Cochlear Implantation in Inner Ear Malformations: Systematic Review of Speech Perception Outcomes and Intraoperative Findings.
Objective (1) To analyze reported speech perception outcomes in patients with inner ear malformations who undergo cochlear implantation, (2) to review the surgical complications and findings, and (3) to compare the 2 classification systems of Jackler and Sennaroglu. Data Sources PubMed, Scopus (including Embase), Medline, and CINAHL Plus. Review Methods Fifty-nine articles were included that contained speech perception and/or intraoperative data. Cases were differentiated depending on whether the Jackler or Sennaroglu malformation classification was used. A meta-analysis of proportions examined incidences of complete insertion, gusher, and facial nerve aberrancy. For speech perception data, weighted means and standard deviations were calculated for all malformations for short-, medium-, and long-term follow-up. Speech tests were grouped into 3 categories-closed-set words, open-set words, and open-set sentences-and then compared through a comparison-of-means t test. Results Complete insertion was seen in 81.8% of all inner ear malformations (95% CI: 72.6-89.5); gusher was reported in 39.1% of cases (95% CI: 30.3-48.2); and facial nerve anomalies were encountered in 34.4% (95% CI: 20.1-50.3). Significant improvements in average performance were seen for closed- and open-set tests across all malformation types at 12 months postoperatively. Conclusions Cochlear implantation outcomes are favorable for those with inner ear malformations from a surgical and speech outcome standpoint. Accurate classification of anatomic malformations, as well as standardization of postimplantation speech outcomes, is necessary to improve understanding of the impact of implantation in this difficult patient population.


[A procedure for calculating needs for antituberculous drugs].
to develop a procedure for calculating needs for antituberculous drugs (ATD). A unified E-form (UEF) was developed as an "Excel" file with the underlying invariable formulas and coefficients for the computer-based calculation of ATD needs in any subject of the Russian Federation. The needs were estimated using the average number of tablets (capsules, vials) of each ATD required per man/course, by taking into account the conventional chemotherapy regimens, the duration of chemoprophylaxis, antirecurrent courses, ATD test therapy, a treatment regimen for complications due to BCG vaccination. Information on the inventory of ATDs at the end of the previous year and their estimated deliveries from various sources was additionally considered. Data to be filled in the UEF were obtained from the reporting documents: 1) TB Form No. 2 "Information on patients registered for treatment" approved by Order No. 50 "On Consummation of Recording and Reporting Documents as to Tuberculosis Monitoring" issued by the Ministry of Health of the Russian Federation on February 13, 2002; 2) Form No. 030-4/y "Tuberculosis Patient Follow-Up Schedule"; and 3) Form No. 33 "Information on Patients with Tuberculosis" approved by Regulation No. 80 issued by the Russian Statistics Agency on November 11, 2005. The filled-in UEFs were obtained from 82 subjects of the Russian Federation. among all the contingents of antituberculosis dispensaries, who were given ATDs, the absolute majority was the persons receiving chemoprophylaxis. Only 18.3% received chemotherapy for active tuberculosis. Of them, 56.8 and 15.3% were treated in accordance with chemotherapy regimens 1 and 3, respectively. The regimes (2B and 4) using second-line agents were given least frequently (7.1 and 7.1%, respectively). Comparing the data from Form No. 33 and those obtained on filling in UEF showed with a fair degree of assurance that the treatment of patients with a chronic tuberculous process had been incompletely registered. Personified registration of patients with multidrug Mycobacterium tuberculosis resistance should be performed in order to have objective information on the scope of required medical aid and the real calculation of needs for second-line ATDs. For unified calculation of needs for ATDs for chemotherapy, it is necessary to introduce a standardized approach to its performance at different dispensaries. By taking into account that ATDs are purchased and dispensed free of change, one should have a responsible attitude to consuming drugs, determining indications for their usage, and filling the UEF. TB Form No. 2 "Information on patients registered for treatment" and Register No, 03-TB/y "Register of patients with tuberculosis" should be improved, by adding data on the number of patients receiving chemoprophylaxis, antirecurrent courses, test therapy, and treatment of complications due to BCG vaccination.


Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: the Pax6 example.
Quite often a single or a combination of protein mutations is linked to specific diseases. However, distinguishing from sequence information which mutations have real effects in the protein's function is not trivial. Protein design tools are commonly used to explain mutations that affect protein stability, or protein-protein interaction, but not for mutations that could affect protein-DNA binding. Here, we used the protein design algorithm FoldX to model all known missense mutations in the paired box domain of Pax6, a highly conserved transcription factor involved in eye development and in several diseases such as aniridia. The validity of FoldX to deal with protein-DNA interactions was demonstrated by showing that high levels of accuracy can be achieved for mutations affecting these interactions. Also we showed that protein-design algorithms can accurately reproduce experimental DNA-binding logos. We conclude that 88% of the Pax6 mutations can be linked to changes in intrinsic stability (77%) and/or to its capabilities to bind DNA (30%). Our study emphasizes the importance of structure-based analysis to understand the molecular basis of diseases and shows that protein-DNA interactions can be analyzed to the same level of accuracy as protein stability, or protein-protein interactions.


Clinical Practice Guidelines for Irritable Bowel Syndrome in Korea, 2017 Revised Edition.
In 2011, the Korean Society of Neurogastroenterology and Motility (KSNM) published clinical practice guidelines on the management of irritable bowel syndrome (IBS) based on a systematic review of the literature. The KSNM planned to update the clinical practice guidelines to support primary physicians, reduce the socioeconomic burden of IBS, and reflect advances in the pathophysiology and management of IBS. The present revised version of the guidelines is in continuity with the previous version and targets adults diagnosed with, or suspected to have, IBS. A librarian created a literature search query, and a systematic review was conducted to identify candidate guidelines. Feasible documents were verified based on predetermined inclusion and exclusion criteria. The candidate seed guidelines were fully evaluated by the Guidelines Development Committee using the Appraisal of Guidelines for Research and Evaluation II quality assessment tool. After selecting 7 seed guidelines, the committee prepared evidence summaries to generate data exaction tables. These summaries comprised the 4 main themes of this version of the guidelines: colonoscopy; a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; probiotics; and rifaximin. To adopt the core recommendations of the guidelines, the Delphi technique (ie, a panel of experts on IBS) was used. To enhance dissemination of the clinical practice guidelines, a Korean version will be made available, and a food calendar for patients with IBS is produced.


Immune-modulation and properties of absorption and blood brain barrier permeability of 1,8-naphthyridine derivatives.
Considering the high selectivity at the cannabinoid CB2 receptor of recently designed 1,8-naphthyridine derivatives and the protective role of this receptor in neurological disorders, in this study we investigated the immune-modulatory and anti-inflammatory effects of these compounds as well as their potential properties of intestinal absorption and blood-brain barrier (BBB) permeability. We used peripheral blood mononuclear cells (PBMC) known to express the CB2 receptor. We observed that test compounds, CB13, CB82 and CB91 reduced PBMC proliferation. The anti-proliferative effect of CB13 and CB91 was partially mediated by the CB2 receptor. These compounds blocked the cells cycle and CB91 reduced T cell activation. CB82 and CB91 down-regulated the expression of phosphorylated proteins like NF-κB, ERK, Akt and the enzyme Cox-2, CB91 blocked the expression of the CB2 receptor and its inhibitory effect was CB2 receptor mediated. We also investigated CB91 properties of intestinal absorption and BBB permeability in order to suggest its potential efficacy on the infiltrating auto-reactive lymphocytes at the level of the central nervous system. For this purpose, CB91 was tested in drug-permeability assays on Caco-2 cells to evaluate its oral bioavailability and on MDCKII-hMDR1 cells to estimate its BBB permeability. The results indicated that this compound possesses medium level of intestinal absorption and BBB permeability. Our data suggest that CB91, modulating the immune response by CB2 receptor mediated mechanism and showing medium level of intestinal absorption and BBB permeability, might be developed as a potential orally delivered drug and might find potential application in pathologies like multiple sclerosis.


War neuroses and Arthur Hurst: a pioneering medical film about the treatment of psychiatric battle casualties.
From 1917 to 1918, Major Arthur Hurst filmed shell-shocked patients home from the war in France. Funded by the Medical Research Committee, and using Pathé cameramen, he recorded soldiers who suffered from intractable movement disorders as they underwent treatment at the Royal Victoria Hospital in Netley and undertook programs of occupational therapy at Seale Hayne in Devon. As one of the earliest UK medical films, Hurst's efforts may have drawn inspiration from the official documentary of the Battle of the Somme and films made in 1916 by French Army neurologists. Although initially motivated to make use of a novel medium to illustrate lectures, Hurst was alert to the wider appeal of the motion picture and saw an opportunity to position himself in the postwar medical hierarchy. Some "before treatment" shots were reenacted for the camera. Hurst, like some other shell shock doctors, openly used deception as a therapeutic measure. On the basis that the ends justified the means, they defended this procedure as ethical. Clinicians also took advantage of changes in military regulations to address functional symptoms. Claims made of "cures" in the film and associated publications by Hurst were challenged by other doctors treating shell shock. The absence of follow-up data and evidence from war pension files suggested that Hurst may have overstated the effectiveness of his methods. Nevertheless, the message conveyed in the film that chronic cases could be treated in a single session had a powerful resonance for ambitious or charismatic doctors and was revived in World War II.


Network neuroscience for optimizing brain-computer interfaces.
Human-machine interactions are being increasingly explored to create alternative ways of communication and to improve our daily life. Based on a classification of the user's intention from the user's underlying neural activity, brain-computer interfaces (BCIs) allow direct interactions with the external environment while bypassing the traditional effector of the musculoskeletal system. Despite the enormous potential of BCIs, there are still a number of challenges that limit their societal impact, ranging from the correct decoding of a human's thoughts, to the application of effective learning strategies. Despite several important engineering advances, the basic neuroscience behind these challenges remains poorly explored. Indeed, BCIs involve complex dynamic changes related to neural plasticity at a diverse range of spatiotemporal scales. One promising antidote to this complexity lies in network science, which provides a natural language in which to model the organizational principles of brain architecture and function as manifest in its interconnectivity. Here, we briefly review the main limitations currently affecting BCIs, and we offer our perspective on how they can be addressed by means of network theoretic approaches. We posit that the emerging field of network neuroscience will prove to be an effective tool to unlock human-machine interactions.


