we talked to adult sex workers and other key informants to identify locations where young women sell sex, followed by direct observation, group discussions and interviews. We collected data on socio-demographic characteristics of young women who sell sex, the structure and organisation of their sexual exchanges, interactions with each other and adult sex workers, and engagement with health services. Over a two-week period, we developed a "social map" for each study site, identifying similarities and differences across contexts and their implications for programming and research. Similarities include the concentration of younger women in street-based venues in town centres, their conflict with older sex workers due to competition for clients and acceptance of lower payments, and reluctance to attend existing services. Key differences were found in the 4 university towns included in our sample, where female students participate in diverse forms of sexual exchange but do not identify themselves as selling sex. In smaller towns where illegal gold panning or trucking routes were found, young women migrated in from surrounding rural areas specifically to sell sex. Young women who sell sex are different from each other, and do not work with or attend the same services as adult sex workers. Our findings are being used to inform appropriate intervention activities targeting these vulnerable young women, and to identify effective strategies for recruiting them into the DREAMS process and impact evaluations.


Cargo-Dependent Targeted Cellular Uptake Using Quaternized Starch as a Carrier.
The tailored design of drug delivery systems for specific therapeutic agents is a prevailing approach in the field. In this paper, we present a study that highlights the potential of our modified starch, Q-starch, as a universal and adaptable drug delivery carrier for diverse therapeutic agents. We investigate the ability of Q-starch/cargo complexes to target different organelles within the cellular landscape, based on the specific activation sites of therapeutic agents. Plasmid DNA (pDNA), small interfering RNA (siRNA), and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) were chosen as representative therapeutic molecules, acting in the nucleus, cytoplasm, and membrane, respectively. By carrying out comprehensive characterizations, employing dynamic light scattering (DLS), determining the zeta potential, and using cryo-transmitting electron microscopy (cryo-TEM), we reveal the formation of nano-sized, positively charged, and spherical Q-starch complexes. Our results demonstrate that these complexes exhibit efficient cellular uptake, targeting their intended organelles while preserving their physical integrity and functionality. Notably, the intracellular path of the Q-starch/cargo complex is guided by the cargo itself, aligning with its unique biological activity site. This study elucidates the versatility and potency of Q-starch as a versatile drug delivery carrier, paving the way for novel applications offering targeted delivery strategies for potential therapeutic molecules.


Kruppel-like factor 4 inhibits epithelial-to-mesenchymal transition through regulation of E-cadherin gene expression.
The Krüppel-like factor 4 (KLF4) is a transcriptional regulator of proliferation and differentiation in epithelial cells, both during development and tumorigenesis. Although KLF4 functions as a tumor suppressor in several tissues, including the colon, the role of KLF4 in breast cancer is less clear. Here, we show that KLF4 is necessary for maintenance of the epithelial phenotype in non-transformed MCF-10A mammary epithelial cells. KLF4 silencing led to alterations in epithelial cell morphology and migration, indicative of an epithelial-to-mesenchymal transition. Consistent with these changes, decreased levels of KLF4 also resulted in the loss of E-cadherin protein and mRNA. Promoter/reporter analyses revealed decreased E-cadherin promoter activity with KLF4 silencing, while chromatin immunoprecipitation identified endogenous KLF4 binding to the GC-rich/E-box region of this promoter. Furthermore, forced expression of KLF4 in the highly metastatic MDA-MB-231 breast tumor cell line was sufficient to restore E-cadherin expression and suppress migration and invasion. These findings identify E-cadherin as a novel transcriptional target of KLF4. The clear requirement for KLF4 to maintain E-cadherin expression and prevent epithelial-to-mesenchymal transition in mammary epithelial cells supports a metastasis suppressive role for KLF4 in breast cancer.


The genome sequence of the Light Brocade, Lacanobia w-latinum (Hufnagel, 1766).
We present a genome assembly from an individual male Lacanobia w-latinum (the Light Brocade; Arthropoda; Insecta; Lepidoptera; Noctuidae). The genome sequence is 903.9 megabases in span. Most of the assembly is scaffolded into 31 chromosomal, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.38 kilobases in length. Gene annotation of this assembly on Ensembl identified 21,592 protein coding genes.


