Sexual selection on spontaneous mutations strengthens the between-sex genetic correlation for fitness.
A proposed benefit to sexual selection is that it promotes purging of deleterious mutations from populations. For this benefit to be realized, sexual selection, which is usually stronger on males, must purge mutations deleterious to both sexes. Here, we experimentally test the hypothesis that sexual selection on males purges deleterious mutations that affect both male and female fitness. We measured male and female fitness in two panels of spontaneous mutation-accumulation lines of the fly, Drosophila serrata, each established from a common ancestor. One panel of mutation accumulation lines limited both natural and sexual selection (LS lines), whereas the other panel limited natural selection, but allowed sexual selection to operate (SS lines). Although mutation accumulation caused a significant reduction in male and female fitness in both the LS and SS lines, sexual selection had no detectable effect on the extent of the fitness reduction. Similarly, despite evidence of mutational variance for fitness in males and females of both treatments, sexual selection had no significant impact on the amount of mutational genetic variance for fitness. However, sexual selection did reshape the between-sex correlation for fitness: significantly strengthening it in the SS lines. After 25 generations, the between-sex correlation for fitness was positive but considerably less than one in the LS lines, suggesting that, although most mutations had sexually concordant fitness effects, sex-limited, and/or sex-biased mutations contributed substantially to the mutational variance. In the SS lines this correlation was strong and could not be distinguished from unity. Individual-based simulations that mimick the experimental setup reveal two conditions that may drive our results: (1) a modest-to-large fraction of mutations have sex-limited (or highly sex-biased) fitness effects, and (2) the average fitness effect of sex-limited mutations is larger than the average fitness effect of mutations that affect both sexes similarly.


Endothelial line associated with pseudophakic bullous keratopathy.
Three patients undergoing uncomplicated cataract extraction with intraocular lens implantation developed an endothelial line, clinically appearing identical to that seen in allograft rejection following corneal transplantation. Both intracapsular and extracapsular surgery were involved. Three different intraocular lens types were implanted (pupillary supported, anterior chamber, and posterior chamber). Each case was associated with postoperative iritis and glaucoma. They were nonresponsive to steroid therapy and eventually resulted in total corneal decompensation. This clinical entity may represent an autoimmune phenomenon stimulated by chronic inflammation induced by the intraocular lens.


The potential of topoisomerase I inhibitors in the treatment of CNS malignancies: report of a synergistic effect between topotecan and radiation.
Despite innovations in imaging, surgery, and radiation therapy, local failure remains the principle clinical problem in most CNS malignancies. To date, chemotherapy has not major impact in the treatment of most adult CNS tumors. The inroads made by chemotherapy in pediatric CNS malignancies suggest that novel drugs, or drug combinations, may improve therapy. Topoisomerase I (Topo I) inhibitors are a relatively new group of chemotherapy drugs with a novel mechanism of action. Drugs in this group currently undergoing clinical trials are the Camptothecin analogues Topotecan, CPT-11, and 9-aminocamptothecin. There is substantial preclinical and some clinical evidence to suggest that these drugs could be useful in the treatment of CNS malignancies. Preclinical studies with the water soluble Topo I inhibitor, Topotecan, demonstrate antineoplastic activity in a variety of CNS malignancies. In addition, Topotecan has good CNS penetration in primates, and recent preliminary phase I and II clinical trials of Topotecan in pediatric and adult CNS malignancies have been promising. In this paper, we describe the unique mechanism of action, antineoplastic activity, and radiosensitizing properties of Topo I inhibitors. We present the first report demonstrating potentiation of radiation lethality by Topotecan in a human glioma (D54) cell line. The dose enhancement ratio was 3.2 at 10% survival. Thus, there is evidence to suggest that Topo I inhibitors may be beneficial in the treatment of CNS neoplasms on the basis of their antineoplastic activity alone, as well as their radiosensitizing effects. Two clinical trials which utilize concurrent Topotecan and radiation in the treatment of pediatric and adult CNS malignancies are discussed.


A biomedical engineer's experience in Nicaragua.
The experiences of a 12-member team composed of physicians, nurses, a respiratory therapist, a rehabilitation engineer with specialty training in prosthetics and orthotics, and a biomedical engineer at a third-world medical facility are described. The obstacles encountered in the form of limited equipment, the state of disrepair of existing equipment, and environmental factors (heat and humidity) are discussed. The question of how best to help developing countries is examined.


Endothelial function in patients with cornea guttata.
Measurements of corneal thickness, endothelial cell size, endothelial permeability to fluorescein, and intraocular pressure were made in two groups of human subjects: 21 persons with cornea guttata (early Fuchs dystrophy without epithelial edema) and 17 persons age- and sex-matched but with normal corneas. Statistically significant differences were found between the two groups in all four measured variables. The two groups did not differ with respect to the variability in endothelial cell sizes. There were statistically significant positive correlations between endothelial permeability to fluorescein, endothelial cell size, and corneal thickness. The endothelial pump rate was calculated for each group, and the difference was not statistically significant. Our results suggest that the earliest defect in Fuchs' dystrophy is solely a breakdown in barrier function and thus increased permeability, resulting in a thicker cornea.


Cryptic lineage divergence in marine environments: genetic differentiation at multiple spatial and temporal scales in the widespread intertidal goby Gobiosoma bosc.
The adaptive radiation of the seven-spined gobies (Gobiidae: Gobiosomatini) represents a classic example of how ecological specialization and larval retention can drive speciation through local adaptation. However, geographically widespread and phenotypically uniform species also do occur within Gobiosomatini. This lack of phenotypic variation across large geographic areas could be due to recent colonization, widespread gene flow, or stabilizing selection acting across environmental gradients. We use a phylogeographic approach to test these alternative hypotheses in the naked goby Gobiosoma bosc, a widespread and phenotypically invariable intertidal fish found along the Atlantic Coast of North America. Using DNA sequence from 218 individuals sampled at 15 localities, we document marked intraspecific genetic structure in mitochondrial and nuclear genes at three main geographic scales: (i) between Gulf of Mexico and Atlantic Coast, (ii) between the west coast of the Florida peninsula and adjacent Gulf of Mexico across the Apalachicola Bay, and (iii) at local scales of a few hundred kilometers. Clades on either side of Florida diverged about 8 million years ago, whereas some populations along the East Cost show divergent phylogroups that have differentiated within the last 200,000 years. The absence of noticeable phenotypic or ecological differentiation among lineages suggests the role of stabilizing selection on ancestral phenotypes, together with isolation in allopatry due to reduced dispersal and restricted gene flow, as the most likely explanation for their divergence. Haplotype phylogenies and spatial patterns of genetic diversity reveal frequent population bottlenecks followed by rapid population growth, particularly along the Gulf of Mexico. The magnitude of the genetic divergence among intraspecific lineages suggests the existence of cryptic species within Gobiosoma and indicates that modes of speciation can vary among lineages within Gobiidae.


Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargo.
Progranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia, while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interactions with prosaposin, another lysosomal protein, first occur within the lumen of the endoplasmic reticulum (ER) and are required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII-coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates that a network of interactions occurring early in the secretory pathway promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.


Four arms robotic-assisted pulmonary resection-left lower lobectomy: how to do it.
Numerous published articles have shown the safety and efficacy of robotic lung resection, including lobectomy. The robotic approach offers similar survival rate to the open and video-assisted thoracoscopic surgery methods. Potential advantages provided by robotic technology, such as three-dimensional (3D) high-quality camera, wristed tools and ergonomic ease that seems to overcome certain video-assisted thoracic surgery (VATS) limits have been widely described. Several techniques have been developed by different surgeons to perform a robotic lobectomy. In this study, we present our technique for performing a four-arm robotic lobectomy for the treatment of early stage lung cancer. This is shown in clear, sequential steps. We also provide an instrument preference card, some operative tips and a high-quality video.


Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality.
While miRNAs are increasingly linked to various immune responses, whether they can be targeted for regulating in vivo inflammatory processes such as endotoxin-induced Gram-negative sepsis is not known. Production of cytokines by the dendritic cells (DCs) plays a critical role in response to endotoxin, lipopolysaccharide (LPS). We profiled the miRNA and mRNA of CD11c⁺ DCs in an unbiased manner and found that at baseline, miR-142-3p was among the most highly expressed endogenous miRs while IL-6 was among the most highly expressed mRNA after LPS stimulation. Multiple computational algorithms predicted the IL-6 3' untranslated region (UTR) to be a target of miR-142-3p. Studies using luciferase reporters carrying wild-type (WT) and mutant IL-6 3'UTR confirmed IL-6 as a target for miR-142-3p. In vitro knockdown and overexpression studies demonstrated a critical and specific role for miR142-3p in regulating IL-6 production by the DCs after LPS stimulation. Importantly, treatment of only WT but not the IL-6-deficient (IL-6(⁻/⁻)) mice with locked nucleic acid (LNA)-modified phosphorothioate oligonucleotide complementary to miR 142-3p reduced endotoxin-induced mortality. These results demonstrate a critical role for miR-142-3p in regulating DC responses to LPS and provide proof of concept for targeting miRs as a novel strategy for treatment of endotoxin-induced mortality.


Remission over 3 years in patients with Paget disease of bone treated with a single intravenous infusion of 5 mg zoledronic acid.
Using data from the Belgian Paget's Disease Registry of 142 patients treated with a 5 mg intravenous infusion of zoledronic acid, we examined disease remission over 3 years in 98 patients with Paget disease of bone (PDB) seen in routine practice. Median age was 76 years, most patients (60.2 %) were male, and all were Caucasian. Median time since PDB diagnosis was 11.5 years, few patients (5.1 %) had a family history of PDB, and 32.6 % had received prior bisphosphonate and/or other treatments. The most common pagetic locations were pelvis, spine, femur, tibia, and skull. The most common symptoms included pain, impaired mobility, bone deformities, and joint disease: 36.7 % of patients had comorbid osteoarthritis and 16.3 % comorbid osteoporosis. Response rates were 93.3 % at 1 year, 89.5 % at 2 years, and 91.6 % at 3 years, statistically similar to an extension study of the original zoledronic acid trials. Twenty-one patients experienced a relapse over the 3-year period at a median of 20.7 months posttreatment; of these, 13 regained remission by the end of the observation period. Relapse was not associated with osteoarthritis, osteoporosis, or other comorbidities. Safety data were similar to those reported elsewhere. In summary, in this somewhat frailer sample of patients with PDB, effectiveness and safety data were similar to those observed in the original trial populations. These findings, which are the first on the use of zoledronic acid for PDB in routine clinical practice, underscore the therapeutic benefits and relative safety of zoledronic acid in the management of PDB in "real-world" clinical settings.