A 2020 Vision Into Hodgkin Lymphoma Biology.
Hodgkin lymphomas (HLs) are lymphoid neoplasms uniquely characterized by a paucity of neoplastic cells embedded in a supportive heterogenous cellular microenvironment. Although first described in the 19th century, systematic biological understanding of HLs has been hindered due to the challenges presented in studying the complex tumor microenvironment and scarce tumorigenic cells. Recent advances in single-cell isolation and characterization, sensitive mutational analytic tools, and multiplex immunohistochemical strategies have allowed further advances in understanding the development and progression of HL. Here we provide a current update on the chromosomal and mutational abnormalities seen in HL, the impact of Epstein-Barr virus infection on driving a subset of HLs, and the possibility of disease monitoring via high-sensitivity detection of genetic aberrations. We also discuss recent developments in understanding the intricate microenvironment through intercellular cross-talk, and describe novel potential biomarkers to aid in distinction of HL from other overlapping entities.


Von hippel-lindau syndrome: diagnosis and management of hemangioblastoma and pheochromocytoma.
Introduction. Von Hippel-Lindau (VHL) syndrome is a pathological condition that causes various clinical symptoms and is difficult to diagnose. The most common pathological lesions are hemangioblastomas of the central nervous system, retinal angiomas, renal clear cell carcinomas, and pheochromocytomas. Case Report. A 23-year-old female had a syncope episode in 2008. Magnetic resonance imaging (MRI) revealed a right temporal hemangioblastoma, which was treated surgically. Genetic screening identified a VHL gene mutation, and computed tomography (CT) revealed a left adrenal mass. Since it was unclear whether the mass was a pheochromocytoma, or another benign or malignant tumors, laparoscopic adrenalectomy was performed. A month after surgery, the patient complained of general fatigue, poor concentration, loss of appetite, and insomnia. After careful clinical investigation, the patient was referred to a psychiatrist due to suspected depression, which was confirmed. Conclusions. VHL genetic screening should be performed in cases of hemangioblastoma. In VHL syndrome cases, pheochromocytoma cannot always be diagnosed by biochemical catecholamine analyses; therefore, CT or MRI scanning of the abdomen must be performed. Due to the long treatment period, some patients may develop episodes of depression, which can simulate VHL syndrome.


New diagnostic methods for laser plasma- and microwave-enhanced combustion.
The study of pulsed laser- and microwave-induced plasma interactions with atmospheric and higher pressure combusting gases requires rapid diagnostic methods that are capable of determining the mechanisms by which these interactions are taking place. New rapid diagnostics are presented here extending the capabilities of Rayleigh and Thomson scattering and resonance-enhanced multi-photon ionization (REMPI) detection and introducing femtosecond laser-induced velocity and temperature profile imaging. Spectrally filtered Rayleigh scattering provides a method for the planar imaging of temperature fields for constant pressure interactions and line imaging of velocity, temperature and density profiles. Depolarization of Rayleigh scattering provides a measure of the dissociation fraction, and multi-wavelength line imaging enables the separation of Thomson scattering from Rayleigh scattering. Radar REMPI takes advantage of high-frequency microwave scattering from the region of laser-selected species ionization to extend REMPI to atmospheric pressures and implement it as a stand-off detection method for atomic and molecular species in combusting environments. Femtosecond laser electronic excitation tagging (FLEET) generates highly excited molecular species and dissociation through the focal zone of the laser. The prompt fluorescence from excited molecular species yields temperature profiles, and the delayed fluorescence from recombining atomic fragments yields velocity profiles.


[The lysosomal proteolytic system and thyroid functional activity in rats administered chloroquine].
A 7-, 14-, and 21-day course of injections of the lysosomotropic drug chloroquine in a dose of 50-mg/kg per day causes a more than two-fold decrease of T3 concentration and insignificant changes in the level of T4 and thyrotropin in the blood serum of rats. In the series with 14- and 21-day courses of chloroquine injections, inhibition of the thiol cathepsins B and L with simultaneous activation of the aspartic proteinase cathepsin D occurred. Permeability of the lysosomal membranes for all hydrolases under study considerably increased after a 7-day course of chloroquine but reduced subsequently to the control level in longer treatment. The possible mechanisms of changes in the spectrum of lysosomal proteinases and functional activity of the thyroid are discussed.


Production and identification of wheat-Agropyron cristatum 6P translocation lines.
The narrow genetic background of wheat is the primary factor that has restricted the improvement of crop yield in recent years. The kernel number per spike is the most important factor of the many potential characteristics that determine wheat yield. Agropyron cristatum (L.) Gaertn., a wild relative of wheat, has the characteristics of superior numbers of florets and kernels per spike, which are controlled by chromosome 6P. In this study, the wheat-A. cristatum disomic addition and substitution lines were used as bridge materials to produce wheat-A. cristatum 6P translocation lines induced by gametocidal chromosomes and irradiation. The results of genomic in situ hybridization showed that the frequency of translocation induced by gametocidal chromosomes was 5.08%, which was higher than the frequency of irradiated hybrids (2.78%) and irradiated pollen (2.12%). The fluorescence in situ hybridization results of the translocation lines showed that A. cristatum chromosome 6P could be translocated to wheat ABD genome, and the recombination frequency was A genome > B genome > D genome. The alien A. cristatum chromosome 6P was translocated to wheat homoeologous groups 1, 2, 3, 5 and 6. We obtained abundant translocation lines that possessed whole-arm, terminal, segmental and intercalary translocations. Three 6PS-specific and four 6PL-specific markers will be useful to rapidly identify and trace the translocated fragments. The different wheat-A. cristatum 6P translocation lines obtained in this study can provide basic materials for analyzing the alien genes carried by chromosome 6P. The translocation line WAT33-1-3 and introgression lines WAI37-2 and WAI41-1, which had significant characteristics of multikernel (high numbers of kernels per spike), could be utilized as novel germplasms for high-yield wheat breeding.


Effect of defolliculation and 17 alpha-hydroxy, 20 beta-dihydroprogesterone on cyclic AMP level in full-grown oocytes of the rainbow trout, Salmo gairdneri.
The changes in cAMP were followed in trout oocytes incubated in vitro after defolliculation performed by either enzymatic or manual dissection. Both defolliculation methods induced a highly significant rise in oocyte cAMP level (4.5 times the basal level of control [follicle-enclosed oocytes], after 6 h). Treatment of defolliculated oocytes with 17 alpha-hydroxy, 20 beta-dihydroprogesterone (17 alpha, 20 beta-OH-P) (10(-6) M), which induced oocyte maturation (germinal vesicle breakdown [GVBD]) was able, first, to interrupt the increase of oocyte cAMP level promoted by defolliculation and then to lower this level significantly down to values that still remained higher than folliculated controls. Very low concentrations of 17 alpha, 20 beta-OH-P (1.38-55.6 10(-9) M), or physiological doses of testosterone (0.35 10(-6) M, in the range found in vivo before ovulation) were able to induce a similar decrease of oocyte cAMP level without inducing GVBD. Under the same experimental conditions estradiol (0.35 10(-6) M) exhibited no action. These results suggest that some factor(s) originating in the follicle (FIF), inhibit the oocytes' tendency to accumulate cAMP before the final surge of 17 alpha, 20 beta-OH-P. This factor might be a follicular steroid such as testosterone or nonmaturing concentrations of 17 alpha, 20 beta-OH-P. Moreover our data favour the hypothesis that the final surge of 17 alpha, 20 beta-OH-P could induce distinct intraoocyte mechanisms: the first induces an irreversible blockage of cAMP level before the inhibitory action of the FIF is suppressed by ovulation, and the second mechanism leads to GVBD.


Zinc as an adjunct to the treatment of severe pneumonia in Ecuadorian children: a randomized controlled trial.
Studies of zinc as an adjunct to treatment of severe pneumonia in children have shown mixed results, possibly because of poor information on zinc status and respiratory pathogens. We evaluated the effect of zinc given with standard antimicrobial treatment on the duration of respiratory signs in children with severe pneumonia. Zinc status and pathogens were assessed. Children aged 2-59 mo with severe pneumonia who were admitted to the main children's hospital in Quito, Ecuador, were given standard antibiotics and randomly allocated to receive zinc supplements twice daily or a placebo. Measurements included anthropometric variables, breastfeeding, hemoglobin, plasma zinc, and common bacteria/viral respiratory pathogens. The primary outcome was time to resolution of respiratory signs. The secondary outcome was treatment failure. We enrolled 225 children in each group. There was no difference between groups in time to resolution of respiratory signs or treatment failure; pathogens were not associated with outcomes. Tachypnea and hypoxemia resolved faster in older children (P = 0.0001) than in younger ones. Higher basal zinc concentration (P = 0.011) and better height-for-age z score (HAZ) (P = 0.044) were associated with faster resolution of chest indrawing. Better weight-for-height z score (WHZ) (P = 0.031) and HAZ (P = 0.048) were associated with faster resolution of tachypnea. Increased C-reactive protein was associated with a longer duration of tachypnea (P = 0.044). Zinc did not affect time to pneumonia resolution or treatment failure, nor did type of respiratory pathogens affect outcomes. Higher basal zinc and better HAZ and WHZ were associated with reduced time to resolution of respiratory signs. These results suggest the need for prevention of chronic zinc deficiency and improvement of general nutritional status among Ecuadorian children.