Fecal microbiota transplantation in Parkinson's disease-A randomized repeat-dose, placebo-controlled clinical pilot study.
The intestinal microbiome plays a primary role in the pathogenesis of neurodegenerative disorders and may provide an opportunity for disease modification. We performed a pilot clinical study looking at the safety of fecal microbiota transplantation (FMT), its effect on the microbiome, and improvement of symptoms in Parkinson's disease. This was a randomized, double-blind placebo-controlled pilot study, wherein orally administered lyophilized FMT product or matching placebo was given to 12 subjects with mild to moderate Parkinson's disease with constipation twice weekly for 12 weeks. Subjects were followed for safety and clinical improvement for 9 additional months (total study duration 12 months). Fecal microbiota transplantation caused non-severe transient upper gastrointestinal symptoms. One subject receiving FMT was diagnosed with unrelated metastatic cancer and was removed from the trial. Beta diversity (taxa) of the microbiome, was similar comparing placebo and FMT groups at baseline, however, for subjects randomized to FMT, it increased significantly at 6 weeks (p = 0.008) and 13 weeks (p = 0.0008). After treatment with FMT, proportions of selective families within the phylum Firmicutes increased significantly, while proportion of microbiota belonging to Proteobacteria were significantly reduced. Objective motor findings showed only temporary improvement while subjective symptom improvements were reported compared to baseline in the group receiving FMT. Constipation, gut transient times (NS), and gut motility index (p = 0.0374) were improved in the FMT group. Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms. ClinicalTrial.gov, identifier: NCT03671785.


[Transmission of drug-resistance through conjugation in Yersinia enterocolitica and Yersinia pseudotuberculosis. (II). With special reference to streptomycin resistant strains isolated from men and domestic animals (author's transl)].
Seven strains of Y. enterocolitica, of which 2 strains being resistant to SM, TC and SA, 2 to SM and SA 3 to SM, and 3 strains of Y. pseudotuberculosis resistant to SM have been isolated from men and domestic animals. Tests were carried out with these 10 isolates for transfer of the drug resistance by bacterial conjugation, and evidence was obtained for transfer of resistance from 1 SM-resistant Y. enterocolitica and 2 Y. pseudotuberculosis strains to the sensitive E. coli K-12. Moreover, secondary transfer of this resistance to sensitive strains of the donor species Y. enterocolitica and Y pseudotuberculosis was also demonstrated. The findings indicate the spontaneous occurrence of organisms carrying the resistance transfer factor, R(Sm), among the populations of these two species in the natural environment.


What factors determine phenotype of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)? Considerations in the context of a novel pathogenic R110C mutation in the NOTCH3 gene.
We report patients from a Polish family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) who possess a novel heterozygous R110C mutation in exon 3 of the NOTCH3 gene leading to stereotypical cysteine loss. The proband had only seizure attacks and her magnetic resonance imaging (MRI) showed very numerous hyperintense foci in the cerebral white matter in a location characteristic of CADASIL. Distinctive ultrastructural assessment of vessels from skin-muscle biopsy revealed only mild degenerative changes but relatively numerous homogeneous deposits of granular osmiophilic material (GOM). In the other symptomatic family members with the same mutation ischaemic strokes were present but not epilepsy. In the proband's affected brother at a similar age, the brain MRI was normal but vessels showed pronounced degenerative changes and irregular GOM deposits. The present report not only extends the list of known pathogenic mutations responsible for CADASIL but also emphasizes clinical and morphologic variability among family members with the same NOTCH3 mutation, suggesting that probably additional factors, not only mutations, may influence the disease phenotype..