Best practices in reporting analyses of questionnaires as objective rating scales of variable measures.
The best practice model states that the highest quality of scientific information in a discipline should be used when addressing pertinent problems. The usefulness of any measure depends on the least allowable error, which implies that best practice approaches must be used during analyses of rating scales. However, modern theories of objective measurement in advanced statistics suggest there are some shortcomings in reports of questionnaire analyses. To highlight some common problems in questionnaire data and suggest techniques of constructing objective measures during rating scale analysis. Questionnaires are frequently used as rating scales of latent variables, such as knowledge, anxiety and outcomes of treatments. However, reports of the steps involved before generating the final 'measures' often fail to present known limitations and robust solutions to the problems common to questionnaire data. Most designers of questionnaires generate variable measures for either educational or clinical research purposes without providing adequate explanations of the steps taken to address inherent limitations that may worsen the error terms in the outcome measure. Cursory attention is given to the problems in questionnaire analysis as most users do not convincingly justify the measurement techniques they used before they present variable estimation. Reporting the techniques used to address data complexity by engaging objective measurement parameters ensures best practice and emphasises the credibility of the outcome measure. Among researchers, using the techniques outlined here will lead to standardisation of questionnaire analysis and elimination of avoidable errors in constructing variable measures, resulting in high-quality data suitable for parametric statistics. For clinicians, these methods will simplify the interpretation of numerical measures to equivalent indicators on Wright maps, thus avoiding inconsistencies and misinterpretations of variable measure.


Evaluation of endocrine and immune responses of steers challenged with infectious bovine rhinotracheitis virus.
To evaluate the endocrine and immune responses of steers challenged with infectious bovine rhinotracheitis virus (IBRV). 12 crossbred beef steers. Steers were randomly assigned to IBRV- (control) or IBRV+ treatment groups. Experimentally challenged steers (IBRV+) received a dose of IBRV intranasally (8.0 50% tissue culture infective doses), IBRV- steers received a saline (0.9% NaCl) solution placebo intranasally, and each group was placed in an isolated paddock. At 72 hours after challenge, all steers were fitted with indwelling jugular catheters and placed into individual stanchions. Blood samples were collected on days 4 through 8. Serum was analyzed for concentrations of cortisol, interleukin-6, interferon-γ, tumor necrosis factor-α, growth hormone, and insulin-like growth factor I. From 72 to 144 hours after challenge inoculation, the IBRV+ group had significantly greater mean rectal temperature, compared with the IBRV- group; the greatest temperatures in both groups were observed at 72 hours. Serum cortisol concentrations were increased in both groups from hours 72 to 136 and serum interferon-γ concentrations were greater in the IBRV+ from 94 to 112 hours after inoculation. Growth hormone concentration was greater in the IBRV+ group at various time points, but no difference in insulin-like growth factor- I concentration was observed. Results indicated that IBVR challenge altered growth hormone concentration at some time points but was not associated with large increases in circulating proinflammatory cytokines.


Axonal projection-specific differences in somatodendritic α2 autoreceptor function in locus coeruleus neurons.
The locus coeruleus (LC) contains the majority of central noradrenergic neurons sending wide projections throughout the entire CNS. The LC is considered to be essential for multiple key brain functions including arousal, attention and adaptive stress responses as well as higher cognitive functions and memory. Electrophysiological studies of LC neurons have identified several characteristic functional features such as low-frequency pacemaker activity with broad action potentials, transient high-frequency burst discharges in response to salient stimuli and an apparently homogeneous inhibition of firing by activation of somatodendritic α2 autoreceptors (α2AR). While stress-mediated plasticity of the α2AR response has been described, it is currently unclear whether different LC neurons projecting to distinct axonal targets display differences in α2AR function. Using fluorescent beads-mediated retrograde tracing in adult C57Bl6/N mice, we compared the anatomical distributions and functional in vitro properties of identified LC neurons projecting either to medial prefrontal cortex, hippocampus or cerebellum. The functional in vitro analysis of LC neurons confirmed their mostly uniform functional properties regarding action potential generation and pacemaker firing. However, we identified significant differences in tonic and evoked α2AR-mediated responses. While hippocampal-projecting LC neurons were partially inhibited by endogenous levels of norepinephrine and almost completely silenced by application of saturating concentrations of the α2 agonist clonidine, prefrontal-projecting LC neurons were not affected by endogenous levels of norepinephrine and only partially inhibited by saturating concentrations of clonidine. Thus, we identified a limited α2AR control of electrical activity for prefrontal-projecting LC neurons indicative of functional heterogeneity in the LC-noradrenergic system.


Healthy physical coactivity in parent-child dyads of children with overweight.
Parent and child physical activity levels are correlated, but are they interdependent? A dyadic version of the theory of planned behavior (TPB) was developed to investigate interdependence in the motivation and intention of parents and their children with overweight to engage in healthy physical coactivity (HPCA). Baseline measures of the TPB constructs (subjective norms, attitude, perceived behavior control, and intention) for both dyad members were used to predict parent-reports of their actual HPCA at 12 weeks using the actor-partner interdependence model. The sample included 65 mother-child dyads and 48 father-child dyads from 66 predominantly Caucasian families. In mother-child dyads, a positive attitude toward HPCA predicted each person's own intention to engage in HPCA (both actor effects). In addition, mother's perceived behavior control over HPCA predicted the child's intention to engage in HPCA (a partner effect). Mother's attitude toward HPCA also predicted mother-reported HPCA. In father-child dyads, perceived behavior control predicted each person's own intention to engage in HPCA (both actor effects). The child's intention was also predicted by the child's subjective norms (an actor effect) and the father's perceived behavior control (a partner effect). Only the child's perceived behavior control predicted father-reported HPCA. There is interdependence in the motivation to engage in HPCA because both parents' perceived behavior control predicted their child's intention. However, interventions targeting mother's attitude toward HPCA with her child and the child's perceived behavior control in relation to the father would be most likely to increase HPCA in the parent-child dyads of children with overweight. (PsycINFO Database Record


Use of Fatty Acid Metal Salts for Preventing Maillard Reaction-Driven Browning of Lecithins.
We previously reported that fluid soybean lecithin (SL) undergoes heat deterioration by the newly reported pseudo-Maillard rearrangement reaction. To inhibit heat deterioration, SLs were treated with metal silicates, such as magnesium silicate and calcium silicate. When soybean fatty acid was added to SL before treatment with calcium silicate, the color index after heating improved significantly as the acid value increased from 10 to 35 mg KOH/g. To elucidate the role of soybean fatty acid, calcium silicate treatment was carried out by adding several fatty acids to SL. Although saturated fatty acids had no effect on the heat deterioration of SL, unsaturated fatty acids were significantly more effective at inhibiting heat deterioration. Furthermore, for unsaturated fatty acids, it was confirmed that the calcium concentration increased in SL. Based on these results, several fatty acid metal salts were added to confirm whether heat deterioration while heating SL could be inhibited. It was observed that the heat deterioration of SL could be inhibited with fatty acid metal salts, regardless of whether the fatty acids were saturated or unsaturated and whether the metal was monovalent, divalent, or trivalent. Therefore, in this study, we clarified that the heat deterioration of SL could be inhibited by adding fatty acid metal salts to SL. Among sodium stearate, calcium stearate, magnesium stearate, barium stearate, and aluminum tristearate, the divalent fatty acid metal salts had a stronger inhibitory effect on heat deterioration than the monovalent and trivalent salts.


Muscular adaptations to computer-guided strength training with eccentric overload.
In order to investigate the muscular adaptations to a novel form of strength training, 18 male untrained subjects performed 4 weeks of low resistance-high repetition knee extension exercise. Nine of them trained on a conventional weight resistance device (Leg curler, CON/ECC group), with loads equivalent to 30% of the concentric one-repetition maximum (1RM) for both the concentric and eccentric phase of movement. The other nine trained on a newly developed computer-driven device (CON/ECC-OVERLOAD group) with the concentric load equivalent to 30% of the concentric 1RM and the eccentric load equivalent to 30% of the eccentric 1RM. Training resulted in significantly (P < or = 0.05) increased peak torque and a tendency (P=0.092) to increased muscle cross-sectional area for the CON/ECC-OVERLOAD but not the CON/ECC group, while strength endurance capacity was significantly (P < or = 0.05) increased in the CON/ECC group only. RT-PCR revealed significantly increased myosin heavy chain (MHC) IIa and lactate dehydrogenase (LDH) A mRNAs, a tendency for increased MHC IIx mRNA (P = 0.056) and high correlations between the changes in MHC IIx and LDH A mRNAs (r=0.97, P=0.001) in the CON/ECC-OVERLOAD group. These results indicate a shift towards a more type II dominated gene expression pattern in the vasti laterales muscles of the CON/ECC-OVERLOAD group in response to training. We suggest that the increased eccentric load in the CON/ECC-OVERLOAD training leads to distinct adaptations towards a stronger, faster muscle.


The historical dynamics of social-ecological traps.
Environmental degradation is a typical unintended outcome of collective human behavior. Hardin's metaphor of the "tragedy of the commons" has become a conceived wisdom that captures the social dynamics leading to environmental degradation. Recently, "traps" has gained currency as an alternative concept to explain the rigidity of social and ecological processes that produce environmental degradation and livelihood impoverishment. The trap metaphor is, however, a great deal more complex compared to Hardin's insight. This paper takes stock of studies using the trap metaphor. It argues that the concept includes time and history in the analysis, but only as background conditions and not as a factor of causality. From a historical-sociological perspective this is remarkable since social-ecological traps are clearly path-dependent processes, which are causally produced through a conjunction of events. To prove this point the paper conceptualizes social-ecological traps as a process instead of a condition, and systematically compares history and timing in one classic and three recent studies of social-ecological traps. Based on this comparison it concludes that conjunction of social and environmental events contributes profoundly to the production of trap processes. The paper further discusses the implications of this conclusion for policy intervention and outlines how future research might generalize insights from historical-sociological studies of traps.