Brain-targeted hypoxia-inducible factor stabilization reduces neonatal hypoxic-ischemic brain injury.
Hypoxia-inducible factor-1α (HIF1α) is a major regulator of cellular adaptation to hypoxia and oxidative stress, and recent advances of prolyl-4-hydroxylase (P4H) inhibitors have produced powerful tools to stabilize HIF1α for clinical applications. However, whether HIF1α provokes or resists neonatal hypoxic-ischemic (HI) brain injury has not been established in previous studies. We hypothesize that systemic and brain-targeted HIF1α stabilization may have divergent effects. To test this notion, herein we compared the effects of GSK360A, a potent P4H inhibitor, in in-vitro oxygen-glucose deprivation (OGD) and in in-vivo neonatal HI via intracerebroventricular (ICV), intraperitoneal (IP), and intranasal (IN) drug-application routes. We found that GSK360A increased the erythropoietin (EPO), heme oxygenase-1 (HO1) and glucose transporter 1 (Glut1) transcripts, all HIF1α target-genes, and promoted the survival of neurons and oligodendrocytes after OGD. Neonatal HI insult stabilized HIF1α in the ipsilateral hemisphere for up to 24 h, and either ICV or IN delivery of GSK360A after HI increased the HIF1α target-gene transcripts and decreased brain damage. In contrast, IP-injection of GSK360A failed to reduce HI brain damage, but elevated the risk of mortality at high doses, which may relate to an increase of the kidney and plasma EPO, leukocytosis, and abundant vascular endothelial growth factor (VEGF) mRNAs in the brain. These results suggest that brain-targeted HIF1α-stabilization is a potential treatment of neonatal HI brain injury, while systemic P4H-inhibition may provoke unwanted adverse effects.


3D dynamic body surface sensing and CT-body matching: a tool for patient set-up and monitoring in radiotherapy.
Recent advances in radical broad-beam conformal radiotherapy for disease at non-rigid sites suggest that the treatment room set-up of patients should be performed using the CT-plan digital body surface as a reference standard. In effect, the CT-plan surface is a "virtual shell" and should be used as such. To do this requires 3D body surface information to be captured live in the treatment room and then manipulated for comparison with the CT virtual shell. To address this situation, a near real-time prototype opto-electronic dynamic 3D surface sensor has been developed and equipped with a novel software utility for visualizing and matching the disparate surfaces arising from planning and treatment environments. Using the CT virtual shell and height-maps produced by the sensor, a two-phase 3D positioning strategy for patient set-up and monitoring is described. Phase one is an image-guided manual "approach". Phase two is automated "docking" using simulated annealing to determine optimum set-up corrections. The concepts and implementation are illustrated using archival patient data and an anthropomorphic phantom "patient" in a treatment room environment.


Experiential avoidance, eating expectancies, and binge eating: A preliminary test of an adaption of the Acquired Preparedness model of eating disorder risk.
This study investigated learned expectancies of eating outcomes as a mechanism through which maladaptive avoidant strategies relate to eating psychopathology. Participants included 244 undergraduate students at a Midwestern university. The participants completed a battery of measures online. Preacher and Hayes's (2008) bootstrapping method of mediation and structural equation modeling were used to analyze the relationships among experiential avoidance, eating expectancies, and binge eating and to test how experiential avoidance fits within the Acquired Preparedness model of eating disorder risk that highlights the role of negative urgency. Results revealed that experiential avoidance was positively related to negative affect eating expectancies and to binge eating. Negative affect eating expectancies mediated the relationship between experiential avoidance and binge eating. Further, experiential avoidance more adequately explained binge eating in the Acquired Preparedness model of eating disorder risk than did negative urgency. The findings from this study suggest an alternative understanding of the pathways through which dispositional and psychosocial characteristics of undergraduate students may impact eating disorder symptomatology.


Real-time dynamic MR image reconstruction using compressed sensing and principal component analysis (CS-PCA): Demonstration in lung tumor tracking.
This work presents a real-time dynamic image reconstruction technique, which combines compressed sensing and principal component analysis (CS-PCA), to achieve real-time adaptive radiotherapy with the use of a linac-magnetic resonance imaging system. Six retrospective fully sampled dynamic data sets of patients diagnosed with non-small-cell lung cancer were used to investigate the CS-PCA algorithm. Using a database of fully sampled k-space, principal components (PC's) were calculated to aid in the reconstruction of undersampled images. Missing k-space data were calculated by projecting the current undersampled k-space data onto the PC's to generate the corresponding PC weights. The weighted PC's were summed together, and the missing k-space was iteratively updated. To gain insight into how the reconstruction might proceed at lower fields, 6× noise was added to the 3T data to investigate how the algorithm handles noisy data. Acceleration factors ranging from 2 to 10× were investigated using CS-PCA and Split Bregman CS for comparison. Metrics to determine the reconstruction quality included the normalized mean square error (NMSE), as well as the dice coefficients (DC) and centroid displacement of the tumor segmentations. Our results demonstrate that CS-PCA performed superior than CS alone. The CS-PCA patient averaged DC for 3T and 6× noise added data remained above 0.9 for acceleration factors up to 10×. The patient averaged NMSE gradually increased with increasing acceleration; however, it remained below 0.06 up to an acceleration factor of 10× for both 3T and 6× noise added data. The CS-PCA reconstruction speed ranged from 5 to 20 ms (Intel i7-4710HQ CPU @ 2.5 GHz), depending on the chosen parameters. A real-time reconstruction technique was developed for adaptive radiotherapy using a Linac-MRI system. Our CS-PCA algorithm can achieve tumor contours with DC greater than 0.9 and NMSE less than 0.06 at acceleration factors of up to, and including, 10×. The reconstruction speed for the Split Bregman CS ranged from 200 to 260 ms, whereas the CS-PCA reconstruction speed ranged from 5 to 20 ms implemented using nonoptimized MATLAB code.


Endothelial activation and repair during hantavirus infection: association with disease outcome.
Endothelial activation and dysfunction play a central role in the pathogenesis of sepsis and viral hemorrhagic fevers. Hantaviral disease is a viral hemorrhagic fever and is characterized by capillary dysfunction, although the underlying mechanisms for hantaviral disease are not fully elucidated. The temporal course of endothelial activation and repair were analyzed during Puumala hantavirus infection and associated with disease outcome and a marker for hypoxia, insulin-like growth factor binding protein 1 (IGFBP-1). The following endothelial activation markers were studied: endothelial glycocalyx degradation (syndecan-1) and leukocyte adhesion molecules (soluble vascular cellular adhesion molecule 1, intercellular adhesion molecule 1, and endothelial selectin). Cytokines associated with vascular repair were also analyzed (vascular endothelial growth factor, erythropoietin, angiopoietin, and stromal cell-derived factor 1). Most of the markers we studied were highest during the earliest phase of hantaviral disease and associated with clinical and laboratory surrogate markers for disease outcome. In particular, the marker for glycocalyx degradation, syndecan-1, was significantly associated with levels of thrombocytes, albumin, IGFBP-1, decreased blood pressure, and disease severity. Hantaviral disease outcome was associated with endothelial dysfunction. Consequently, the endothelium warrants further investigation when designing future medical interventions.


Sleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex.
We previously found that Mertk and its ligand Gas6, astrocytic genes involved in phagocytosis, are upregulated after acute sleep deprivation. These results suggested that astrocytes may engage in phagocytic activity during extended wake, but direct evidence was lacking. Studies in humans and rodents also found that sleep loss increases peripheral markers of inflammation, but whether these changes are associated with neuroinflammation and/or activation of microglia, the brain's resident innate immune cells, was unknown. Here we used serial block-face scanning electron microscopy to obtain 3D volume measurements of synapses and surrounding astrocytic processes in mouse frontal cortex after 6-8 h of sleep, spontaneous wake, or sleep deprivation (SD) and after chronic (∼5 d) sleep restriction (CSR). Astrocytic phagocytosis, mainly of presynaptic components of large synapses, increased after both acute and chronic sleep loss relative to sleep and wake. MERTK expression and lipid peroxidation in synaptoneurosomes also increased to a similar extent after short and long sleep loss, suggesting that astrocytic phagocytosis may represent the brain's response to the increase in synaptic activity associated with prolonged wake, clearing worn components of heavily used synapses. Using confocal microscopy, we then found that CSR but not SD mice show morphological signs of microglial activation and enhanced microglial phagocytosis of synaptic elements, without obvious signs of neuroinflammation in the CSF. Because low-level sustained microglia activation can lead to abnormal responses to a secondary insult, these results suggest that chronic sleep loss, through microglia priming, may predispose the brain to further damage.SIGNIFICANCE STATEMENT We find that astrocytic phagocytosis of synaptic elements, mostly of presynaptic origin and in large synapses, is upregulated already after a few hours of sleep deprivation and shows a further significant increase after prolonged and severe sleep loss, suggesting that it may promote the housekeeping of heavily used and strong synapses in response to the increased neuronal activity of extended wake. By contrast, chronic sleep restriction but not acute sleep loss activates microglia, promotes their phagocytic activity, and does so in the absence of overt signs of neuroinflammation, suggesting that like many other stressors, extended sleep disruption may lead to a state of sustained microglia activation, perhaps increasing the brain's susceptibility to other forms of damage.


A practical review of energy saving technology for ageing populations.
Fuel poverty is a critical issue for a globally ageing population. Longer heating/cooling requirements combine with declining incomes to create a problem in need of urgent attention. One solution is to deploy technology to help elderly users feel informed about their energy use, and empowered to take steps to make it more cost effective and efficient. This study subjects a broad cross section of energy monitoring and home automation products to a formal ergonomic analysis. A high level task analysis was used to guide a product walk through, and a toolkit approach was used thereafter to drive out further insights. The findings reveal a number of serious usability issues which prevent these products from successfully accessing an important target demographic and associated energy saving and fuel poverty outcomes. Design principles and examples are distilled from the research to enable practitioners to translate the underlying research into high quality design-engineering solutions.


Context-dependent Cryptic Roles of Specific Residues in Substrate Selectivity of the UapA Purine Transporter.
Members of the ubiquitous Nucleobase Ascorbate Transporter (NAT) family are H+ or Na+ symporters specific for the cellular uptake of either purines and pyrimidines or L-ascorbic acid. Despite the fact that several bacterial and fungal members have been extensively characterised at a genetic, biochemical or cellular level, and crystal structures of NAT members from Escherichia coli and Aspergillus nidulans have been determined pointing to a mechanism of transport, we have little insight on how substrate selectivity is determined. Here, we present systematic mutational analyses, rational combination of mutations, and novel genetic screens that reveal cryptic context-dependent roles of partially conserved residues in the so-called NAT signature motif in determining the specificity of the UapA transporter of A. nidulans. We show that specific NAT signature motif substitutions, alone and in combinations with each other or with distant mutations in residues known to affect substrate selectivity, lead to novel UapA versions possessing variable transport capacities and specificities for nucleobases. In particular, we show that a UapA version including the quadruple mutation T405S/F406Y/A407S/Q408E in the NAT signature motif (UapA-SYSE) becomes incapable of purine transport, but gains a novel pyrimidine-related profile, which can be further altered to a more promiscuous purine/pyrimidine profile when combined with replacements at distantly located residues, especially at F528. Our results reveal that UapA specificity is genetically highly modifiable and allow us to speculate on how the elevator-type mechanism of transport might account for this flexibility.