Predictive role of Carhart's notch in pre-operative assessment for middle-ear surgery.
To evaluate the predictive role of the audiometric Carhart's notch for the assessment of middle-ear pathology prior to surgical intervention. In this retrospective analysis, a total of 315 operated ears of 305 patients were evaluated regarding their pre-operative pure tone audiograms and peri-operative findings. The probable relationship between the middle-ear pathologies found and the Carhart's notch found on pre-operative pure tone audiometry was investigated. Patients with conductive hearing loss who obtained at least a 10 dB improvement (at 1 and 2 kHz frequencies) in their bone conduction threshold post-operatively were included in the Carhart's notch group. The pathologies underlying Carhart's notch were compared. Three hundred and fifteen ears of 305 consecutive patients with conductive hearing loss were operated on due to middle-ear pathology. In patients with otosclerosis and tympanosclerosis, a Carhart's notch was seen at 2 kHz in 28 (93 per cent) patients but at 1 kHz in only two (7 per cent). However, in patients with chronic otitis media, a Carhart's notch was seen at 1 kHz in 10 (55 per cent) patients and at 2 kHz in eight (45 per cent) patients. Otitis media with effusion, tympanosclerosis and congenital malformations should be considered in the differential diagnosis of a patient with a Carhart's notch seen on pure tone audiometry. A Carhart's notch at 2 kHz indicates stapes footplate fixation, whereas one at 1 kHz indicates a mobile stapes footplate; the footplate mobility can thus be predicted pre-operatively.


Effects of workaholism on volunteer firefighters' performance: a moderated mediation model including supervisor recognition and emotional exhaustion.
Background and Objectives: Although workaholism has been associated with job performance, the mechanisms that explain this relationship remain unclear. In this study, we investigated the conditional indirect effects of workaholism on performance via emotional exhaustion, across low and high levels of supervisor recognition. Methods: We conducted an empirical cross-sectional study using a sample of 1028 volunteer firefighters who completed a self-report questionnaire assessing workaholism, emotional exhaustion, work performance, and supervisor recognition. Results: Tests of latent interactions were performed using the latent moderated structural equation modeling approach. Consistent with our predictions, results revealed that the negative indirect effects of workaholism on performance, through emotional exhaustion, were stronger when supervisor recognition was low. Conclusions: Theorical contributions and perspectives, as well as implications for practice are discussed.


Intracystic treatments for craniopharyngioma.
Craniopharyngioma is a benign tumor histopathologically and in theory should be curable by radical resection. In practice, this tumor behaves like a chronic disease, with many issues related to the effect of the tumor itself and the various treatments on the adjacent structures, such as the pituitary stalk and gland, hypothalamus, visual apparatus, and suprasellar arteries. A multimodality approach to the management of these tumors may produce the optimal outcome, balancing disease control and quality of life. In this paper, the role of intracystic therapies is reviewed, with the major focus on intracystic bleomycin and interferon-alpha.


Atlantoaxial rotatory fixation. A case report and proposal of a new classification system.
Atlantoaxial rotatory fixation (AARF) remains a relatively rare finding. A case of AARF is reported and the existing Fielding and Hawkins classification is reviewed. Furthermore a new classification system is proposed.


[Mitral valve prolapse or late systolic click syndrome in childhood].
6 Children with late systolic murmur and systolic click in mitral valve prolapse syndrome are reported. The clinical, electrocardiographic, phonocardiographic and echocardiographic findings are represented. In differentiating the mitral valve prolapse from the idipathic hypertrophic subaortic stenosis, the mitral insufficiency and the pure accidental murmur, this non-invasive technique is a good enrichment of the diagnostic procedures.


Mode of Infection of Metarhizium spp. Fungus and Their Potential as Biological Control Agents.
Chemical insecticides have been commonly used to control agricultural pests, termites, and biological vectors such as mosquitoes and ticks. However, the harmful impacts of toxic chemical insecticides on the environment, the development of resistance in pests and vectors towards chemical insecticides, and public concern have driven extensive research for alternatives, especially biological control agents such as fungus and bacteria. In this review, the mode of infection of Metarhizium fungus on both terrestrial and aquatic insect larvae and how these interactions have been widely employed will be outlined. The potential uses of Metarhizium anisopliae and Metarhizium acridum biological control agents and molecular approaches to increase their virulence will be discussed.