Definitive Chemoradiotherapy for Vulvar Cancer.
This study aimed to evaluate clinical outcomes after chemoradiation (CRT) for the definitive (nonsurgical) treatment of vulvar cancer. Women with vulvar cancer treated with definitive CRT at a single academic institution between 1994 and 2015 were retrospectively identified. Overall survival (OS), freedom from local recurrence, freedom from distant recurrence, and late toxicities were estimated using the Kaplan-Meier method at 3 years after radiotherapy completion. Univariate Cox regression models were used to estimate the effects of risk factors on these clinical end points. Acute and late toxicities were assessed according to the Common Terminology Criteria for Adverse Events v. 4.0. Twenty-five women met criteria for inclusion. At 3 years, OS was 71% (95% confidence interval [CI], 49%-93%), freedom from local recurrence was 65% (95% CI, 43%-87%), and freedom from distant recurrence was 78% (95% CI, 59%-97%). Older age was significantly associated with decreased OS (hazard rate, 1.069/y; 95% CI, 1.005-1.124; P = 0.035) and local recurrence (hazard rate, 1.077/y; 95% CI, 1.009-1.150; P = 0.026). Larger size of the primary was borderline associated with distant recurrence (P = 0.057). Skin changes were the most common late toxicity, with a 3-year rate of late G3 skin toxicity of 45% (95% CI, 20%-69%). The rate of lymphedema at 3 years was 25% (95% CI, 5%-44%). Definitive CRT for advanced vulvar cancer was an effective and well-tolerated approach for women with unresectable disease. Further work is needed to more appropriately select women who will benefit most from a nonsurgical approach.


Single-sweep analysis of the theta frequency band during an auditory oddball task.
The P300 component and the oscillatory 4-7 Hz electroencephalographic activity of auditory event-related brain potentials (ERPs) were assessed to study differences between passive and oddball task conditions. Theta responses from 15 adults were analyzed for single-sweep amplitude, phase locking, and enhancement against prestimulus activity. ERPs were characterized by enhanced and strongly phase-locked theta oscillations in the early (0-300 ms) poststimulus epoch, with only the late (300-600 ms) theta responses at Fz and Pz affected by the oddball condition. P300 was strongly associated not only with the concurrent theta oscillations but also with the evoked theta activity preceding P300 (0-300 ms). It was concluded that single theta response parameters can reveal specific functional differences between passive and oddball conditions and that a strong relationship exists between the theta frequency component and the time domain P300 ERP component.


Efficacy of low-dose oral use of type I interferon in cytomegalovirus infections in vivo.
Oral administration of type I interferons (IFNs; murine IFN-alpha and IFN-beta) reduces early replication of murine cytomegalovirus (MCMV) in both the spleen and liver of MCMV-infected BALB/c mice. Examination of a range of doses of IFN (1 to 1000 IU) showed that 10 IU administered daily for 1 week prior to virus infection was optimal for inhibition of MCMV replication. Furthermore, low-dose orally administered IFN (10 IU/day) was effective in mice challenged with lethal and sublethal virus inocula. The antiviral efficacy of low-dose orally administered IFN was not restricted by either the route of virus inoculation or the mouse genotype. Analysis by immunohistochemistry of IFN-alpha receptor-bearing cells of the gastrointestinal tract revealed predominant staining of perivascular smooth muscle and the lamina propria of the anterior tongue, small intestine and rectum. These tissues, dense in IFN-alpha receptor-bearing cells, are likely to be the sites of interaction of the orally administered IFNs with the mucosal immune system. In conclusion, we propose that low-dose oral use of type I IFN therapy may have broad applications in the treatment of CMV infections.


Understanding and improving inpatient mortality in academic medical centers.
The purpose of this article is to describe factors contributing to potentially preventable mortality in academic medical centers and the organizational characteristics associated with success in reducing mortality. Sixteen U.S. academic medical centers that wished to improve risk-adjusted inpatient mortality rates requested a consultation that included interviews with physicians, nurses, and hospital leaders; review of medical records; and evaluation of systems and processes of care. The assessments took place on-site; they identified key factors contributing to preventable mortality, and each hospital received specific recommendations. Changes in observed mortality and in the ratio of observed to expected mortality were measured from 2002 to final follow-up in 2007. Evaluations determined each hospital's success factors and key barriers to improvement. The key factors contributing to preventable mortality were delays in responding to deteriorating patients, suboptimal critical care, hospital-acquired infections, postoperative complications, medical errors, and community issues such as the availability of hospice care. Of the 16 hospitals, 12 were able to reduce their mortality index. The five hospitals that had the greatest improvement in mortality were the only hospitals with a broad level of engagement among hospital and physician leaders, including the department chairs. In the hospitals whose performance did not improve, the department chairs were not engaged in the process. The academic medical centers that focused on mortality reduction and had engagement of physicians, especially department chairs, were able to achieve meaningful reductions in hospital mortality. The necessary ingredients for achieving meaningful improvement in clinical outcomes included good data, a sound method for change, and physician leadership.


Layered double hydroxide nanoparticles to enhance organ-specific targeting and the anti-proliferative effect of cisplatin.
To evaluate the role of charge in the nanoparticle distribution we modified the external surface of layered double hydroxide nanoparticles with various organic groups bearing different charges and further a near-infrared (NIR) fluorescent dye (Cy5.5) is conjugated in the layered structure to assess the biodistribution. The functionalized nanocomposites performed as highly efficient contrast agents since Cy5.5 molecule stabilization inside the layered structure can safeguard them from metabolization in the physiological environments. The cell viability, lactate dehydrogenase and hemolytic assays showed no cytotoxicity with an exceptionally low release of both lactate dehydrogenase and hemoglobin from the treated cells. The in vivo biodistribution results disclosed a high accumulation of positive amino-layered double hydroxides (LDHs) in the lungs. In contrast, there is a rapid clearance of negatively charged carboxylate-LDHs from blood flow by liver uptake. Interestingly neutral LDH-PEG5000 showed enhanced blood circulation time, without high fluorescent accumulation in the major organs. In vitro cellular uptake studies from flow cytometry are relevant to the interactions between the nanoparticle surfaces and various cell types and the data are relevant to effects observed for in vivo biodistribution. To further demonstrate that surface functionalization on LDH nanoparticles can promote targeted drug release, we further immobilized hydroxo-substituted cisplatin (CP) on carboxylate-modified LDHs by coordination bonding. Due to the ideal cleaving property of the carboxylate group the coordinated CP can be efficiently released by the increase of acidic proton and Cl- concentration in the endosomal environment. Functionalized LDHs can be successfully employed as targeted drug delivery systems. When the LDH-CP complex accumulate primarily in the targeted organ, the high positive charge on the framework of LDHs cause susceptibility to rapid endocytosis, which facilitates sustained drug release with minimal systemic toxicity providing the apt treatment in the targeted organ.


Formation of disubstituted beta-lactones using bifunctional catalysis.
[reaction: see text] Acid chlorides and aromatic aldehydes react in the presence of a stoichiometric amount of a tertiary amine and catalytic amounts of a cinchona alkaloid derivative and a Lewis acid to produce beta-lactones in high diastereo- and enantioselectivity. The sense of the diastereoselectivity depends on the substitution of the acid chloride, with the reactions of aliphatic acid chlorides giving predominantly the trans-isomer and those of alkoxyacetyl chlorides favoring formation of the cis-isomer.


Effect of primary polydipsia on aquaporin and sodium transporter abundance.
Chronic primary polydipsia (POLY) in humans is associated with impaired urinary concentrating ability. However, the molecular mechanisms responsible for this finding have not been elucidated. The purpose of this study was to examine the effect of chronic primary POLY on water metabolism and renal aquaporin (AQP) water channels and sodium and urea transporter abundance in rats. Primary POLY was induced in male Sprague-Dawley rats by daily administration of 15 g powdered rat chow mixed in 100 ml water for 10 days. Control rats (CTL) received 15 g powdered rat chow per day and ad libitum drinking water. Rats were studied following this period before further intervention and with a 36-h period of water deprivation to examine maximal urinary concentrating ability. At baseline, POLY rats demonstrated significantly greater water intake (100 +/- 1 vs. 22 +/- 2 ml/day, P < 0.0001) and urinary output (80 +/- 1 vs. 11 +/- 1 ml/day, P < 0.0001) and decreased urinary osmolality (159 +/- 13 vs. 1,365 +/- 188 mosmol/kgH2O, P < 0.001) compared with CTL rats. These findings were accompanied by decreased inner medulla AQP-2 protein abundance in POLY rats compared with CTL rats before water deprivation (76 +/- 2 vs. 100 +/- 7% CTL mean, P < 0.007). With water deprivation, maximal urinary osmolality was impaired in POLY vs. CTL rats (2,404 +/- 148 vs. 3,286 +/- 175 mosmol/kgH2O, P < 0.0005). This defect occurred despite higher plasma vasopressin concentrations and similar medullary osmolalities in POLY rats. In response to 36-h water deprivation, inner medulla AQP-2 protein abundance was decreased in POLY rats compared with CTL rats (65 +/- 5 vs. 100 +/- 5% CTL mean, P < 0.0006). No significant differences were noted in renal protein abundance of either AQP-3 or AQP-4 or sodium and urea transporters. We conclude that the impaired urinary concentrating ability associated with primary POLY in rats is due to impaired osmotic equilibration in the collecting duct that is mediated primarily by decreased AQP-2 protein abundance.


