MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway.
Nasopharayngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Here we report frequent downregulation of the microRNA miR-218 in primary NPC tissues and cell lines where it plays a critical role in NPC progression. Suppression of miR-218 was associated with epigenetic silencing of SLIT2 and SLIT3, ligands of ROBO receptors that have been previously implicated in tumor angiogenesis. Exogenous expression of miR-218 caused significant toxicity in NPC cells in vitro and delayed tumor growth in vivo. We used an integrated trimodality approach to identify targets of miR-218 in NPC, cervical, and breast cell lines. Direct interaction between miR-218 and the 3'-untranslated regions (UTR) of mRNAs encoding ROBO1, survivin (BIRC5), and connexin43 (GJA1) was validated in a luciferase-based transcription reporter assay. Mechanistic investigations revealed a negative feedback loop wherein miR-218 regulates NPC cell migration via the SLIT-ROBO pathway. Pleotropic effects of miR-218 on NPC survival and migration were rescued by enforced expression of miR-218-resistant, engineered isoforms of survivin and ROBO1, respectively. In clinical specimens of NPC (n=71), ROBO1 overexpression was significantly associated with worse overall (P=0.04, HR=2.4) and nodal relapse-free survival (P=0.008, HR=6.0). Our findings define an integrative tumor suppressor function for miR-218 in NPC and further suggest that restoring miR-218 expression in NPC might be useful for its clinical management.


The distribution of Na+,K(+)-ATPase and 5A11 antigen in apical microvilli of the retinal pigment epithelium is unrelated to alpha-spectrin.
The retinal pigment epithelium was used to study the relationship between the cortical cytoskeleton and two plasma membrane proteins that associate with it. These proteins were the Na+,K(+)-ATPase, an ion pump, and the 5A11 antigen, a member of the immunoglobulin superfamily of receptor proteins. The cytoskeleton was marked by two of its constituents, alpha-spectrin and ankyrin. Ankyrin links the Na+,K(+)-ATPase to spectrin in many cells. The RPE is of interest, because unlike most epithelia it distributes the Na+,K(+)-ATPase to the apical membrane. The development of polarity was studied during chick embryogenesis. On embryonic day 6 (E6), each of these proteins was observed in the apical and lateral plasma membranes. As development proceeded, only the Na+,K(+)-ATPase was removed from the lateral membranes. Beginning on E12, ankyrin, spectrin and 5A11 appeared together in patches along the basal plasma membrane. By E16, these patches coalesced into a uniform distribution along the basal membrane. At the apical pole, alpha-spectrin appeared near the base of the microvilli, but was undetected in the microvilli themselves. This distribution resembled the distribution of alpha-spectrin in the intestine and proximal kidney tubule. By contrast, a pool of ankyrin and 5A11 and nearly all the Na+,K(+)-ATPase appeared in the microvilli. Despite its segregation from alpha-spectrin, the Na+,K(+)-ATPase appeared to associate with a macromolecular complex, as judged by extraction with Triton X-100. Changes in spectrin distribution could not be related to changes in isoform expression, as only one isoform of beta-spectrin was detected by co-immunoprecipitation with alpha-spectrin. By contrast, multiple ankyrin-like peptides could be identified by immunoblotting. These data illustrate some of the unique properties of RPE microvilli. These properties prevent the Na+,K(+)-ATPase from complexing with the alpha-spectrin-based cytoskeleton by sequestering the enzyme into the compartment where its activity is required.