The Prevalence of Redo-Ureteroneocystostomy and Associated Risk Factors inPediatric Vesicoureteral Reflux Patients Treated with Ureteroneocystostomy.
The aim of the study was to examine the prevalence of redo-ureteroneocystostomy (redo-UNC) in pediatric vesicouretheral reflux (VUR) patients following open UNC and factors associated with redo-UNC. Data on 122 patients who underwent open UNC for VUR were analyzed in this retrospective case-control study. The patients were divided into a successful initial UNC group (UNC group, control) and an unsuccessful initial UNC group (redo-UNC group, case). The following variables were analyzed: sex, age, dysfunctional voiding, laterality of VUR (unilateral or bilateral), VUR grade, etiology of VUR (primary or secondary), relative renal function on renal scintigraphy, and surgical technique. The use of the following procedures in the initial UNC was recorded: an endoscopic subureteric injection(ESI) and ureteral tapering. In our clinic, 122 patients (177 ureters), with an average age of 55.7 ± 41.2 months (range, 1-18 years) underwent open UNC for VUR between November 2005 and June 2014. Of these,67 (55%) had unilateral VUR, and 55 (45%) had bilateral VUR. There were 127 (71.8%) cases of grade 4-5 reflux. Postoperatively, hydronephrosis was noted in 19 (15.6%) patents. Ten (8.2%) patients underwent redo-UNC. In eight cases (6.5%), redo-UNC was performed because of ureterovesical (UV) junction obstruction.In the other two cases (1.7%), redo-UNC was dueto high-grade reflux. There were no statistically significant differences between the redo-UNC and UNC groups in any of the variables studied. Redo-UNC was required in 10 (8.2%) of cases after UNC. Age, sex, laterality of VUR, VUR grade,existence of primary or secondary VUR, relative renal function on renal scintigraphy, UNC technique, ESI procedure,and ureteral tapering were not risk factors for redo-UNC in our series.


An araC-controlled bacterial cre expression system to produce DNA minicircle vectors for nuclear and mitochondrial gene therapy.
The presence of CpG motifs and their associated sequences in bacterial DNA causes an immunotoxic response following the delivery of these plasmid vectors into mammalian hosts. We describe a biotechnological approach to the elimination of this problem by the creation of a bacterial cre recombinase expression system, tightly controlled by the arabinose regulon. This permits the Cre-mediated and -directed excision of the entire bacterial vector sequences from plasmid constructs to create supercoiled gene expression minicircles for gene therapy. Minicircle yields using standard culture volumes are sufficient for most in vitro and in vivo applications whereas minicircle expression in vitro is significantly increased over standard plasmid transfection. By the simple expedient of removing the bacterial DNA complement, we significantly reduce the size and CpG content of these expression vectors, which should also reduce DNA-induced inflammatory responses in a dose-dependent manner. We further describe the generation of minicircle expression vectors for mammalian mitochondrial gene therapy, for which no other vector systems currently exist. The removal of bacterial vector sequences should permit appropriate transcription and correct transcriptional cleavage from the mitochondrial minicircle constructs in a mitochondrial environment and brings the realization of mitochondrial gene therapy a step closer.


Dosage form suitability in vulnerable populations: A focus on paracetamol acceptability from infants to centenarians.
Medicine acceptability is a multi-faceted concept driven by both product and user characteristics. Although a key factor for treatment effectiveness, especially in vulnerable populations, knowledge of those medicine features that best promote individual user acceptability remains fragmented. Focusing on paracetamol, this study has explored the appropriateness of pharmaceutical products in different dosage forms to achieve adequate patient acceptability from infants to centenarians. This observational, multicentre, prospective study was carried out in 10 hospitals, 8 nursing homes and over 150 community dispensaries. Observers reported several behaviours/events evaluating acceptability for 1016 different pharmaceutical product uses in paediatrics (<18y.) and 1288 in the elderly (≥65y.). Using mapping and clustering, a multivariate approach offered an intelligible reference framework for each population, providing comprehensive scores: positively or negatively accepted. Among all the evaluations supporting the acceptability reference frameworks, there were 502 reports on paracetamol products intake. Herein we focused on the 5 products with ≥30 evaluations. Although oral suspension and powder for oral solution were positively-accepted in the paediatric group, the powder had a higher rate of negative patient reaction (p<0.001). Of those that received this formulation, 72% were ≤8y., and therefore suitable to receive the better accepted oral suspension. In the elderly, patients with swallowing disorders were preferentially treated with such powders (p<0.001), which were less often fully taken than orally disintegrating tablets (p<0.001). Even in those patients ≥90y., capsule formulations appeared to be the best accepted product in patients without swallowing alterations, and thus could be a suitable alternative to the powder in this population. By better integrating patient characteristics when choosing dosage forms, clinicians and caregivers may improve treatment acceptability and adherence. Moreover, hospitals and healthcare institutions could optimise purchasing to best suit their local population, disseminating information to help staff align specific dosage forms to targeted patients.


A New 1,5-Disubstituted Triazole DNA Backbone Mimic with Enhanced Polymerase Compatibility.
Triazole linkages (TLs) are mimics of the phosphodiester bond in oligonucleotides with applications in synthetic biology and biotechnology. Here we report the RuAAC-catalyzed synthesis of a novel 1,5-disubstituted triazole (TL2) dinucleoside phosphoramidite as well as its incorporation into oligonucleotides and compare its DNA polymerase replication competency with other TL analogues. We demonstrate that TL2 has superior replication kinetics to these analogues and is accurately replicated by polymerases. Derived structure-biocompatibility relationships show that linker length and the orientation of a hydrogen bond acceptor are critical and provide further guidance for the rational design of artificial biocompatible nucleic acid backbones.


Docetaxel conjugate nanoparticles that target α-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis.
Docetaxel-conjugate nanoparticles, known as Cellax, were synthesized by covalently conjugating docetaxel and polyethylene glycol to acetylated carboxymethylcellulose via ester linkages, yielding a polymeric conjugate that self-assembled into 120 nm particles suitable for intravenous administration. In 4T1 and MDA-MB-231 orthotopic breast tumor models, Cellax therapy reduced α-smooth muscle actin (α-SMA) content by 82% and 70%, respectively, whereas native docetaxel and nab-paclitaxel (albumin-paclitaxel nanoparticle, Abraxane) exerted no significant antistromal activity. In Cellax-treated mice, tumor perfusion was increased by approximately 70-fold (FITC-lectin binding), tumor vascular permeability was enhanced by more than 30% (dynamic contrast-enhanced magnetic resonance imaging), tumor matrix was decreased by 2.5-fold (immunohistochemistry), and tumor interstitial fluid pressure was suppressed by approximately 3-fold after Cellax therapy compared with the control, native docetaxel, and nab-paclitaxel groups. The antistromal effect of Cellax treatment corresponded to a significantly enhanced antimetastatic effect: lung nodules were reduced by 7- to 24-fold by Cellax treatment, whereas native docetaxel and nab-paclitaxel treatments were ineffective. Studies of the 4T1 tumor showed that more than 85% of the Cellax nanoparticles were delivered to the α-SMA+ stroma. Significant tumor stromal depletion occurred within 16 hours (∼50% depletion) postinjection, and the α-SMA+ stroma population was almost undetectable (∼3%) by 1 week. The 4T1 tumor epithelial cell population was not significantly reduced in the week after Cellax injection. These data suggest that Cellax targets tumor stroma and performs more efficaciously than docetaxel and nab-paclitaxel.


Sustained-release butorphanol microparticles.
Various butorphanol-loaded microparticles have been prepared with a biodegradable copolymer P(FAD-SA) of erucic acid dimer (FAD) and sebacic acid (SA) and a copolymer P(CPP-SA) of carboxyphenoxypropane (CPP) and SA using a melt compounding and milling method. Drug release was measured in vitro following incubation of drug-loaded microparticles in water for injection at 37 degrees C. It was found that butorphanol was released in a sustained manner, yielding a cumulative drug release of about 100% over a period of 48 hr. Also, drug release was affected by drug loading and the size of the microparticles; however, it was not significantly influenced by the copolymer composition. Scanning electron microscopic (SEM) results showed that most of the particles were irregular in shape with uneven surfaces. The molecular weights of the copolymers were not changed after this fabrication process. In addition, 20% butorphanol-encapsulated microspheres were prepared with copolymer P(FAD-SA) by spray-drying. The SEM micrograph shows that the particle sizes of the microspheres ranged from 2 to 10 microns, and the external surfaces appear smooth. Moreover, rapid drug release was observed for these microspheres, with more than 92% of the encapsulated drug released within the first 2 hr.


Depression as a moderator of STAIR Narrative Therapy for women with post-traumatic stress disorder related to childhood abuse.
Background: Depression among those who have experienced childhood abuse is associated with earlier onset, more persistent and severe symptoms, more frequent relapse, and poorer treatment outcomes across a variety of psychiatric disorders. In addition, individuals with a history of childhood abuse are more likely to develop post-traumatic stress disorder (PTSD) co-occurring with depression. Objective: This study evaluated whether severity of depression moderated the outcome in a PTSD treatment for childhood abuse survivors. Specifically, we assessed whether individuals with significant depression obtained better outcomes when provided with a two-module treatment which included a skills training component with behavioral activation interventions, Skills Training in Affective and Interpersonal Regulation (STAIR) followed by a trauma-focused component, Narrative Therapy, as compared to two control conditions where one component (STAIR or Narrative Therapy) was replaced with Supportive Counseling. Method: Participants were 104 women with PTSD related to childhood abuse. Participants were randomized into three conditions: (1) STAIR plus Narrative Therapy (SNT), (2) STAIR plus Supportive Counseling (SSC), and (3) Supportive Counseling plus Narrative Therapy (SCNT). Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) PTSD symptom severity was assessed at pre-treatment, post-treatment, and 3 and 6 month follow-up. Results: Participants with severe depression showed superior PTSD symptom reduction following SNT, while those in the other two conditions experienced a loss of improvement after treatment ended. A similar finding was obtained among those with moderate depression, while among those with low levels of depression, outcomes did not differ across the three treatment conditions. Conclusions: Childhood abuse survivors with severe depression obtained superior outcomes in a treatment that combined skills training with trauma-focused work. Skills packages which contain behavioral activation interventions in combination with trauma-focused work may be particularly beneficial for patients with childhood abuse and severe depression.