CT approach to benign nasopharyngeal masses.
The physical characteristics of the fascial planes of the nasopharynx provide a basis for categorizing growth patterns of the more common benign nasopharyngeal masses. Lymphoid hyperplasias are confined to the surface by the very dense pharyngobasilar fascia that lies beneath the submucosa. It takes a very aggressive process to cross this fascial plane. More laterally throughout the paranasopharyngeal space the loose areolar nature of the buccopharyngeal fascia permits benign tumors in this space to assume a spherical configuration. The carotid sheath is also a loose areolar arrangement that permits free movement of the carotid artery in the neck. Juvenile angiofibromas permeate natural foramina, displace bony septa, and extend widely but do not invade the carotid sheath. Neurogenic tumors and paragangliomas are intimately associated with contents of the carotid sheath; therefore, they obliterate the low density regions surrounding the carotid vessels.


Early dioxin exposure causes toxic effects in adult zebrafish.
The acute effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure have been well documented in many vertebrate species. However, less is known about the consequences in adulthood from sublethal exposure during development. To address this, we exposed zebrafish to sublethal levels of TCDD (1h; 50 pg/ml), either in early embryogenesis (day 0) or during sexual determination (3 and 7 weeks), and assessed the effects later in adulthood. We found that exposure during embryogenesis produced few effects on the adults themselves but did affect the offspring of these fish: Malformations and increased mortality were observed in the subsequent generation. Zebrafish exposed during sexual development showed defects in the cranial and axial skeleton as adults. This was most clearly manifested as scoliosis caused by malformation of individual vertebrae. These fish also showed defects in reproduction, producing fewer eggs with lower fertilization success. Both males and females were affected, with males contributing to the decrease in egg release from the females and exposed females contributing to fertilization failure. TCDD exposure at 3 and 7 weeks produced feminization of the population. Surprisingly, part of this was due to the appearance of fish with clearly female bodies, yet carrying testes in place of ovaries. Our results show that exposures that produce little if any impact during development can cause severe consequences during adulthood and present a model for studying this process.


Comparison of yeast-derived commercial feed additives on Salmonella Enteritidis survival and microbiota populations in rooster cecal in vitro incubations.
Yeast-derived products have become more of an interest in the poultry industry as of late because of their use in modulating the gastrointestinal tract (GIT) microbiome to both improve production parameters and prevent infection. This study aimed to evaluate the effects of various yeast-derived products on Salmonella enterica inoculation in un in vitro rooster cecal incubations and associated effects on the cecal microbiome. Cecal contents were obtained from 53-wk old White Leghorn H & N Nick Chick roosters (n = 3) fed a wheat-based, commercial-type basal diet. Cecal contents were diluted 1:3000 in anaerobic dilution solution (ADS) in an anaerobic chamber, with 20 mL aliquoted to each serum bottle. There were three controls (n = 3): basal diet only, diluted cecal contents only, and basal diet and diluted cecal contents; and five treatments containing the basal diet and diluted cecal contents (n = 3): Citristim® (ADM), ImmunoWall® (ICC), Maxi-Gen Plus® (CBS Bio Platforms), Hilyses® (ICC), and Original XPC® (Diamond V). All treatments were applied at a rate of 2.5 kg/tonne or less. All groups were inoculated with a nalidixic acid-resistant strain of Salmonella Enteritidis at 10^7 CFU/mL and incubated at 37 deg C. Samples were collected at 0, 24, and 48 h for S. Enteritidis enumeration and 16S rDNA microbial sequencing. Salmonella data were log-transformed and analyzed in a two-way ANOVA with means separated using Tukey's HSD (P≤0.05). Genomic DNA was extracted, and resulting libraries were prepared and sequenced using an Illumina MiSeq. Sequencing data were analyzed in QIIME2 (2021.4) with diversity metrics (alpha and beta), and an analysis of the composition of microbiomes (ANCOM) was performed. Main effects were considered significant at P≤0.05, with pairwise differences considered significant at Q≤0.05. There was an interaction of treatment and time on the enumeration of Salmonella where treatments of Citristim, Immunowall, Hilyses, and XPC reduced Salmonella by 1 log CFU/mL compared to the controls. At 48 h, each yeast product treatment reduced Salmonella by 3 log CFU/mL compared to the controls. There was no main effect of treatment on the alpha diversity metrics, richness, or evenness (P > 0.05). Treatment affected the beta diversity, abundance, and phylogenetic differences, but there were no pairwise differences (P>0.05, Q>0.05). Using ANCOM at the genus level, the taxa Synergistes, Alloprevotella, Sutterella, and Megasphaera abundance were significantly different (W = 154,147,145,140, respectively). These results demonstrate the potential of these yeast-derived products to reduce foodborne pathogens, such as Salmonella Enteriditis, in vitro, without negatively disrupting the cecal microbiome.


Novel Role for ESCRT-III Component CHMP4C in the Integrity of the Endocytic Network Utilized for Herpes Simplex Virus Envelopment.
Enveloped viruses exploit cellular trafficking pathways for their morphogenesis, providing potential scope for the development of new antiviral therapies. We have previously shown that herpes simplex virus 1 (HSV1) utilizes recycling endocytic membranes as the source of its envelope, in a process involving four Rab GTPases. To identify novel factors involved in HSV1 envelopment, we have screened a small interfering RNA (siRNA) library targeting over 80 human trafficking proteins, including coat proteins, adaptor proteins, fusion factors, fission factors, and Rab effectors. The depletion of 11 factors reduced virus yields by 20- to 100-fold, including three early secretory pathway proteins, four late secretory pathway proteins, and four endocytic pathway proteins, three of which are membrane fission factors. Five of the 11 targets were chosen for further analysis in virus infection, where it was found that the absence of only 1, the fission factor CHMP4C, but not the CHMP4A or CHMP4B paralogues, reduced virus production at the final stage of morphogenesis. Ultrastructural and confocal microscopy of CHMP4C-depleted, HSV1-infected cells showed an accumulation of endocytic membranes; extensive tubulation of recycling, transferrin receptor-positive endosomes indicative of aberrant fission; and a failure in virus envelopment. No effect on the late endocytic pathway was detected, while exogenous CHMP4C was shown to localize to recycling endosomes. Taken together, these data reveal a novel role for the CHMP4C fission factor in the integrity of the recycling endosomal network, which has been unveiled through the dependence of HSV1 on these membranes for the acquisition of their envelopes.IMPORTANCE Cellular transport pathways play a fundamental role in secretion and membrane biogenesis. Enveloped viruses exploit these pathways to direct their membrane proteins to sites of envelopment and, as such, are powerful tools for unraveling subtle activities of trafficking factors, potentially pinpointing therapeutic targets. Using the sensitive biological readout of virus production, over 80 trafficking factors involved in diverse and poorly defined cellular processes have been screened for involvement in the complex process of HSV1 envelopment. Out of 11 potential targets, CHMP4C, a key component in the cell cycle abscission checkpoint, stood out as being required for the process of virus wrapping in endocytic tubules, where it localized. In the absence of CHMP4C, recycling endocytic membranes failed to undergo scission in infected cells, causing transient tubulation and accumulation of membranes and unwrapped virus. These data reveal a new role for this important cellular factor in the biogenesis of recycling endocytic membranes.


Adjoint-based optimization of sound reinforcement including non-uniform flow.
The determination of optimal geometric arrangements and electronic drives of loudspeaker arrays in sound reinforcement applications is an ill-posed inverse problem. This paper introduces an innovative method to determine complex driving functions, also considering complex environmental conditions. As an alternative to common frequency domain methods, the authors present an adjoint-based approach in the time domain: Acoustic sources are optimized in order to generate a given target sound field. Instead of the Helmholtz equation, the full non-linear Euler equations are considered. This enables an easier treatment of non-uniform flow and boundary conditions. As proof of concept, a circular and a linear monopole array are examined. For the latter, the environmental conditions include wind and thermal stratification. For all examples, the method is able to provide appropriate driving functions.


Gene transfers can date the tree of life.
Biodiversity has always been predominantly microbial, and the scarcity of fossils from bacteria, archaea and microbial eukaryotes has prevented a comprehensive dating of the tree of life. Here, we show that patterns of lateral gene transfer deduced from an analysis of modern genomes encode a novel and abundant source of information about the temporal coexistence of lineages throughout the history of life. We use state-of-the-art species tree-aware phylogenetic methods to reconstruct the history of thousands of gene families and demonstrate that dates implied by gene transfers are consistent with estimates from relaxed molecular clocks in Bacteria, Archaea and Eukarya. We present the order of speciations according to lateral gene transfer data calibrated to geological time for three datasets comprising 40 genomes for Cyanobacteria, 60 genomes for Archaea and 60 genomes for Fungi. An inspection of discrepancies between transfers and clocks and a comparison with mammalian fossils show that gene transfer in microbes is potentially as informative for dating the tree of life as the geological record in macroorganisms.


SARS-COV-2 Omicron variants conformationally escape a rare quaternary antibody binding mode.
The ongoing evolution of SARS-CoV-2 into more easily transmissible and infectious variants has provided unprecedented insight into mutations enabling immune escape. Understanding how these mutations affect the dynamics of antibody-antigen interactions is crucial to the development of broadly protective antibodies and vaccines. Here we report the characterization of a potent neutralizing antibody (N3-1) identified from a COVID-19 patient during the first disease wave. Cryogenic electron microscopy revealed a quaternary binding mode that enables direct interactions with all three receptor-binding domains of the spike protein trimer, resulting in extraordinary avidity and potent neutralization of all major variants of concern until the emergence of Omicron. Structure-based rational design of N3-1 mutants improved binding to all Omicron variants but only partially restored neutralization of the conformationally distinct Omicron BA.1. This study provides new insights into immune evasion through changes in spike protein dynamics and highlights considerations for future conformationally biased multivalent vaccine designs.