Zyg-11 and cul-2 regulate progression through meiosis II and polarity establishment in C. elegans.
The mechanisms that ensure coupling between meiotic cell cycle progression and subsequent developmental events, including specification of embryonic axes, are poorly understood. Here, we establish that zyg-11 and the cullin cul-2 promote the metaphase-to-anaphase transition and M phase exit at meiosis II in Caenorhabditis elegans. Our results indicate that ZYG-11 acts with a CUL-2-based E3 ligase that is essential at meiosis II and that functions redundantly with the anaphase-promoting complex/cyclosome at meiosis I. Our data also indicate that delayed M phase exit in zyg-11(RNAi) embryos is due to accumulation of the B type cyclin CYB-3. We demonstrate that PAR proteins and P granules become polarized in an inverted manner during the meiosis II delay resulting from zyg-11 or cul-2 inactivation, and that zyg-11 and cul-2 can regulate polarity establishment independently of a role in cell cycle progression. Furthermore, we find that microtubules appear dispensable for ectopic polarity during the meiosis II delay in zyg-11(RNAi) embryos, as well as for AP polarity during the first mitotic cell cycle in wild-type embryos. Our findings suggest a model in which a CUL-2-based E3 ligase promotes cell cycle progression and prevents polarity establishment during meiosis II, and in which the centrosome acts as a cue to polarize the embryo along the AP axis after exit from the meiotic cell cycle.


Reduced end-systolic pressure-volume ratio response to exercise: a marker of subclinical myocardial disease in type 2 diabetes.
Limitations in the predictive value of negative exercise echocardiography in type 2 diabetes mellitus has been linked to a reduced end-systolic pressure-volume response (ESPVR). We sought whether abnormal ESPVR reflected subclinical diabetic heart disease by examining the association between the ESPVR and markers of myocardial dysfunction and to establish if the change (Delta) or peak systolic blood pressure/end-systolic left ventricular volume ratio (SP/ESV) is a better marker of contractile reserve in type 2 diabetes mellitus. Resting and exercise echocardiography was performed in 167 apparently healthy patients with type 2 diabetes mellitus (97 men; age, 55+/-10 years) without ischemia, other cardiac disease, or noncardiac complications of diabetes. Standard echocardiographic and color tissue Doppler measures (early diastolic tissue velocity, strain, and strain rate) were acquired at baseline and peak stress in apical long-axis views. Calibrated integrated backscatter was calculated from a resting parasternal long-axis view. DeltaSP/ESV was calculated as [(peak stress SP/ESV)-(rest SP/ESV)]. The 83 subjects who demonstrated a DeltaSP/ESV < or =12 mm Hg/mL/m(2) after exercise were older and had lower peak heart rate, resting diastolic and stress systolic tissue velocity, stress ejection fraction, and exercise capacity than the remainder. There was no significant association between DeltaSP/ESV and metabolic derangement or echocardiographic measures of deformation or backscatter. Change in Sm and stress ejection fraction were independent correlates of DeltaSP/ESV. DeltaSP/ESV ratio is associated with established features of subclinical diabetic heart disease as well as determinants of contractile reserve (peak hemodynamic response and stress systolic function). Peak ESPVR is poorly associated with markers of myocardial dysfunction.


Large hepatocellular carcinoma treated with sequential SBRT and immunotherapy with anti-VEGF (Vascular Endothelial Growth Factor) therapy.
Managing large solitary hepatocellular carcinoma (HCC) remains challenging as guidelines recommend a palliative approach given the general poor prognosis without accounting for variations in the underlying tumour biology. Surgical resection provides significantly better survival than other modalities for HCC, but only a small proportion of patients with large tumours qualify for surgical resection. Recently, with technological advances in radiation therapy, stereotactic body radiation therapy (SBRT) has emerged as an alternative treatment option for HCC . In this paper, we present a patient who was diagnosed with a 13 cm HCC with vascular invasion. SBRT was delivered as a locoregional therapy followed by immunotherapy with the outcome of complete pathological response observed on right hemi-hepatectomy.


Identifying Personal Goals of Patients With Long Term Condition: A Service Design Thinking Approach.
Care for patients with long term conditions is often characterized as fragmented and ineffective, and fails to engage the resources of patients and their families in the care process. Information and communication technology can potentially help bridge the gap between patients' lives and resources and services provided by professionals. However, there is little attention on how to identify and incorporate the patients' individual needs, values, preferences and care goals into the digitally driven care settings. We conducted a case study with healthcare professionals and patients participated applying a service design thinking approach. The participants could elaborate some personal goals of patients with long term condition which can potentially be incorporated in digitally driven care plans using examples from their own experiences.