XIAP Limits Autophagic Degradation of Sox2 and Is A Therapeutic Target in Nasopharyngeal Carcinoma Stem Cells.
Rationale: Nasopharyngeal carcinoma (NPC) is the most frequent head and neck tumor in South China. The presence of cancer stem cells (CSCs) in NPC contributes to tumor maintenance and therapeutic resistance, while the ability of CSCs to escape from the apoptosis pathway may render them the resistant property to the therapies. Inhibitor of apoptosis proteins family proteins (IAPs), which are overexpressed in nasopharyngeal carcinoma stem cells, may play an important role in maintaining nasopharyngeal cancer stem cell properties. Here, we develop a novel CSC-targeting strategy to treat NPC through inhibiting IAPs. Methods: Human NPC S-18 and S-26 cell lines were used as the model system in vitro and in vivo. Fluorescence activated cell sorting (FACS) assay was used to detect nasopharyngeal SP cells and CD44+ cells. The characteristics of CSCs were defined by sphere suspension culture, colony formation assay and cell migration. The role of XIAP on the regulation of Sox2 protein stability and ERK1-mediated phosphorylation of Sox2 signaling pathway were analyzed using immunoblotting, immunoprecipitation, immunofluorescence, phosphorylation mass spectrometry, siRNA silencing and plasmid overexpression. The correlation between XIAP and Sox2 in NPC biopsies and their role in prognosis was performed by immunohistochemistry. APG-1387 or chemotherapies-induced cell death and apoptosis in S-18 and S-26 were determined by WST, immunoblotting and flow cytometry assay. Results: IAPs, especially X chromosome-linked IAP (XIAP), were elevated in CSCs of NPC, and these proteins were critically involved in the maintenance of CSCs properties by enhancing the stability of Sox2. Mechanistically, ERK1 kinase promoted autophagic degradation of Sox2 via phosphorylation of Sox2 at Ser251 and further SUMOylation of Sox2 at Lys245 in non-CSCs. However, XIAP blocked autophagic degradation of Sox2 by inhibiting ERK1 activation in CSCs. Additionally, XIAP was positively correlated with Sox2 expression in NPC tissues, which were associated with NPC progression. Finally, we discovered that a novel antagonist of IAPs, APG-1387, exerted antitumor effect on CSCs. Also, the combination of APG-1387 with CDDP /5-FU has a synergistic effect on NPC. Conclusion: Our study highlights the importance of IAPs in the maintenance of CSCs in NPC. Thus, XIAP is a promising therapeutic target in CSCs and suggests that NPC patients may benefit from a combination treatment of APG-1387 with conventional chemotherapy.


Activation of CD38 by interleukin-8 signaling regulates intracellular Ca2+ level and motility of lymphokine-activated killer cells.
CD38 is an ADP-ribosyl cyclase, producing a potent Ca(2+) mobilizer cyclic ADP-ribose (cADPR). In this study, we have investigated a role of CD38 and its regulation through interleukin-8 (IL8) signaling in lymphokine-activated killer (LAK) cells. Incubation of LAK cells with IL8 resulted in an increase of cellular cADPR level and a rapid rise of intracellular Ca(2+) concentration ([Ca(2+)](i)), which was sustained for a long period of time (>10 min). Preincubation of an antagonistic cADPR analog, 8-Br-cADPR (8-bromo-cyclic adenosine diphosphate ribose), abolished the sustained Ca(2+) signal only but not the initial Ca(2+) rise. An inositol 1,4,5-trisphosphate (IP(3)) receptor antagonist blocked both Ca(2+) signals. Interestingly, the sustained Ca(2+) rise was not observed in the absence of extracellular Ca(2+). Functional CD38-null (CD38(-)) LAK cells showed the initial rapid increase of [Ca(2+)](i) but not the sustained Ca(2+) rise in response to IL8 treatment. An increase of cellular cADPR level by cGMP analog, 8-pCPT-cGMP (8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate), but not cAMP analog or phorbol 12-myristate 13-acetate was observed. IL8 treatment resulted in the increase of cGMP level that was inhibited by the IP(3) receptor blocker but not a protein kinase C inhibitor. cGMP-mediated Ca(2+) rise was blocked by 8-Br-cADPR. In addition, IL8-mediated LAK cell migration was inhibited by 8-Br-cADPR and a protein kinase G inhibitor. Consistent with these observations, IL8-induced migration of CD38(-) LAK cells was not observed. However, direct application of cADPR or 8-pCPT-cGMP stimulated migration of CD38(-) cells. These results demonstrate that CD38 is stimulated by sequential activation of IL8 receptor, IP(3)-mediated Ca(2+) rise, and cGMP/protein kinase G and that CD38 plays an essential role in IL8-induced migration of LAK cells.