Community-Based Preventive Interventions for Depression and Anxiety in Women.
Depression and anxiety are the most common mental disorders and currently, they constitute one of the main causes of disability and death. The high prevalence of psychiatric disorders and their increasing burden are noteworthy. The aim of this study is to investigate the effectiveness of community-based preventive interventions for depression and anxiety in women. We systematically searched for articles published up to the beginning of 2018, which addressed community-based preventive interventions for depression and anxiety in women. The studies were searched in PubMed, Scopus, Cochrane Library, Web of Science, PsycInfo, IranMedex, SID and EMBASE electronic databases. Articles that complied with our inclusion criteria (preventive interventions involving healthy adult women aged 18 to 65 years) were reviewed. Quality assessment of the articles was performed using standard tools. We extracted the required data and reported the results in a narrative form. Twenty-three articles were identified and entered into the final review. Depression and anxiety symptoms were decreased in more than 70% of interventions. Cognitive behavioral therapy (CBT) and exercise were the most effective interventions. In addition, computer and internet-based programs had positive outcomes in both categories of depression and anxiety. Community-based preventive programs for depression and anxiety in women had promising and positive results. CBT and exercise were the most effortless, yet the most effective interventions to apply. Computer and internet-based programs had the benefit of covering many people simultaneously. These interventions are cost-effective and feasible among Iranian women.


Randomized trial of adjuvant tamoxifen and/or goserelin in premenopausal breast cancer--self-rated physiological effects and symptoms.
After primary surgery, 149 premenopausal breast cancer patients, with node-negative disease, were randomized to one of four treatment groups: goserelin, tamoxifen, goserelin plus tamoxifen or to a systematically untreated control group. The aim was to assess the effects of adjuvant endocrine therapy in terms of physical symptoms and perception of anxiety and depressive symptoms. Assessments were made before randomization, at 3-4 months and at 12 months. Treatment with goserelin resulted in early and more intense menopausal symptoms, while the effects of tamoxifen were slower and milder. The side effects with goserelin appeared to be alleviated by concurrent tamoxifen except for vasomotor symptoms (hot flashes, sweating, feeling warm). No significant group differences were found for anxiety and depressive symptoms. In conclusion, chemical castration with goserelin was associated with the highest level of physical symptoms. The group treated with tamoxifen alone showed the lowest levels of symptoms among the treatment groups, except for vaginal discharge and irregular bleedings.


Acting performance and flow state enhanced with sensory-motor rhythm neurofeedback comparing ecologically valid immersive VR and training screen scenarios.
Actors were trained in sensory-motor rhythm (SMR) neurofeedback interfaced with a computer rendition of a theatre auditorium. Enhancement of SMR led to changes in the lighting while inhibition of theta and high beta led to a reduction in intrusive audience noise. Participants were randomised to a virtual reality (VR) representation in a ReaCTor, with surrounding image projection seen through glasses, or to a 2D computer screen, which is the conventional neurofeedback medium. In addition there was a no-training comparison group. Acting performance was evaluated by three experts from both filmed, studio monologues and Hamlet excerpts on the stage of Shakespeare's Globe Theatre. Neurofeedback learning reached an asymptote earlier as did identification of the required mental state following training in the ReaCTor training compared with the computer screen, though groups reached the same asymptote. These advantages were paralleled by higher ratings of acting performance overall, well-rounded performance, and especially the creativity subscale including imaginative expression, conviction and characterisation. On the Flow State scales both neurofeedback groups scored higher than the no-training controls on self-ratings of sense of control, confidence and feeling at-one. This is the first demonstration of enhancement of artistic performance with eyes-open neurofeedback training, previously demonstrated only with eyes-closed slow-wave training. Efficacy is attributed to psychological engagement through the ecologically relevant learning context of the acting-space, putatively allowing transfer to the real world otherwise achieved with slow-wave training through imaginative visualisation. The immersive VR technology was more successful than a 2D rendition.


Synergistic Effect of Dazomet Soil Fumigation and Clonostachys rosea Against Cucumber Fusarium Wilt.
Soil fumigation and biological control are two control measures frequently used against soilborne diseases. In this study, the chemical fumigant dazomet was applied in combination with the biocontrol agent (BCA) Clonostachys rosea 67-1 to combat cucumber wilt caused by Fusarium oxysporum f. sp. cucumerinum KW2-1. When the mycoparasite C. rosea 67-1 was applied after dazomet fumigation, disease control reached 100%, compared with 88.1 and 69.8% for dazomet and 67-1 agent, respectively, applied alone, indicating a synergistic effect of dazomet and C. rosea in combating cucumber Fusarium wilt based on analysis of Bliss Independence. To understand the synergistic mechanism, the effects of chemical fumigation on the colonization potential and activity of F. oxysporum f. sp. cucumerinum, and the interaction between the BCA and the pathogen were investigated. The results showed that growth of the pathogen decreased with increasing dazomet concentration subsequent to fumigation. When exposed to dazomet at 100 ppm, the fungal sporulation rate decreased by 94.4%. Severe damage was observed in fumigated isolates using scanning electron microscopy. In the greenhouse, disease incidence of cucumber caused by fumigated F. oxysporum f. sp. cucumerinum significantly decreased. Whereas germination of C. rosea 67-1 spores increased by >sixfold in fumigated soil, and its ability to parasitize fumigated F. oxysporum f. sp. cucumerinum significantly increased (P = 0.014).


A Phase II Trial on Osimertinib as a First-Line Treatment for EGFR Mutation-Positive Advanced NSCLC in Elderly Patients: The SPIRAL-0 Study.
Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear. This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis. Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).


Mental Health Literacy, Attitudes to Help Seeking, and Perceived Need as Predictors of Mental Health Service Use: A Longitudinal Study.
Many people with mental health problems do not use mental health care, resulting in poorer clinical and social outcomes. Reasons for low service use rates are still incompletely understood. In this longitudinal, population-based study, we investigated the influence of mental health literacy, attitudes toward mental health services, and perceived need for treatment at baseline on actual service use during a 6-month follow-up period, controlling for sociodemographic variables, symptom level, and a history of lifetime mental health service use. Positive attitudes to mental health care, higher mental health literacy, and more perceived need at baseline significantly predicted use of psychotherapy during the follow-up period. Greater perceived need for treatment and better literacy at baseline were predictive of taking psychiatric medication during the following 6 months. Our findings suggest that mental health literacy, attitudes to treatment, and perceived need may be targets for interventions to increase mental health service use.


The Importance of Multidisciplinary Approach in Early Detection of BAP1 Tumor Predisposition Syndrome: Clinical Management and Risk Assessment.
Germline BAP1 (BRCA1-associated protein-1) mutations are involved into a novel specific cancer syndrome and strictly associated with a high cancer susceptibility. Recent data suggest that BAP1 has activity toward target substrates explaining why loss of BAP1 causes a pro-tumorigenic deregulation of gene expression. The recently published data reviewed raise the hypothesis that BAP1 regulates a common subset of substrates, which in turn causes a pro-tumorigenic deregulation of gene expression, and alternatively suggest the role of BAP1 as tumorigenesis suppressor/promoter also by independent mechanisms. The clinical phenotype of BAP1 alterations includes MBAITs (melanocytic BAP1-mutated atypical intradermal tumors), uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), mesothelioma (MM), and possibly several other tumors. In clinical practice, early diagnosis is crucial for curative resection of all these tumor types. The uniformed and unambiguous definition of MBAITs as clinical/pathological predictive markers could provide physicians means to identify patients who may carry germline BAP1 mutations and thus could be at high risk of developing CM, UM, MM, RCC, and possibly other tumors. As part of a novel multidisciplinary approach, physicians, pathologists, and clinicians involved into diagnostics should be aware of the histological features and the spectrum of tumors associated with BAP1 loss. Further clinical, epidemiological, and functional studies are required to fully explain the roles of BAP1 and its interaction partners in neoplasia, to define mechanisms behind shared and non-shared clinical and pathological criteria.


Poly(A)-specific ribonuclease (PARN): an allosterically regulated, processive and mRNA cap-interacting deadenylase.
Deadenylation of eukaryotic mRNA is a mechanism critical for mRNA function by influencing mRNA turnover and efficiency of protein synthesis. Here, we review poly(A)-specific ribonuclease (PARN), which is one of the biochemically best characterized deadenylases. PARN is unique among the currently known eukaryotic poly(A) degrading nucleases, being the only deadenylase that has the capacity to directly interact during poly(A) hydrolysis with both the m(7)G-cap structure and the poly(A) tail of the mRNA. In short, PARN is a divalent metal-ion dependent poly(A)-specific, processive and cap-interacting 3'-5' exoribonuclease that efficiently degrades poly(A) tails of eukaryotic mRNAs. We discuss in detail the mechanisms of its substrate recognition, catalysis, allostery and processive mode of action. On the basis of biochemical and structural evidence, we present and discuss a working model for PARN action. Models of regulation of PARN activity by trans-acting factors are discussed as well as the physiological relevance of PARN.


Evolutionary history of Indian Ocean nycteribiid bat flies mirroring the ecology of their hosts.
Bats and their parasites are increasingly investigated for their role in maintenance and transmission of potentially emerging pathogens. The islands of the western Indian Ocean hold nearly 50 bat species, mostly endemic and taxonomically well studied. However, investigation of associated viral, bacterial, and external parasites has lagged behind. In the case of their ectoparasites, more detailed information should provide insights into the evolutionary history of their hosts, as well as pathogen cycles in these wild animals. Here we investigate species of Nycteribiidae, a family of obligate hematophagous wingless flies parasitizing bats. Using morphological and molecular approaches, we describe fly species diversity sampled on Madagascar and the Comoros for two cave-roosting bat genera with contrasting ecologies: Miniopterus and Rousettus. Within the sampling area, 11 endemic species of insect-feeding Miniopterus occur, two of which are common to Madagascar and Comoros, while fruit-consuming Rousettus are represented by one species endemic to each of these zones. Morphological and molecular characterization of flies reveals that nycteribiids associated with Miniopterus bats comprise three species largely shared by most host species. Flies of M. griveaudi, one of the two bats found on Madagascar and certain islands in the Comoros, belong to the same taxon, which accords with continued over-water population exchange of this bat species and the lack of inter-island genetic structuring. Flies parasitizing Rousettus belong to two distinct species, each associated with a single host species, again in accordance with the distribution of each endemic bat species.