Bacillus crassostreae sp. nov., isolated from an oyster (Crassostrea hongkongensis).
A novel Gram-stain-positive, motile, catalase- and oxidase-positive, endospore-forming, facultatively anaerobic rod, designated strain JSM 100118(T), was isolated from an oyster (Crassostrea hongkongensis) collected from the tidal flat of Naozhou Island in the South China Sea. Strain JSM 100118(T) was able to grow with 0-13% (w/v) NaCl (optimum 2-5%), at pH 5.5-10.0 (optimum pH 7.5) and at 5-50 °C (optimum 30-35 °C). The cell-wall peptidoglycan contained meso-diaminopimelic acid as the diagnostic diamino acid. The predominant respiratory quinone was menaquinone-7 and the major cellular fatty acids were anteiso-C15 : 0, iso-C15 : 0, C16 : 0 and C16 : 1ω11c. The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, an unknown glycolipid and an unknown phospholipid. The genomic DNA G+C content was 35.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain JSM 100118(T) belonged to the genus Bacillus , and was most closely related to Bacillus litoralis SW-211(T) (98.9% 16S rRNA gene sequence similarity), Bacillus halosaccharovorans E33(T) (98.3%), Bacillus niabensis 4T19(T) (97.8%) and Bacillus herbersteinensis D-1,5a(T) (97.1%). The combination of results from the phylogenetic analysis, DNA-DNA hybridization, and phenotypic and chemotaxonomic characterization supported the conclusion that strain JSM 100118(T) represents a novel species of the genus Bacillus , for which the name Bacillus crassostreae sp. nov. is proposed. The type strain is JSM 100118(T) ( = CTCC AB 2010452(T) =DSM 24486(T) =JCM 17523(T)).


Informing the children when a parent is diagnosed as having multiple sclerosis.
The aim of this study was to gain an understanding of how health-care services can support the empowerment of children when a parent is diagnosed as having multiple sclerosis (MS). The study focuses on what information parents with MS, their partners, and their children desire from health-care professionals. Focus group interviews were conducted with nine adolescents, nine parents with diagnosed MS, and five partners representing members of ten families. The main finding was that parents with MS, their partners, and the adolescents stressed their need to be well informed about the disease. Information should be provided at the time of diagnosis and then offered regularly throughout the disease course. The information should be suited to the recipient's level of maturity and individualized to reflect the parent's clinical picture. It is usually beneficial for children if their parents feel informed about the illness and encourage their children to ask questions and discuss the situation. This knowledge, gained from several sources, is likely to be of value for health-care professionals and their ongoing efforts to improve services for parents with MS, their partners, and their children.


[Clinical aspects of the osteolytic (inflammatory) phase of cochlear otosclerosis].
During the last years it has been demonstrated that the active stage of otosclerosis (French: otospongieuse) is caused by an osteolytic inflammation associated with a measles-virus infection. Under influences that are not yet well understood (e.g. estrogens), the osteolytic process is arrested and changed to osteoblast activity accompanied by new bone formation. This latter process can be understood as a scar formation. If the process takes place within the area of the oval window, it results in fixation of the stapes and conductive hearing loss. When the otosclerotic process is restricted to the cochlea, clinical signs are not well defined. We report on exemplary cases of progressive bilateral sensorineural hearing loss caused by otosclerosis, restricted to the cochlea. The characteristics of the clinical course include: 1. Bilateral asymmetric sensorineural hearing loss. 2. Roaring tinnitus. 3. Episodes of sudden hearing loss. 4. Excellent response to prednisolone therapy. 5. In the late stage of the disease a small but transitory conductive hearing loss. High resolution computed tomography in such cases reveals diffuse osteolytic foci within the cochlear walls. In severe cases of such progressive deafness we discuss an antiproliferative (immunosuppressive) therapy with cyclosporine and/or a radionuclide therapy with Sn-117 m, an isotope with a very small irradiation radius.


Capillary blood flow and tissue metabolism in skeletal muscle during sympathetic trunk stimulation.
NADH fluorescence at tissue sites 15-20 microns in diameter and red blood cell velocity in adjacent capillaries were measured in resting sartorius muscle of the anesthetized cat during a 3-min period of sympathetic trunk stimulation. At stimulation frequencies of 2 and 4 Hz, red blood cell velocity fell briefly to 30-40% of control and then returned to approximately 75% of control values (vascular escape). No change in NADH fluorescence was observed. With stimulus frequencies of 6-12 Hz, flow reduction was greater and led to an increase in fluorescence when the flow reduction was > 50% and was sustained for > 30 s. NADH changes were more pronounced at tissue sites near venous capillaries than at sites near arterial capillaries. Hyperemia ensued after the end of sympathetic stimulation only when NADH fluorescence rose during stimulation. Resting blood flow in this muscle appears to be well above the minimum required to support oxidative metabolism. A shift to anaerobic metabolism does not appear to cause vascular escape during sympathetic stimulation but appears to be required for poststimulation hyperemia. These observations suggest that two separate oxygen-dependent mechanisms elicit vasodilation during and after sympathetic trunk stimulation.


The effect of the anticholinergic burden on mortality following elective cardiac surgery.
The cumulative effect of drugs with anticholinergic properties may pose a significant risk in the post-discharge period of patients who have undergone elective cardiac surgery. The aim of this study was to investigate the association between anticholinergic burden and 6-month postdischarge mortality in older cardiac surgery patients. This study performed a retrospective longitudinal analysis of patients undergoing elective cardiac surgery at a tertiary care centre from January 2021 to January 2022. The Deyo-Charlson comorbidity index (D-CCI) was used to estimate the burden of comorbidities. The anticholinergic burden was assessed using the Anticholinergic Cognitive Burden scale (ACB) and Drug Burden Index (DBI) scale. All-cause postdischarge mortality was determined from electronic medical records. A total of 255 older adults who had undergone elective cardiac surgery and had been followed up for at least 6 months were included in this study. Approximately 12.5% (n = 32) of older patients died within 6 months of discharge. In multivariate Cox regression analysis, ACB (HR:1.31, 95%CI:1.10-1.56 p = 0.01) and DBI (HR:2.08, 95%CI:1.27-3.39 p = 0.01) showed significantly increased risk of 6-month postdischarge mortality after adjusting for several possible confounders (age, gender, D-CCl, and American Society of Anaesthesiologists (ASA) score). Overall event-free survival differed significantly between patients undergoing cardiac surgery based on anticholinergic burden according to the group-stratified ACB and DBI scales (χ2: 5.907, log-rank test, p = 0.015 and χ2: 15.389, log-rank test, p < 0.001 respectively). The anticholinergic burden is associated with 6-month all-cause post-discharge mortality in older cardiac surgery patients. A deprescribing approach should be considered, especially for older adults in the perioperative period. The trial was retrospectively registered at ClinicalTrials.gov. Identifier: NCT05312684 Registered on 5 April 2022.


Simulating the N400 ERP component as semantic network error: insights from a feature-based connectionist attractor model of word meaning.
The N400 ERP component is widely used in research on language and semantic memory. Although the component's relation to semantic processing is well-established, the computational mechanisms underlying N400 generation are currently unclear (Kutas & Federmeier, 2011). We explored the mechanisms underlying the N400 by examining how a connectionist model's performance measures covary with N400 amplitudes. We simulated seven N400 effects obtained in human empirical research. Network error was consistently in the same direction as N400 amplitudes, namely larger for low frequency words, larger for words with many features, larger for words with many orthographic neighbors, and smaller for semantically related target words as well as repeated words. Furthermore, the repetition-induced decrease was stronger for low frequency words, and for words with many semantic features. In contrast, semantic activation corresponded less well with the N400. Our results suggest an interesting relation between N400 amplitudes and semantic network error. In psychological terms, error values in connectionist models have been conceptualized as implicit prediction error, and we interpret our results as support for the idea that N400 amplitudes reflect implicit prediction error in semantic memory (McClelland, 1994).


Clinical phenotypes and prognoses of microscopic polyangiitis based on kidney biopsies.
To classify the different clinical phenotypes and compare the distinct prognoses of microscopic polyangiitis (MPA). A retrospective analysis of 436 patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) from 2015 to 2022 was conducted in our center, of which 90 patients were diagnosed with MPA and underwent renal biopsy. Among the 90 MPA patients, 63% were female, and the median age at onset was 63 years (25th-75th percentile: 58-68). The median follow-up time was 26 months (25th-75th percentile: 10-53). We identified four subtypes: renal impairment type (cluster 1, 39%), pure type (cluster 2, 22%), systemic inflammation type (cluster 3, 26%), and rapid progress type (cluster 4, 13%). Cluster 1, characterized by renal dysfunction at onset (80%), demonstrated poor prognoses with only 26% achieved complete remission (CR), 11% dying, and 19% developing renal failure. In contrast, patients in cluster 2, exclusively female, most had only kidney involvement showed the best prognoses with 55% achieving CR and none experiencing death or renal failure within 10 years. Cluster 3 mostly consisted of males; high fever and C-reactive protein levels were the primary characteristics. These cases exhibited moderate prognoses with 53% achieving CR, 9% dying, and 4% developing renal failure. Finally, patients in cluster 4, which was characterized by rapidly progressive glomerulonephritis, had the worst prognoses, with none achieving CR, 8% dying, and 75% developing renal failure despite aggressive treatment. MPA is classified into four subtypes with distinct clinical manifestations and prognoses.