CD4+ T cell-targeted immunomodulation and the therapy of allergic disease.
In recent years there have been considerable advances in our knowledge of the cellular and molecular events following ligation of the T cell receptor. The quantitative and qualitative characteristics of the signal(s) received by a naive or memory T cell largely determine whether receptor ligation results in cell activation, cell death, or the induction of a state of antigen-specific nonresponsiveness. Furthermore, microenvironmental conditions, including the presence of secreted cytokines or the structure of the peptide antigen, strongly influence the differentiation of CD4+ helper cells into functionally distinct subsets. The interregulation of these functional subsets appears pivotal to the development of many immune-mediated disorders, including allergic disease. We suggest that the selective manipulation of the immune response to specific antigens may be an effective strategy for the therapy of such disorders and we review recent studies which support this concept.


The synthesis of novel lanthanum hydroxyborate at extreme conditions.
The novel structure of lanthanum hydroxyborate La2B2O5(OH)2 was synthesized by the reaction of partially hydrolyzed lanthanum and boron oxide in a diamond anvil cell under high-pressure/high-temperature (HPHT) conditions of 30 GPa and ∼2,400 K. The single-crystal X-ray structure determination of the lanthanum hydroxyborate revealed: P3¯c1, a = 6.555(2) Å, c = 17.485(8) Å, Z = 6, R1 = 0.056. The three-dimensional structure consists of discrete planar BO3 groups and three crystallographically different La ions: one is surrounded by 9, one by 10, and one by 12 oxygen anions. The band gap was estimated using ab initio calculations to be 4.64 eV at ambient pressure and 5.26 eV at 30 GPa. The current work describes the novel HPHT lanthanum hydroxyborate with potential application as a deep-ultraviolet birefringent material.


Antiproliferative, antiinvasive, and proapoptotic activity of folate receptor α-targeted liposomal doxorubicin in nonfunctional pituitary adenoma cells.
There is an urgent need for novel therapeutic strategies for the treatment of nonfunctional pituitary adenomas (NFPAs), especially those that are invasive. The folate receptor (FR)α is overexpressed in several cancers, including NFPA. The aim of this study was to determine the efficacy of FRα-targeted liposomes loaded with doxorubicin (F-L-DOX) in the treatment of NFPA. We evaluated targeting, cytotoxicity, antiinvasive, and proapoptotic activity of F-L-DOX in 25 primary cell lines derived from patients with NFPAs. We found that these liposomes effectively targeted NFPA cells through FRα and that endocytosis of the liposomes was blocked by 1mM free folic acid. F-L-DOX inhibited proliferation of NFPA cells and promoted apoptosis through activation of caspase-8, caspase-9, and caspase-3/7 more effectively than L-DOX. Furthermore, F-L-DOX also exerted greater antiinvasive ability in NFPA cells than L-DOX through suppression of the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9. Addition of 1mM free folic acid significantly reduced the pleotropic effects of F-L-DOX in NFPA cells, suggesting that FRα plays a critical role in mediating the antitumor effect of F-L-DOX. Our findings warrant further investigation of F-L-DOX as an alternative therapeutic strategy for the treatment of NFPAs that express FRα.


Not under my PIN.
Your story 'Concern remains over nursing associate role' (news, 1 March) warns that the new role should not be used to replace registered nurses.


Teaching bioethics as a new paradigm for health professionals.
In The Clouds by Aristophanes, Strepsiades brings his son before Socrates so that he could learn Philosophy for he has heard that this science teaches how to overcome the most difficult causes with reasons. And Strepsiades wants his son to learn the art of failing to pay debts. Regarding medical education in our time, Edmund Pellegrino has noted that the educational philosophy of medical schools determines what a "good" physician is. Thus, teaching bioethics to future health professionals makes us face old problems now: What teaching method to choose among all the possible various ones? What should teaching aim at? Which will be our educational philosophy? Therefore I shall introduce here the epistemological basis of our Bioethics teaching program in Argentina and its implementing strategies in the undergraduate curriculum and the post-graduate level.