Smoking in schizophrenia: diagnostic specificity, symptom correlates, and illness severity.
Cigarette smoking was consistently found to be more prevalent in individuals with schizophrenia than in other psychiatric groups and the general population. These findings have been interpreted as evidence of a specific association between schizophrenia and smoking. However, the supporting data come primarily from cross-sectional studies, which are susceptible to confounding. Our aim was to test specificity of this link longitudinally in an epidemiologic sample. A cohort of 542 inpatients with psychosis was followed for 10 years after first hospitalization, completing 5 face-to-face interviews. Assessments included ratings of specific symptoms (psychotic, negative, disorganized, and depressive), Global Assessment of Functioning, and a categorical measure of cigarette consumption. All participants were assigned longitudinal consensus diagnoses by study psychiatrists, and 229 were diagnosed with schizophrenia spectrum disorders (SZ). At baseline, 52.4% of participants were current smokers and 69.3% were lifetime smokers. Smoking rates did not differ among the diagnostic groups (schizophrenia spectrum, major depressive, bipolar, or other psychotic disorder) at any assessment point. Smokers were more severely ill than nonsmokers but did not differ in specific symptoms either cross-sectionally or longitudinally. Among smokers, changes in cigarette consumption were linked only with changes in depression (beta = .16, P < .001). Rates of smoking were elevated in subjects with schizophrenia but were just as high with other psychotic disorders. Smoking was not associated with psychotic symptoms, but cigarette consumption covaried with depression over time. Given the devastating health consequences of cigarette use, smoking cessation interventions are urgently needed in this population and should specifically address depression.


Malignancy in perinatally human immunodeficiency virus-infected children in the United States.
To determine the incidence of and factors associated with malignancy in perinatally human immunodeficiency virus (HIV)-infected children in the United States. Included were 2969 children followed in the Pediatric AIDS Clinical Trials Group (PACTG) 219/219C cohort from 1993 through 2003. Cancer incidence by sex, race, age, histology and highly active antiretroviral therapy (HAART) era (pre-HAART, 1993-1997; HAART, 1998-2003) was estimated, and the standardized incidence ratio contrasting infected and uninfected children was determined. Poisson regression was used to further investigate the relation between HAART use (> or =3 drugs of > or =2 classes, 1 of which was a protease inhibitor), CD4% and cancer. There were 37 cancers (17 prevalent and 20 incident) diagnosed in 2969 children for a prevalence of 0.6% [95% confidence interval (CI), 0.3, 0.9] and an incidence of 1.56/1000 person-years (95% CI 0.95, 2.41). Compared with uninfected children, the standardized incidence ratio was 10.08 (95% CI 5.87, 16.14). Incidence did not significantly differ by sex, race, age or HAART era. Of the cases, 35% were immunocompetent (CD4 > or =25%), 25% were moderately immunosuppressed (15%< or = CD4 < or =24%) and 40% were severely immunosuppressed (CD4 <15%) at diagnosis. In multivariate regression, the cancer rate was 3.09 (95% CI 1.22, 7.85) times higher in children with < or =2 years of HAART use than in children with >2 years of HAART and 3.20 (95% CI 1.32, 7.76) times higher in children with CD4 <15% at cohort enrollment than in children with CD4 > or =15%. Cancer incidence in this U.S. pediatric cohort was lower than that of European cohorts but was markedly higher than that of HIV-uninfected children. Cancer incidence was highest in children who were severely immunosuppressed and in children who received HAART for < or =2 years.


Differential Patterns of Delayed Emotion Circuit Maturation in Abused Girls With and Without Internalizing Psychopathology.
Childhood abuse represents one of the most potent risk factors for developing psychopathology, especially in females. Evidence suggests that exposure to early-life adversity may be related to advanced maturation of emotion processing neural circuits. However, it remains unknown whether abuse is related to early circuit maturation and whether maturation patterns depend on the presence of psychopathology. A multisite sample of 234 girls (ages 8-18 years) completed clinical assessment, maltreatment histories, and high-resolution T1-weighted structural MRI. Girls were stratified by abuse history and internalizing disorder diagnosis into typically developing (no abuse/no diagnosis), resilient (abuse/no diagnosis), and susceptible (abuse/current diagnosis) groups. Machine learning models of normative brain development were aggregated in a stacked generalization framework trained to predict chronological age using gray matter volume in whole-brain, emotion, and language circuit parcellations. Brain age gap estimations (BrainAGEs; predicted age minus true chronological age) were calculated as indices of relative circuit maturation. Childhood abuse was related to reduced BrainAGE (delayed maturation) specific to emotion circuits. Delayed emotion circuit BrainAGE was further related to increased hyperarousal symptoms. Childhood physical neglect was associated with increased whole-brain BrainAGE (advanced maturation). Neural contributors to emotion circuit BrainAGE differed in girls with and without an internalizing diagnosis, especially in the lateral prefrontal, parietal, and insular cortices and the hippocampus. Abuse exposure in girls is associated with a delayed structural maturation pattern specific to emotion circuitry, a potentially adaptive mechanism enhancing threat generalization. Physical neglect, on the other hand, is associated with a broader brain-wide pattern of advanced structural maturation. The differential influence of fronto-parietal cortices and the hippocampus on emotion circuit maturity in resilient girls may represent neurodevelopmental markers of reduced psychiatric risk following abuse.


What style of leadership do women in STEMM fields perform? Findings from an international survey.
It is widely acknowledged that women in science, technology, engineering, mathematics, and medicine (STEMM) fields are underrepresented in leadership globally. However, little is known about how leadership styles of women in STEMM relate to this underrepresentation. This article discusses findings from a survey examining how 61 women in STEMM define leadership and describe their own leadership styles. Using content analysis and drawing on Full Range Leadership Model factors, findings suggest that women define leadership and describe their own leadership styles using transformational factors. However, there was no consistency in how participants defined ideal leadership or how they defined their own leadership styles. This finding unsettles ideas of distinctly gendered leadership styles. We argue that expectations that leadership will be performed in distinctly gendered styles may be contributing to the underrepresentation of women in leadership roles in STEMM.


Influence of bursectomy on bone growth and anemia induced by avian osteopetrosis viruses.
This study examines the contribution of the bursa of Fabricius to the pathogenic manifestations of two myeloblastosis-associated viruses which primarily cause osteopetrosis [MAV-1(O) and MAV-2(O)]. MAV-2(O) infection of surgically bursectomized 1-month-old chicks resulted in a rapidly fatal anemia whereas infection of untreated chicks of the same age resulted in a transient drop in hematocrit. Surgical bursectomy of embryos before or after embryonal infection with MAV-2(O) did not alter the course of osteopetrosis, indicating that the bursa was not a source of target cells. Bursectomy prolonged the period of susceptibility to MAV-2(O) induced osteopetrosis until one day posthatching; untreated chicks were not susceptible to osteopetrosis induction at that age. MAV-1(O) infection of eight-day-old bursectomized chicks resulted in osteopetrosis in the absence of anemia; untreated eight-day-old chicks infected with MAV-1(O) showed no effects of virus infection. A role for the bursa in MAV-2(O) infection was found in the participation of neutralizing antibodies in the recovery from anemia. A single dose of antiviral antibody was found to prevent the appearance of anemia. The protective effect of antiviral antibody was dose dependent, and antiserum administration had to be initiated within three days after virus in order to be effective. Antiviral antibody against MAV-1(O) did not protect against MAV-2(O)-induced anemia, suggesting subgroup specificity. These results suggest that the bursa does not provide a stem cell which participates in the bone hyperplasia induced by MAV-1(O) and MAV-2(O). Rather, the humoral antibodies provided by cells derived from the bursa may serve to eliminate viremia and limit virus-specific cytopathogenic effects.


Cognition, symptom perception, and medication non-adherence in older adults with asthma.
Cognitive impairment (CI) is highly prevalent in elderly asthmatics and is associated with worse asthma self-management (SM) and outcomes. CI may also explain why older adults may under-perceive asthma symptoms. We hypothesized that CI would be associated with low medication adherence and asthma symptom under-perception (ASP). We also hypothesized that ASP would mediate the relationship between CI and medication adherence. Participants of this longitudinal cohort study were asthmatics (N = 334) ≥60 years (51% Hispanic, 25% Black). Cognitive measures assessed general cognition, attention, processing speed, executive functioning, memory, and language. Measures of SM were self-reported and electronically measured adherence to controller medications. ASP was assessed for 6 weeks by participants entering estimates of peak expiratory flow (PEF) into a programmable peak flow meter, followed by PEF blows. Participants were blinded to actual PEF values. Percentage of time that participants were in the over-perception zone was calculated as an average. In regression analyses, those with impairments in memory and general cognition had lower odds ratios (OR) for self-reported non-adherence (OR: 0.96, 95% CI 0.93 - 0.98 & OR: 0.90, 95% CI 0.83 - 0.96, respectively). CI was not associated with electronically measured non-adherence or ASP. In structural equation modeling, while CI was associated with adherence (β = 0.04, SE = 0.021, p = 0.04), ASP did not mediate this relationship. While results confirmed the importance of cognition in asthma SM, these findings were not linked to ASP. Future analyses are needed to understand the role of confounding factors.


Sensory Deprivation and Visual Speed: An Analysis.
Speeds of moving objects were markedly underestimated by human observers after prolonged patternless visual stimulation. Even greater underestimation followed exposure to a "noisy" visual field; on the other hand, exposure to a hyperstable field caused overestimation. The effects of external visual noise simulate those of deprivation; this finding suggests that similarly disordered but spontaneous neural discharge dominates the visual nervous system in deprivation.