Action observation and imitation in Parkinson's disease: The influence of biological and non-biological stimuli.
Action observation and imitation have been found to influence movement in people with Parkinson's disease (PD), but simple visual stimuli can also guide their movement. To investigate whether action observation may provide a more effective stimulus than other visual cues, the present study examined the effects of observing human pointing movements and simple visual stimuli on hand kinematics and eye movements in people with mild to moderate PD and age-matched controls. In Experiment 1, participants observed videos of movement sequences between horizontal positions, depicted by a simple cue with or without a moving human hand, then imitated the sequence either without further visual input (consecutive task) or while watching the video again (concurrent task). Modulation of movement duration, in accordance with changes in the observed stimulus, increased when the simple cue was accompanied by the hand and in the concurrent task, whereas modulation of horizontal amplitude was greater with the simple cue alone and in the consecutive task. Experiment 2 compared imitation of kinematically-matched dynamic biological (human hand) and non-biological (shape) stimuli, which moved with a high or low vertical trajectory. Both groups exhibited greater modulation for the hand than the shape, and differences in eye movements suggested closer tracking of the hand. Despite producing slower and smaller movements overall, the PD group showed a similar pattern of imitation to controls across tasks and conditions. The findings demonstrate that observing human action influences aspects of movement such as duration or trajectory more strongly than non-biological stimuli, particularly during concurrent imitation.


Determinants of trophoblast lineage and cell subtype specification in the mouse placenta.
Cells of the trophoblast lineage make up the epithelial compartment of the placenta, and their rapid development is essential for the establishment and maintenance of pregnancy. A diverse array of specialized trophoblast subtypes form throughout gestation and are responsible for mediating implantation, as well as promotion of blood to the implantation site, changes in maternal physiology, and nutrient and gas exchange between the fetal and maternal blood supplies. Within the last decade, targeted mutations in mice and the study of trophoblast stem cells in vitro have contributed greatly to our understanding of trophoblast lineage development. Here, we review recent insights into the molecular pathways regulating trophoblast lineage segregation, stem cell maintenance, and subtype differentiation.


Chlorination products: emerging links with allergic diseases.
Exposure of the human population to chlorination products has considerably increased during the 20(th) century especially after the 1960s with the development of public and leisure pools. The present article summarizes current knowledge regarding the human exposure to chlorination products and reviews studies suggesting that these chemicals might be involved in the development or exacerbation of allergic diseases. Populations regularly in contact with chlorination products such as swimmers, lifeguards or workers using chlorine as cleaning or bleaching agent show increased risks of allergic diseases or of respiratory disorders frequently associated with allergy. Experimental evidence suggests that chlorination products promote allergic sensitization by compromising the permeability or the immunoregulatory function of epithelial barriers. These findings led to the chlorine hypothesis proposing that the rise of allergic diseases could result less from the declining exposure to microbial agents (the hygiene hypothesis) than from the increasing and largely uncontrolled exposure to products of chlorination, the most widely used method to achieve hygiene in the developed world. Giving the increasing popularity of water recreational areas, there is an obvious need to assess the effects of chlorine-based oxidants on human health and their possible implication in the epidemic of allergic diseases.


A simple, single, trial-learning paradigm for conditioned increase in natural killer cell activity.
A change in natural killer (NK) cell activity can be conditioned with one trial learning when conditioned stimulus (CS) precedes the unconditioned stimulus (US). To avoid the problems associated with two reexposures in our earlier studies, we have developed a reliable and simple conditioning protocol utilizing the one trial learning and one reexposure to the odor CS. The conditioned change in NK cell activity was significantly different (P less than 0.05) from the control groups of mice. The paradigm is short and simple in that the conditioned change could be demonstrated within 3 days. We have also compared the effects of temporal association of CS and US on conditioned increase in NK cell activity. Forward conditioning (CS preceded the US) demonstrated a conditioned change, but the backward conditioning protocol did not. The paradigm provides a reliable approach to the study of mechanisms of the phenomenon of odor-NK conditioning.


Calcifying epithelial odontogenic tumors: a clinicopathologic study of nine cases.
Nine cases of CEOT are reported. There are seven intra-osseous and two extraosseous tumors. All but one occurred in the mandible. The age range was 20 to 64 years; averaging 34.2 years. There were 7 females and 2 males. Radiographically, they appeared either as monocystic or polycystic translucent lesions with radiopaque spots or masses. Embedded teeth were seen in six cases. Microscopically, four different patterns are described. No recurrence has been found postoperatively within 2-14 years of follow-up study. The nature of the reddish homogeneous material, the histogenesis of the tumor and the treatment are briefly discussed.


Harnessing the Effect of pH on Lipid Production in Batch Cultures of Yarrowia lipolytica SKY7.
The objective of this research was to investigate the kinetics of lipid production by Yarrowia lipolytica SKY7 in the crude glycerol-supplemented media with and without the control of pH. Lipid and citric acid production were improved with the pH control condition. There was no significant difference observed in the biomass concentration with or without the pH control. In the pH-controlled experiments, the biomass and lipid concentration reached 18 and 7.78 g/L, (45.5% w/w), respectively, with lipid yield (Yp/s) of 0.179 g/g at 60 h of fermentation. The lipid production was directly correlated with growth and the process was defined as growth associated. After 60 h of fermentation, the lipid degradation was noticed in the pH-controlled reactor whereas it occurred after 84 h in the pH-uncontrolled reactor. Apart from lipid, citric acid was produced as the major extracellular product in both fermentations but the much lower concentration in uncontrolled pH. Based on the experimental results, it is evident that controlling the pH will enhance the lipid production by 15% compared to pH-uncontrolled fermentation.


Single administration of p2TA (AB103), a CD28 antagonist peptide, prevents inflammatory and thrombotic reactions and protects against gastrointestinal injury in total-body irradiated mice.
The goal of this study was to elucidate the action of the CD28 mimetic peptide p2TA (AB103) that attenuates an excessive inflammatory response in mitigating radiation-induced inflammatory injuries. BALB/c and A/J mice were divided into four groups: Control (C), Peptide (P; 5 mg/kg of p2TA peptide), Radiation (R; total body irradiation with 8 Gy γ-rays), and Radiation + Peptide (RP; irradiation followed by p2TA peptide 24 h later). Gastrointestinal tissue damage was evaluated by analysis of jejunum histopathology and immunohistochemistry for cell proliferation (Cyclin D1) and inflammation (COX-2) markers, as well as the presence of macrophages (F4/80). Pro-inflammatory cytokines IL-6 and KC as well as fibrinogen were quantified in plasma samples obtained from the same mice. Our results demonstrated that administration of p2TA peptide significantly reduced the irradiation-induced increase of IL-6 and fibrinogen in plasma 7 days after exposure. Seven days after total body irradiation with 8 Gy of gamma rays numbers of intestinal crypt cells were reduced and villi were shorter in irradiated animals compared to the controls. The p2TA peptide delivery 24 h after irradiation led to improved morphology of villi and crypts, increased Cyclin D1 expression, decreased COX-2 staining and decreased numbers of macrophages in small intestine of irradiated mice. Our study suggests that attenuation of CD28 signaling is a promising therapeutic approach for mitigation of radiation-induced tissue injury.


IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours.
Somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in gliomas and acute myeloid leukaemia (AML). Since patients with multiple enchondromas have occasionally been reported to have these conditions, we hypothesized that the same mutations would occur in cartilaginous neoplasms. Approximately 1200 mesenchymal tumours, including 220 cartilaginous tumours, 222 osteosarcomas and another ∼750 bone and soft tissue tumours, were screened for IDH1 R132 mutations, using Sequenom(®) mass spectrometry. Cartilaginous tumours and chondroblastic osteosarcomas, wild-type for IDH1 R132, were analysed for IDH2 (R172, R140) mutations. Validation was performed by capillary sequencing and restriction enzyme digestion. Heterozygous somatic IDH1/IDH2 mutations, which result in the production of a potential oncometabolite, 2-hydroxyglutarate, were only detected in central and periosteal cartilaginous tumours, and were found in at least 56% of these, ∼40% of which were represented by R132C. IDH1 R132H mutations were confirmed by immunoreactivity for this mutant allele. The ratio of IDH1:IDH2 mutation was 10.6 : 1. No IDH2 R140 mutations were detected. Mutations were detected in enchondromas through to conventional central and dedifferentiated chondrosarcomas, in patients with both solitary and multiple neoplasms. No germline mutations were detected. No mutations were detected in peripheral chondrosarcomas and osteochondromas. In conclusion, IDH1 and IDH2 mutations represent the first common genetic abnormalities to be identified in conventional central and periosteal cartilaginous tumours. As in gliomas and AML, the mutations appear to occur early in tumourigenesis. We speculate that a mosaic pattern of IDH-mutation-bearing cells explains the reports of diverse tumours (gliomas, AML, multiple cartilaginous neoplasms, haemangiomas) occurring in the same patient.


The unreliability of mammalian glomerular markers in teleostean renal studies.
1. The assumption that (3H) methoxy inulin, (14C) polyethylene glycol (PEG) and (125) iothalamate (glofil) are reliable volume and glomerular markers in teleosts was tested. 2. PEG occupied smaller volumes than inulin and glofil in sea-water-adapted Salmo gairdneri. Ureteral clearances of PEG were about 22% higher than those of inulin and glofil, and urine-to-plasma ratios were significantly greater for PEG than for the other two markers. 3. After introduction into the urinary bladder the three macro-molecules appeared in the plasma, PEG at the lowest rates. 4. These observations indicate that mammalian glomerular markers can penetrate the bladder and possibly the ureters and renal tubules. Therefore, their clearances may not give a true measure of glomerular filtration rates in teleosts.


Therapeutic potential of chemically modified siRNA: Recent trends.
Small interfering RNAs (siRNAs) are one of the valuable tools to investigate the functions of genes and are also used for gene silencing. It has a wide scope in drug discovery through in vivo target validation. siRNA therapeutics are not optimal drug-like molecules due to poor bioavailability and immunogenic and off-target effects. To overcome the challenges associated with siRNA therapeutics, identification of appropriate chemical modifications that improves the stability, specificity and potency of siRNA is essential. This review focuses on the various chemical modifications and their implications in siRNA therapy.