Osteogenic impact of pro-apoptotic caspase inhibitors in MC3T3-E1 cells.
Caspases are proteases traditionally associated with inflammation and cell death. Recently, they have also been shown to modulate cell proliferation and differentiation. The aim of the current research was to search for osteogenic molecules affected by caspase inhibition and to specify the individual caspases critical for these effects with a focus on proapoptotic caspases: caspase-2, -3, -6, -7, -8 and -9. Along with osteocalcin (Ocn), general caspase inhibition significantly decreased the expression of the Phex gene in differentiated MC3T3-E1 cells. The inhibition of individual caspases indicated that caspase-8 is a major contributor to the modification of Ocn and Phex expression. Caspase-2 and-6 had effects on Ocn and caspase-6 had an effect on Phex. These data confirm and expand the current knowledge about the nonapoptotic roles of caspases and the effect of their pharmacological inhibition on the osteogenic potential of osteoblastic cells.


Receptor-mediated binding of leukocyte elastase by chondrocytes.
Studies on the effect of leukocyte elastase on the metabolism of chondrocytes in culture have demonstrated that these cells possess a specific cell surface receptor for leukocyte-derived elastase. Purified elastase from rabbit and human leukocytes is capable of modulating the metabolism of the cell by causing a marked decrease in both proteoglycan and protein biosynthesis. Addition of 125I-labeled elastase to chondrocytes maintained in suspension culture has shown that binding occurs, and that it is saturable and is inhibited by the addition of unlabeled enzyme. We ascertained that the active site of the enzyme was necessary for binding to the chondrocyte, since phenylmethylsulfonyl fluoride-inactivated leukocyte elastase failed to bind. Pancreatic elastase had only a slight affinity for the receptor, whereas trypsin and bovine serum albumin failed to bind to any significant extent. Autoradiographic studies and the use of inhibitors of endocytosis, such as dansyl cadaverine, confirmed that endocytosis of elastase was the secondary event after cell binding.


Recent Advances in Natural Products with Anti-Leukemia and Anti-Lymphoma Activities.
Leukemia and lymphoma are the most common blood cancers, which pose a critical threat to the health of adults and children. The total incidence and mortality rates of both are approximately 6% globally. Compared with the expensive cost of CAR T cell therapy, natural products from animals, plants and microorganisms have the characteristics of wide-range sources and costeffectiveness in the treatment of cancer. Moreover, the drug resistance that emerged in leukemia and lymphoma treatments shows an urgent need for new drugs. However, in addition to the natural products that have been marketed in the treatment of leukemia and lymphoma, there have been a large number of studies on natural products that fight blood cancer in recent years. This review summarized the recent studies on natural compounds with anti-lymphoma and anti-leukemia activities, hoping to provide novel weapons into the drug development arsenal.


Glycemic control and burnt-out diabetes in ESRD.
Treatment of early diabetes mellitus, the most common cause of chronic kidney disease (CKD), may prevent or slow the progression of diabetic nephropathy and lower mortality and the incidence of cardiovascular disease in the general diabetic population and in patients with early stages of CKD. It is unclear whether glycemic control in patients with advanced CKD, including those with end-stage renal disease (ESRD) who undergo maintenance dialysis treatment is beneficial. Aside from the uncertain benefits of treatment in ESRD, hypoglycemic interventions in this population are also complicated by the complex changes in glucose homeostasis related to decreased kidney function and to dialytic therapies, occasionally leading to spontaneous resolution of hyperglycemia and normalization of hemoglobin A1c levels, a condition which might be termed "burnt-out diabetes." Further difficulties in ESRD are posed by the complicated pharmacokinetics of antidiabetic medications and the serious flaws in our available diagnostic tools used for monitoring long-term glycemic control. We review the physiology and pathophysiology of glucose homeostasis in advanced CKD and ESRD, the available antidiabetic medications and their specifics related to kidney function, and the diagnostic tools used to monitor the severity of hyperglycemia and the therapeutic effects of available treatments, along with their deficiencies in ESRD. We also review the concept of burnt-out diabetes and summarize the findings of studies that examined outcomes related to glycemic control in diabetic ESRD patients, and emphasize areas in need of further research.