Cerebrovascular diseases in nuclear workers first employed at the Mayak PA in 1948-1972.
Incidence and mortality from cerebrovascular diseases (CVD) (430-438 ICD-9 codes) have been studied in a cohort of 18,763 workers first employed at the Mayak Production Association (Mayak PA) in 1948-1972 and followed up to the end of 2005. Some of the workers were exposed to external gamma-rays only while others were exposed to a mixture of external gamma-rays and internal alpha-particle radiation due to incorporated (239)Pu. After adjusting for non-radiation factors, there were significantly increasing trends in CVD incidence with total absorbed dose from external gamma-rays and total absorbed dose to liver from internal alpha radiation. The CVD incidence was statistically significantly higher among workers with total absorbed external gamma-ray doses greater than 0.20 Gy compared to those exposed to lower doses; the data were consistent with a linear trend in risk with external dose. The CVD incidence was statistically significantly higher among workers with total absorbed internal alpha-radiation doses to liver from incorporated (239)Pu greater than 0.025 Gy compared to those exposed to lower doses. There was no statistically significant trend in CVD mortality risk with either external gamma-ray dose or internal alpha-radiation dose to liver. The risk estimates obtained are generally compatible with those from other large occupational studies, although the incidence data point to higher risk estimates compared to those from the Japanese A-bomb survivors. Further studies of the unique cohort of Mayak workers chronically exposed to external and internal radiation will allow improving the reliability and validating the radiation safety standards for occupational and public exposure.


Synaptic transmission and the susceptibility of HIV infection to anti-viral drugs.
Cell-to-cell viral transmission via virological synapses has been argued to reduce susceptibility of the virus population to anti-viral drugs through multiple infection of cells, contributing to low-level viral persistence during therapy. Using a mathematical framework, we examine the role of synaptic transmission in treatment susceptibility. A key factor is the relative probability of individual virions to infect a cell during free-virus and synaptic transmission, a currently unknown quantity. If this infection probability is higher for free-virus transmission, then treatment susceptibility is lowest if one virus is transferred per synapse, and multiple infection of cells increases susceptibility. In the opposite case, treatment susceptibility is minimized for an intermediate number of virions transferred per synapse. Hence, multiple infection via synapses does not simply lower treatment susceptibility. Without further experimental investigations, one cannot conclude that synaptic transmission provides an additional mechanism for the virus to persist at low levels during anti-viral therapy.


The three-dimensional structure of mammalian ribonucleotide reductase protein R2 reveals a more-accessible iron-radical site than Escherichia coli R2.
The three-dimensional structure of mouse ribonucleotide reductase R2 has been determined at 2.3 A resolution using molecular replacement and refined to an R-value of 19.1% (Rfree = 25%) with good stereo-chemistry. The overall tertiary structure architecture of mouse R2 is similar to that from Escherichia coli R2. However, several important structural differences are observed. Unlike the E. coli protein, the mouse dimer is completely devoid of beta-strands. The sequences differ significantly between the mouse and E. coli R2s, but there is high sequence identity among the eukaryotic R2 proteins, and the identities are localized over the whole sequence. Therefore, the three-dimensional structures of other mammalian ribonucleotide reductase R2 proteins are expected to be very similar to that of the mouse enzyme. In mouse R2 a narrow hydrophobic channel leads to the proposed binding site for molecular oxygen near to the iron-radical site in the interior of the protein. In E. coli R2 this channel is blocked by the phenyl ring of a tyrosine residue, which in mouse R2 is a serine. These structural variations may explain the observed differences in sensitivity to radical scavengers. The structure determination is based on diffraction data from crystals grown at pH 4.7. Unexpectedly, the protein is not iron-free, but contains one iron ion bound at one of the dinuclear iron sites. This ferric ion is bound with partial occupancy and is coordinated by three glutamic acids (one bidentate) and one histidine in a bipyramidal coordination that has a free apical coordination position. Soaking of crystals in a solution of ferrous salt at pH 4.7 increased the occupancy on the already occupied site, but without any detectable binding at the second site.


Evaluating the Impact of Applying Personal Glucose Targets in a Closed-Loop System for People With Type 1 Diabetes.
CamAPS FX is a hybrid closed-loop smartphone app used to manage type one diabetes. The closed-loop algorithm has a default target glucose of 5.8 mmol/L (104.5 mg/dL), but users can select personal glucose targets (adjustable between 4.4 mmol/L and 11.0 mmol/L [79 mg/dL and 198 mg/dL, respectively]). In this post-hoc analysis, we evaluated the impact of personal glucose targets on glycemic control using data from participants in five randomized controlled trials. Personal glucose targets were widely used, with 20.3% of all days in the data set having a target outside the default target bin (5.5-6.0 mmol/L [99-108 mg/dL]). Personal glucose targets >6.5 mmol/L (117 mg/dL) were associated with significantly less time in target range (3.9-10.0 mmol/L [70-180 mg/dL]; 6.5-7.0 mmol/L [117-126 mg/dL]: mean difference = -3.2 percentage points [95% CI: -5.3 to -1.2; P < .001]; 7.0-7.5 mmol/L [126-135 mg/dL]: -10.8 percentage points [95% CI: -14.1 to -7.6; P < .001]). Personal targets >6.5 mmol/L (117 mg/dL) were associated with significantly lower time (<3.9 mmol/L [<70 mg/dL]; 6.5-7.0 mmol/L [117-126 mg/dL]: -1.85 percentage points [95% CI: -2.37 to -1.34; P < .001]; 7.0-7.5 mmol/L [126-135 mg/dL]: -2.68 percentage points [95% CI: -3.49 to -1.86; P < .001]). Discrete study populations showed differences in glucose control when applying similar personal targets.


[Dynamics of formation of individual enzymes of the proteolytic complex during cultivation of Streptomyces griseus].
The activity of the following peptide hydrolases was studied in the course of submerged cultivation of Streptomyces griseus: proteinases (decomposing casein, benzoyl-arginine-ethyl ester, benzoyl-arginine-p-nitroanilide), carboxypeptidases, aminopeptidases, aminotripeptidases and dipeptidases (decomposing carbobenzoxy-glycyl-leucine, leucyl-glycyl-glycine, triglycine, glycyl-leucine, and glycyl-glycine). The dynamics of production differs among individual enzymes of the complex of peptide hydrolases, suggesting that they are not synthesized at the same time. The ratio between proteases in the cultural broth varies in the course of growth; therefore, the preparations with different types of action prevailing (proteinase, peptidase, etc.) can be obtained. Comparatively small changes in the composition of the medium caused considerable modifications in the processes of synthesis of peptide hydrolase and in their quantities. The overall proteolytic activity increased by a factor of 1.6 to 2.5 when the fermentation was prolonged from 120 hours to 160 to 180 hours. The most pronounced was an increase in the activity of proteinases and aminopeptidase decomposing leucyl-glycyl-glycine. These enzymes seem to be the most important in the action of the protease complex of Str. griseus.


Molecular interactions at the hexadecane/water interface in the presence of surfactants studied with second harmonic generation.
It is important to investigate the influence of surfactants on structures and physical/chemical properties of oil/water interfaces. This work reports a second harmonic generation study of the adsorption of malachite green (MG) on the surfaces of oil droplets in a hexadecane/water emulsion in the presence of surfactants including sodium dodecyl sulfate, polyoxyethylene-sorbitan monooleate (Tween80), and cetyltrimethyl ammonium bromide. It is revealed that surfactants with micromolar concentrations notably influence the adsorption of MG at the oil/water interface. Both competition adsorption and charge-charge interactions played very important roles in affecting the adsorption free energy and the surface density of MG at the oil/water interface. The sensitive detection of the changing oil/water interface with the adsorption of surfactants at such low concentrations provides more information for understanding the behavior of these surfactants at the oil/water interface.


Portal osmopressor mechanism linked to transient receptor potential vanilloid 4 and blood pressure control.
Human subjects with impaired baroreflex function cannot buffer rises or falls in blood pressure (BP), thus allowing BP effects of endogenous or environmental stimuli that previously escaped detection to emerge dramatically. Studies in these patients led us to discover that water ingestion induced a robust increase in BP and vascular resistance. Here, using a mouse model of baroreflex impairment, we show that the increase in blood pressure after water ingestion is mediated through sympathetic nervous system activation and that the osmosensitive transient receptor potential vanilloid 4 channel (Trpv4) is an essential component of the response. Although portal osmolality decreases after water ingestion in both wild-type and Trpv4(-/-) mice, only the wild-type animals show a pressor response. The same volume of physiological saline does not elicit an increase in BP, suggesting osmolality as the stimulus. The osmopressor response to water, and Trpv4 thus represent new factors now implicated in the physiology of BP regulation.


HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation.
HIV type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 as coreceptors for entry into target cells. Here we show that the HIV-1 envelope gp120 (Env) activates multiple ionic signaling responses in primary human macrophages, which are important targets for HIV-1 in vivo. Env from both CCR5-dependent JRFL (R5) and CXCR4-dependent IIIB (X4) HIV-1 opened calcium-activated potassium (K(Ca)), chloride, and calcium-permeant nonselective cation channels in macrophages. These signals were mediated by CCR5 and CXCR4 because macrophages lacking CCR5 failed to respond to JRFL and an inhibitor of CXCR4 blocked ion current activation by IIIB. MIP-1beta and SDF-1alpha, chemokine ligands for CCR5 and CXCR4, respectively, also activated K(Ca) and Cl(-) currents in macrophages, but nonselective cation channel activation was unique to gp120. Intracellular Ca(2+) levels were also elevated by gp120. The patterns of activation mediated by CCR5 and CXCR4 were qualitatively similar but quantitatively distinct, as R5 Env activated the K(Ca) current more frequently, elicited Cl(-) currents that were approximately 2-fold greater in amplitude, and elevated intracellular Ca(+2) to higher peak and steady-state levels. Env from R5 and X4 primary isolates evoked similar current responses as the corresponding prototype strains. Thus, the interaction of HIV-1 gp120 with CCR5 or CXCR4 evokes complex and distinct signaling responses in primary macrophages, and gp120-evoked signals differ from those activated by the coreceptors' chemokine ligands. Intracellular signaling responses of macrophages to HIV-1 may modulate postentry steps of infection and cell functions apart from infection.