Navigating networks by using homophily and degree.
Many large distributed systems can be characterized as networks where short paths exist between nearly every pair of nodes. These include social, biological, communication, and distribution networks, which often display power-law or small-world structure. A central challenge of distributed systems is directing messages to specific nodes through a sequence of decisions made by individual nodes without global knowledge of the network. We present a probabilistic analysis of this navigation problem that produces a surprisingly simple and effective method for directing messages. This method requires calculating only the product of the two measures widely used to summarize all local information. It outperforms prior approaches reported in the literature by a large margin, and it provides a formal model that may describe how humans make decisions in sociological studies intended to explore the social network as well as how they make decisions in more naturalistic settings.


Rieger's anomaly associated with Marfan's syndrome.
A 7 1/2-year-old girl was found to have clinical evidence of Marfan's syndrome associated with abnormalities of the anterior segment, including a prominent, anteriorly displaced Schwalbe's line with iris attachments and iris hypoplasia. The unusual association of Marfan's syndrome and Rieger's anomaly is discussed.


Assessment of improvement in knowledge and skills amongst trainees of workshop on "labour and partograph".
To assess the improvement in knowledge and skills amongst the trainees of the workshop on "labour and partograph". Cross sectional study where 100 trainees were evaluated for improvement in knowledge and skills after workshops. Assessment tool selected for predefined objectives were a) feedback forms b) pre and post test questionnaire c )pre and post training assessment of skills. These competency based workshops were conducted at Hamdard university hospital and attended by 85 graduating final year students, 10 house officers and 5 labour room nurses. The data was entered and analyzed on SPSS. Eighty percent of the trainees strongly agreed that workshop had improved their knowledge and skills and appreciated the hands on practice session. In assessment of improvement in knowledge by pre and post test questionnaire it was found that only 14.9% scored > 80% in pre test whereas in post test 87.8% scored > 80% with a mean of 89.5 +/- 9.1. In, overall, assessment of skills only 3.6% trainees scored > 80% in pre-training assessment while in post training assessment almost 98.2% scored > 80%. The overall results showed significant improvement in both knowledge and skills of the trainee after the workshop. Objectivity in teaching, learning and assessment gives good outcomes. We also feel that such training workshops should be done on a larger scale to train the staff in order to achieve the targets set under millennium development goals.


Hydrogen Sulfide Ameliorates Homocysteine-Induced Cardiac Remodeling and Dysfunction.
Patients with diabetes, a methionine-rich meat diet, or certain genetic polymorphisms show elevated levels of homocysteine (Hcy), which is strongly associated with the development of cardiovascular disease including diabetic cardiomyopathy. However, reducing Hcy levels with folate shows no beneficial cardiac effects. We have previously shown that a hydrogen sulfide (H2S), a by-product of Hcy through transsulfuration by cystathionine beta synthase (CBS), donor mitigates Hcy-induced hypertrophy in cardiomyocytes. However, the in vivo cardiac effects of H2S in the context of hyperhomocysteinemia (HHcy) have not been studied. We tested the hypothesis that HHcy causes cardiac remodeling and dysfunction in vivo, which is ameliorated by H2S. Twelve-week-old male CBS+/- (a model of HHcy) and sibling CBS+/+ (WT) mice were treated with SG1002 (a slow release H2S donor) diet for 4 months. The left ventricle of CBS+/- mice showed increased expression of early remodeling signals c-Jun and c-Fos, increased interstitial collagen deposition, and increased cellular hypertrophy. Notably, SG1002 treatment slightly reduced c-Jun and c-Fos expression, decreased interstitial fibrosis, and reduced cellular hypertrophy. Pressure volume loop analyses in CBS+/- mice revealed increased end systolic pressure with no change in stroke volume (SV) suggesting increased afterload, which was abolished by SG1002 treatment. Additionally, SG1002 treatment increased end-diastolic volume and SV in CBS+/- mice, suggesting increased ventricular filling. These results demonstrate SG1002 treatment alleviates cardiac remodeling and afterload in HHcy mice. H2S may be cardioprotective in conditions where H2S is reduced and Hcy is elevated.


Carotid Atheroinflammation Is Associated With Cerebral Small Vessel Disease Severity.
Background: Atherosclerosis is a systemic inflammatory disease, with common inflammatory processes implicated in both atheroma vulnerability and blood-brain barrier disruption. This prospective multimodal imaging study aimed to measure directly the association between systemic atheroma inflammation ("atheroinflammation") and downstream chronic cerebral small vessel disease severity. Methods: Twenty-six individuals with ischemic stroke with ipsilateral carotid artery stenosis of >50% underwent 18fluoride-fluorodeoxyglucose-positron emission tomography within 2 weeks of stroke. Small vessel disease severity and white matter hyperintensity volume were assessed using 3-tesla magnetic resonance imaging also within 2 weeks of stroke. Results: Fluorodeoxyglucose uptake was independently associated with more severe small vessel disease (odds ratio 6.18, 95% confidence interval 2.1-18.2, P < 0.01 for the non-culprit carotid artery) and larger white matter hyperintensity volumes (coefficient = 14.33 mL, P < 0.01 for the non-culprit carotid artery). Conclusion: These proof-of-concept results have important implications for our understanding of the neurovascular interface and potential therapeutic exploitation in the management of systemic atherosclerosis, particularly non-stenotic disease previously considered asymptomatic, in order to reduce the burden of chronic cerebrovascular disease.


Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia.
Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4-hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL.


Effectiveness of nurse-coordinated, person-centered comprehensive assessment on improving quality of life of community-dwelling, frail older people: a systematic review protocol.
The objective of this systematic review is to determine the effectiveness of nurse-coordinated, person-centered comprehensive assessment on improving quality of life of community-dwelling, frail older people. There is a growing need to meet the challenges of the increasingly frail and older population, and to provide proactive, holistic care close to home. A standardized assessment and care planning intervention could be implemented in primary care, which could be delivered by a primary or community healthcare nurse to address these challenges. However, it is not yet clear if an assessment and care planning intervention will improve outcomes for patients, such as quality of life. This review will consider studies that evaluate nurse-coordinated, person-centered, comprehensive assessment delivered in partnership with community-dwelling, frail older people, and will compare the intervention to usual care. Studies that include people aged 60 years and older living at home or in supported living accommodation with a recognized level of frailty as assessed by use of frailty screening or assessment tools, will be considered. Studies that include outcomes of health-related quality of life, social functioning, and well-being will also be considered. An initial limited search of PubMed and CINAHL has been undertaken to identify articles on the topic. The following sources will be searched for eligible papers: PubMED, CINAHL, Embase, PsycINFO, BNI, AMED, and OpenGrey. Retrieval of full-text studies, assessment of methodological quality, and data extraction will be performed independently by two reviewers. Meta-analysis will be performed, if possible, and a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Summary of Findings presented. PROSPERO CRD42019137886.


Hypoxia-Irrelevant Photonic Thermodynamic Cancer Nanomedicine.
The hypoxic tumor microenvironment severely lowers the therapeutic efficacy of oxygen-dependent anticancer modalities because tumor hypoxia hinders the generation of toxic reactive oxygen species. Here we report a thermodynamic cancer-therapeutic modality that employs oxygen-irrelevant free radicals generated from thermo-labile initiators for inducing cancer cell death. A free radical nanogenerator was engineered via direct growth of mesoporous silica layer onto the surface of two-dimensional Nb2C MXene nanosheets toward multifunctionality, where the mesopore provided the reservoirs for initiators and the MXene core acted as the photonic-thermal trigger at the near-infrared-II biowindow (NIR-II). Upon illumination by a 1064 nm NIR-II laser, the photothermal-conversion effect of Nb2C MXene induced the fast release and quick decomposition of the encapsulated initiators (AIPH) to produce free radicals, which promoted cancer cell apoptosis in both normoxic and hypoxic microenvironment. Systematic in vitro and in vivo evaluations have demonstrated the synergistic-therapeutic outcome of this intriguing photonic nanoplatform-enabled thermodynamic cancer therapy for completely eradicating the 4T1 tumors without recurrence by NIR-II laser irradiation. This work pioneers the thermodynamic therapy for oxygen-independent cancer treatment by photonic triggering at the NIR-II biowindow.


Structure and Chemical Composition of Soil C-Rich Al-Si-Fe Coprecipitates at Nanometer Scale.
Soil carbon stabilization is mainly driven by organo-mineral interactions. Coprecipitates, of organic matter with short-range order minerals, detected through indirect chemical extraction methods, are increasingly recognized as key carbon sequestration phases. Yet the atomic structure of these coprecipitates is still rather conceptual. We used transmission electron microscopy imaging combined with energy-dispersive X-ray and electron energy loss spectroscopy chemical mappings, which enabled direct nanoscale characterization of coprecipitates from Andosols. A comparison with reference synthetic coprecipitates showed that the natural coprecipitates were structured by an amorphous Al, Si, and Fe inorganic skeleton associated with C and were therefore even less organized than short-range order minerals usually described. These amorphous types of coprecipitates resembled previously conceptualized nanosized coprecipitates of inorganic oligomers with organics (nanoCLICs) with heterogeneous elemental proportions (of C, Al, Si, and Fe) at nanoscale. These results mark a new step in the high-resolution imaging of organo-mineral associations, while shedding further light on the mechanisms that control carbon stabilization in soil and more broadly in aquatic colloid, sediment, and extraterrestrial samples.


Inequities in global cancer surgery: Challenges and solutions.
The disparity in access to and quality of surgical cancer care between high and low resource settings impacts immediate and long-term oncological outcomes. With cancer incidence and mortality set to increase rapidly in the next few decades, we examine the factors leading to inequities in global cancer surgery, and look at potential solutions to overcome these challenges.