Fundoplication wrap disruption: an experimental study in rats.
Antireflux surgery usually gives long lasting control of gastroesophageal reflux disease, but late failures can occur from fundoplication wrap disruption. Disruption presumably occurs when physiological mechanical stresses cause the sutures to pull out of the fundoplication wrap. We hypothesized that complete fundoplications (fundus sutured to fundus) would withstand disruptive forces better than partial fundoplications (fundus sutured to esophagus). Forty-eight rats underwent fundoplication (24 partial and 24 complete). Fundoplication wraps were disrupted by distending the stomach (bursting pressure technique) and by distracting the wrap in a tensiometer (breaking strength technique). Bursting pressures were similar in the partial (103.7 +/- 13.5 mmHg) and complete (100.5 +/- 13.1 mmHg) fundoplication wraps (P = 0.93, not significant). In both groups, all disruptions occurred by sutures tearing through the stomach wall. Breaking strength was also equivalent for the two types of wrap. Partial wraps disrupted at 6.69 +/- 1.49 N and complete wraps disrupted at 6.52 +/- 1.28 N (P = 0.77, not significant). Sutures tore out of the stomach side of the partial wrap in five rats and out of the esophagus in the other seven rats with partial wraps. Disruption occurred by sutures tearing through the stomach in all rats with complete fundoplications. This experimental study in the rat did not show any difference in the ability of partial and complete fundoplication wraps to withstand disruptive forces.


A short-term cost-effectiveness study comparing robot-assisted laparoscopic and open retropubic radical prostatectomy.
To evaluate cost effectiveness and cost utility comparing robot-assisted laparoscopic prostatectomy (RALP) versus retropubic radical prostatectomy (RRP). In a retrospective cohort study a total of 231 men between the age of 50 and 69 years and with clinically localised prostate cancer underwent radical prostatectomy (RP) at the Department of Urology, Aarhus University Hospital, Skejby from 1 January 2004 to 31 December 2007, were included. The RALP and RRP patients were matched 1:2 on the basis of age and the D'Amico Risk Classification of Prostate Cancer; 77 RALP and 154 RRP. An economic evaluation was made to estimate direct costs of the first postoperative year and an incremental cost-effectiveness ratio (ICER) per successful surgical treatment and per quality-adjusted life-year (QALY). A successful RP was defined as: no residual cancer (PSA <0.2 ng/ml, preserved urinary continence and erectile function. A one-way sensitivity analysis was made to investigate the impact of changing one variable at a time. The ICER per extra successful treatment was €64,343 using RALP. For indirect costs, the ICER per extra successful treatment was €13,514 using RALP. The difference in effectiveness between RALP and RRP procedures was 7% in favour of RALP. In the present study no QALY was gained 1 year after RALP, however this result is uncertain due to a high degree of missing data. The sensitivity analysis did not change the results noticeably. The study was limited by the design resulting in a low percentage of information on the effect of medication for erectile dysfunction and only short-term quality of life was measured at 1 year postoperatively. RALP was more effective and more costly. A way to improve the cost effectiveness may be to perform RALP at fewer high volume urology centres and utilise the full potential of each robot.


Annurca apple polyphenol extract promotes mesenchymal-to-epithelial transition and inhibits migration in triple-negative breast cancer cells through ROS/JNK signaling.
Aberrant activation of epithelial-to-mesenchymal transition has been shown to correlate with triple-negative breast cancer (TNBC) progression and metastasis. Thus, the induction of the reverse process might offer promising opportunities to restrain TNBC metastatic spreading and related mortality. Recently, the Annurca apple polyphenol extract (APE) has been highlighted as a multi-faceted agent that selectively kills TNBC cells by ROS generation and sustained JNK activation. Here, by qualitatively and quantitatively monitoring the real-time movements of live cells we provided the first evidence that APE inhibited the migration of MDA-MB-231 and MDA-MB-468 TNBC cells and downregulated metalloproteinase-2 and metalloproteinase-9. In MDA-MB-231 cells APE decreased SMAD-2/3 and p-SMAD-2/3 levels, increased E-cadherin/N-cadherin protein ratio, induced the switch from N-cadherin to E-cadherin expression and greatly reduced vimentin levels. Confocal and scanning electron microscopy imaging of APE-treated MDA-MB-231 cells evidenced a significant cytoskeletal vimentin and filamentous actin reorganization and revealed considerable changes in cell morphology highlighting an evident transition from the mesenchymal to epithelial phenotype with decreased migratory features. Notably, all these events were reverted by N-acetyl-L-cysteine and JNK inhibitor SP600125 furnishing evidence that APE exerted its effects through the activation of ROS/JNK signaling. The overall data highlighted APE as a potential preventing agent for TNBC metastasis.


COVID-19 Vaccination Among Diverse Population Groups in the Northern Governorates of Iraq.
Objectives: The present study was carried out to investigate COVID-19 vaccination coverage among populations of internally displaced persons (IDPs), refugees, and host communities in northern Iraq and the related underlying factors. Methods: Through a cross-sectional study conducted in five governorates in April-May 2022, 4,564 individuals were surveyed. Data were collected through an adapted questionnaire designed to gather data on participants. Results: 4,564 subjects were included (59.55% were 19-45 years old; 54.51% male). 50.48% of the participants (51.49% of host communities, 48.83% of IDPs, and 45.87% of refugees) had been vaccinated with at least one dose of COVID-19 vaccine. 40.84% of participants (42.28% of host communities, 35.75% of IDPs, and 36.14% of refugees) had been vaccinated by two doses, and 1.56% (1.65% of host communities, 0.93% of IDPs, and 1.46% of refugees) were vaccinated with three doses. Conclusion: Sociodemographic factors including age, gender, education, occupation, and nationality could affect vaccination coverage. Moreover, higher acceptance rate of vaccination is associated with belief in vaccine safety and effectiveness and trust in the ability of the vaccine to prevent complications.


Can the clinical examination diagnose left-sided heart failure in adults?
We systematically reviewed the literature to ascertain how well clinicians determine the probability and type of left-sided heart failure in their patients. Left-sided heart failure is characterized by decreased left ventricular ejection fraction or increased filling pressure. The type of heart failure determines optimal treatment. Systolic dysfunction exists when ejection fraction is reduced. Diastolic dysfunction is presumed to be present when filling pressure is increased with a normal ejection fraction and without another explanatory diagnosis. Many findings are associated with heart failure, and wide variation exists in clinicians' ability to detect these findings. The best findings for detecting increased filling pressure are jugular venous distention and radiographic redistribution. The best findings for detecting systolic dysfunction are abnormal apical impulse, radiographic cardiomegaly, and q waves or left bundle branch block on an electrocardiogram. Diastolic dysfunction is especially difficult to diagnose, but is associated with an elevated blood pressure during heart failure.


Leaping forward in amphibian health and nutrition.
The Epidemiology Working Group, a subgroup of the participants of the Disney's Animal Kingdom Workshop on "Ex situ Amphibian Medicine and Nutrition," identified a critical need to design and implement approaches that will facilitate the assessment and evaluation of factors impacting amphibian health. In this manuscript, we describe and summarize the outcomes of this workshop with regards (a) the identified gaps in knowledge, (b) identified priorities for closing these gaps, and (c) compile a list of actions to address these priorities. Four general areas of improvement were identified in relation to how measurements are currently being taken to evaluate ex situ amphibian health: nutrition, infectious diseases, husbandry, and integrated biology including genetics and endocrinology. The proposed actions that will be taken in order to address the identified gaps include: (1) identify and quantify major health issues affecting ex situ amphibian populations, (2) identify and coordinate laboratories to conduct analyses using standardized and validated protocols to measure nutritional, infectious diseases, genetic, and hormonal parameters, (3) determine in situ baseline distribution of parameters related to amphibian health, and (4) establish an inter-disciplinary research approach to target specific hypotheses related to amphibian health such as the effects of population genetics (e.g., relatedness, inbreeding) on disease susceptibility, or how environmental parameters are related to chronic stress and hormone production. We think is important to address current gaps in knowledge regarding amphibian health in order to increase the probability to succeed in addressing the issues faced by in situ and ex situ amphibians populations. We are confident that the recommendations provided in this manuscript will facilitate to address these challenges and could have a positive impact in both the health of in situ and ex situ amphibian populations, worldwide.


Hemodynamic evoked response of the sensorimotor cortex measured noninvasively with near-infrared optical imaging.
We have performed a noninvasive bilateral optical imaging study of the hemodynamic evoked response to unilateral finger opposition task, finger tactile, and electrical median nerve stimulation in the human sensorimotor cortex. This optical study shows the hemoglobin-evoked response to voluntary and nonvoluntary stimuli. We performed measurements on 10 healthy volunteers using block paradigms for motor, sensory, and electrical stimulations of the right and left hands separately. We analyzed the spatial/temporal features and the amplitude of the optical signal induced by cerebral activation during these three paradigms. We consistently found an increase (decrease) in the cerebral concentration of oxy-hemoglobin (deoxy-hemoglobin) at the cortical side contralateral to the stimulated side. We observed an optical response to activation that was larger in size and amplitude during voluntary motor task compared to the other two stimulations. The ipsilateral response was consistently smaller than the contralateral response, and even reversed (i.e., a decrease in oxy-hemoglobin, and an increase in deoxy-hemoglobin) in the case of the electrical stimulation. We observed a systemic contribution to the optical signal from the increase in the heart rate increase during stimulation, and we made a first attempt to subtract it from the evoked hemoglobin signal. Our findings based on optical imaging are in agreement with results in the literature obtained with positron emission tomography and functional magnetic resonance imaging.


Light-controlled nitric oxide delivering molecular assemblies.
The multiple roles nitric oxide (NO) plays as a bioregulatory, anticancer, antimicrobial and antioxidant agent has triggered an explosive interest in recent years in compounds able to deliver this diatomic radical for therapeutic purposes. A major issue associated with NO donors is the precise control of the NO release, which effect is highly concentration and flux dependent. Light represents a convenient non-invasive on/off trigger to deliver NO on demand since it allows the accurate control of site, timing and dosage. The assembling of NO photodonors through different approaches may lead to intriguing light-responsive molecular constructs including nanostructured films, polymers, gels, nanoparticles and molecular conjugates which exhibit promising potential in view of practical applications. This tutorial review illustrates the recent research from our and other laboratories towards the fabrication of these molecular assemblies, highlighting the logical design and the relevance in the biomedical field. Therefore, this review is aimed to be a source of inspiration for a wide range of scientists belonging to the chemical, materials science and biochemical communities, facing the common challenge of fabricating controllable NO dispensers.