No effects of probiotics on atopic dermatitis in infancy: a randomized placebo-controlled trial.
Studies have been performed suggesting that administration of probiotics may have therapeutic and/or preventive benefits in the development of sensitization and atopic disease, particularly in infants with atopic dermatitis (AD). The purpose of this study was to evaluate the clinical and immunological effects of supplementation of a hydrolysed formula with two probiotic strains of bacteria on symptoms of AD in infancy. We conducted a randomized, double-blind, placebo-controlled study. After 4-6 weeks of baseline and double-blind, placebo-controlled challenges for diagnosis of cow's milk allergy (CMA), infants less than 5 months old with AD received a hydrolysed whey-based formula as placebo (n = 17), or supplemented with either Lactobacillus rhamnosus (n = 17) or Lactobacillus GG (n = 16) for 3 months. Before, during and after intervention, the clinical severity of AD was evaluated using SCORing index Atopic Dermatitis (SCORAD). Allergic sensitization was evaluated by measurement of total IgE and a panel of food-specific IgEs as well as skin prick testing for cow's milk. Inflammatory parameters were blood eosinophils, eosinophil protein X in urine, fecal alpha-1-antitrypsin and production of IL-4, IL-5 and IFN-gamma by peripheral blood mononuclear cells after polyclonal stimulation. No statistically significant effects of probiotic supplementation on SCORAD, sensitization, inflammatory parameters or cytokine production between groups were found. Only four infants were diagnosed with CMA. We found no clinical or immunological effect of the probiotic bacteria used in infants with AD. Our results indicate that oral supplementation with these probiotic bacterial strains will not have a significant impact on the symptoms of infantile AD.


Weight change among registered nurses in a self-help smoking cessation program.
Abstract Weight-related beliefs, attitudes, and patterns of weight change were analyzed for 144 registered nurses followed for one year in a self-help smoking cessation study. Smoking history and outcome status, physical descriptors, weight orientation, and use of self-help smoking cessation materials were examined in relation to weight change. A multiple regression analysis which included all subjects yielded three predictors of weight gain: continuous abstainer smoking status, lower body mass index, and greater fear of weight gain. A logistic regression confirmed the influence of smoking status at outcome on weight change. Abstinence was associated with weight gain; continuous abstainers were more likely to gain weight (88.2%) than noncontinuous abstainers (50%) and never quitters (35.9%). Weight variables were found to be interrelated, forming an "eating orientation" linked to smoking behavior.


Transcriptome analysis of egg viability in rainbow trout, Oncorhynchus mykiss.
Maternal transcripts are accumulated in the oocyte during oogenesis to provide for protein synthesis from oocyte maturation through early embryonic development, when nuclear transcription is silenced. The maternal mRNAs have short poly(A) tails after undergoing post-transcriptional processing necessary for stabilizing them for storage. The transcripts undergo cytoplasmic polyadenylation when they are to be translated. Transcriptome analyses comparing total mRNA and elongated poly(A) mRNA content among eggs of different quality can provide insight into molecular mechanisms affecting egg developmental competence in rainbow trout. The present study used RNA-seq to compare transcriptomes of unfertilized eggs of rainbow trout females yielding different eyeing rates, following rRNA removal and poly(A) retention for construction of the libraries. The percentage of embryos to reach the 32-cell stage at 24 h post fertilization was significantly correlated to family eyeing rate, indicating that inviable embryos were developmentally compromised before zygotic genome activation. RNA sequencing identified 2 differentially expressed transcripts (DETs) from total mRNA sequencing comparing females with low-quality (< 5% eyeing), medium-quality (30-50% eyeing), and high-quality (> 80% eyeing) eggs. In contrast, RNA sequencing from poly(A) captured transcripts identified 945 DETs between low- and high-quality eggs, 1012 between low- and medium-quality eggs, and only 2 between medium- and high-quality eggs. The transcripts of mitochondrial genes were enriched with polyadenylated transcript sequencing and they were significantly reduced in low-quality eggs. Similarly, mitochondrial DNA was reduced in low-quality eggs compared with medium- and high-quality eggs. The functional gene analysis classified the 945 DETs between low- and high-quality eggs into 31 functional modules, many of which were related to ribosomal and mitochondrial functions. Other modules involved transcription, translation, cell division, apoptosis, and immune responses. Our results indicate that differences in egg quality may be derived from differences in maternal nuclear transcript activation and cytoplasmic polyadenylation before ovulation, as opposed to accumulation and storage of maternal nuclear transcripts during oogenesis. Transcriptome comparisons suggest low-quality eggs suffered from impaired oxidative phosphorylation and translation. The DETs identified in this study provide insight into developmental competence in rainbow trout eggs.


Regulation of the activity of the tumor suppressor PTEN by thioredoxin in Drosophila melanogaster.
Human Thioredoxin-1 (hTrx-1) is a small redox protein with a molecular weight of 12 kDa that contains two cysteine residues found in its catalytic site. HTrx-1 plays an important role in cell growth, apoptosis, and cancer patient prognosis. Recently, we have demonstrated that hTrx-1 binds to the C2 domain of the human tumor suppressor, PTEN, in a redox dependent manner. This binding leads to the inhibition of PTEN lipid phosphatase activity in mammalian tissue culture systems. In this study, we show that over-expression of hTrx-1 in Drosophila melanogaster promotes cell growth and proliferation during eye development as measured by eye size and ommatidia size. Furthermore, hTrx-1 rescues the small eye phenotype induced by the over-expression of PTEN. We demonstrate that this rescue of the PTEN-induced eye size phenotype requires cysteine-218 in the C2 domain of PTEN. We also show that hTrx-1 over-expression results in increased Akt phosphorylation in fly head extracts supporting our observations that the hTrx-1-induced eye size increase results from the inhibition of PTEN activity. Our study confirms the redox regulation of PTEN through disulfide bond formation with the hTrx-1 in Drosophila and suggests conserved mechanisms for thioredoxins and their interactions with the phosphatidylinositol-3-kinase signaling pathway in humans and fruit flies.


Stereoselective syntheses of racemic quercitols and bromoquercitols starting from cyclohexa-1,4-diene: gala-, epi-, muco-, and neo-quercitol.
The efficient synthesis of gala-, epi-, neo-, and muco-quercitols and some brominated quercitols starting from cyclohexa-1,4-diene is reported. Treatment of the dibromide, obtained by the addition of bromine to cyclohexa-1,4-diene, with m-chloroperbenzoic acid (m-CPBA) yielded the dibromoepoxide, which was successfully converted to the desired dibromodiol by treatment with sulfuric acid. The resulting diol was reacted with 2,2-dimethoxypropane to give the dibromoketal. Hydrogen bromide elimination with NaOMe gave the key compound methoxyketal, rel-(3aS,5R,7aS)-5-methoxy-2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxole. The second key compound, an isomeric methoxyketal, was prepared by ketalization of 4,5-dibromocyclohexane-1,2-diol with dimethoxypropane followed by the reaction with NaOMe. Deprotection of ketal functionality with sulfuric acid followed by acetylation with acetic anhydride in pyridine resulted in the formation of diacetate rel-(1S,2R,5R)-5-methoxycyclohex-3-ene-1,2-diyl diacetate. Epoxidation of the double bonds in isomeric methoxy diacetates and cis-hydroxylation followed by epoxide-opening and deprotection resulted in the formation of various quercitol derivatives. The inhibition activity of eleven quercitols, methoxyquercitols and bromoquercitols was tested against α-glycosidase.


Condom use among low-literate, rural females in Ethiopia: the role of vulnerability to HIV infection, condom attitude, and self-efficacy.
To date, studies on psychosocial determinants of condom use among adolescents in Africa have mainly focused on more literate urban youth. In this study, we investigated the psychosocial determinants of condom use among low-literate females in rural Ethiopia. Moreover, some controversy exists on the role of perceived vulnerability to HIV infection to promote HIV preventive behavior in Africa, which we also tried to clarify in this study. In this study, 200 rural females participated, aged 13-24, from the Amhara Highland in Ethiopia. Using data collectors who interviewed the low-literate females with a structured questionnaire, we assessed perceived vulnerability to HIV infection, response efficacy of condom use, self-efficacy, attitude to condom use, and subjective norm to condom use. Moreover, we assessed intended and actual condom use. Compared to non-users of condoms, users of condoms scored significantly higher on all psychosocial determinants. Regression analysis indicated that vulnerability, condom attitude, and self-efficacy were significantly related to intended condom use. Attitude, vulnerability, and response-efficacy were significantly related to actual condom use. Among low-literate females in rural Ethiopia, psychosocial determinants were strongly related to intended and actual condom use, which indicates the usability of psychosocial models of condom use among low-literate females.


Mcs4, a two-component system response regulator homologue, regulates the Schizosaccharomyces pombe cell cycle control.
The Schizosaccharomyces pombe cdc2-3w wee1-50 double mutant displays a temperature-sensitive lethal phenotype termed mitotic catastrophe. Six mitotic catastrophe suppressor (mcs1-6) genes were identified in a genetic screen designed to identify regulators of cdc2. Mutations in mcs1-6 suppress the cdc2-3w wee1-50 temperature-sensitive growth defect. Here, the cloning of mcs4 is described. The mcs4 gene product displays significant sequence homology to members of the two-component system response regulator protein family. Strains carrying the mcs4 and cdc25 mutations display a synthetic osmotic lethal phenotype along with an inability to grow on minimal synthetic medium. These phenotypes are suppressed by a mutation in wee1. In addition, the wis1 gene, encoding a stress-activated mitogen-activated protein kinase kinase, was identified as a dosage suppressor in this screen. These findings link the two-component signal transduction system to stress response and cell cycle control in S. pombe.


Analysis of progress curves. Rate law of pyruvate kinase type I from Escherichia coli.
Progress curves of the reaction catalysed by pyruvate kinase from Escherichia coli K12, designed to cover the four-dimensional concentration space of phosphoenolpyruvate, ADP, Mg2+ and ATP in the regulatory region, were recorded with the pH-stat method (pH 7.0 and 25 degrees C). Additional initial-rate measurement were performed to assess specific points. Two methods for the evaluation of progress curves were used: fitting the rate law to the rates obtained from the tangents of the progress curves and fitting the integrated rate law directly to the curves. Two models, both extensions of the concerted model given by Monod, Wyman & Changeux [(1965) J. Mol. Biol. 12, 88--118] with four protomers, could be fitted to the data within the experimental error. Model discrimination in favour of one of these models was possible by proper experimental design. In the selected model one conformational state of the enzyme forms the active complex. The active site of a second conformational state forms abortive complexes with Mg2+, causing strong inhibition at high Mg2+ concentrations. In the absence of ligands, most of the enzyme is in a third state that binds ATP at an allosteric site.