Selective synthesis of mono- and bis-butenolide α-aminomethyl adducts.
The selective installation of α-methylamine residues at the butenolide core is described using α-bromomethylene-γ-butenolide and primary as well as secondary amines in methanol at 0 °C. The preparation of mono- and bis-butenolide α-adducts is described. Bis-γ-butenolide adducts as well as mono α-aminomethyl-γ-butenolides can be selectively obtained depending on the nature of the reacting primary amine. In contrast, the use of secondary amines allows two different pathways leading either to the expected amino derivatives or to the formation of a C-O bond.


Repeated assessments of symptom severity improve predictions for risk of death among patients with cancer.
Although prior studies show the importance of self-reported symptom scores as predictors of cancer survival, most are based on scores recorded at a single point in time. To show that information on repeated assessments of symptom severity improves predictions for risk of death and to use updated symptom information for determining whether worsening of symptom scores is associated with a higher hazard of death. This was a province-based longitudinal study of adult outpatients who had a cancer diagnosis and had assessments of symptom severity. We implemented a time-to-death Cox model with a time-varying covariate for each symptom to account for changing symptom scores over time. This model was compared with that using only a time-fixed (baseline) covariate for each symptom. The regression coefficients of each model were derived based on a randomly selected 60% of patients, and then, the predictive performance of each model was assessed via concordance probabilities when applied to the remaining 40% of patients. This study had 66,112 patients diagnosed with cancer and more than 310,000 assessments of symptoms. The use of repeated assessments of symptom scores improved predictions for risk of death compared with using only baseline symptom scores. Increased pain and fatigue and reduced appetite were the strongest predictors for death. If available, researchers should consider including changing information on symptom scores, as opposed to only baseline information on symptom scores, when examining hazard of death among patients with cancer. Worsening of pain, fatigue, and appetite may be a flag for impending death.


Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications.
Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular complexity of gliomas, as well as inconsistencies in histopathological grading, resulting in an inaccurate prediction of disease progression and failure in the use of standard therapy. The updated 2016 World Health Organization (WHO) classification of tumors of the central nervous system reflects a refinement of tumor diagnostics by integrating the genotypic and phenotypic features, thereby narrowing the defined subgroups. The new classification recommends molecular diagnosis of isocitrate dehydrogenase (IDH) mutational status in gliomas. IDH-mutant gliomas manifest the cytosine-phosphate-guanine (CpG) island methylator phenotype (G-CIMP). Notably, the recent identification of clinically relevant subsets of G-CIMP tumors (G-CIMP-high and G-CIMP-low) provides a further refinement in glioma classification that is independent of grade and histology. This scheme may be useful for predicting patient outcome and may be translated into effective therapeutic strategies tailored to each patient. In this review, we highlight the evolution of our understanding of the G-CIMP subsets and how recent advances in characterizing the genome and epigenome of gliomas may influence future basic and translational research.


The relation between total finger ridge-count and variability of counts from finger: genetic implications of racial variation.
The measure of ridge-count diversity, S/square root 10, was computed for a sample of American Whites, American Blacks and African Blacks, and the regression of S/square root 10 on total ridge-count was determined for each group. The shapes of the regression lines differed considerably. The American White curve was very similar to that obtained by Holt in an English sample, while the two Negro curves generally showed lower lower S/square root 10 values for ridge-counts over 80. The American Negro curve was found to behave like a mixture of the White and African Negro curve to a degree approximating to the fraction of White genes in their gene pool. Holt's parent-child data are used to construct a simple test of the hypothesis that that S/square root 10 reflects zygosity in total ridge-count genotypes. The preliminary results support this hypothesis.


Influence of coffee and caffeine consumption on atrial fibrillation in hypertensive patients.
Coffee and caffeine are widely consumed in Western countries. Little information is available on the influence of coffee and caffeine consumption on atrial fibrillation (AF) in hypertensive patients. We sought to investigate the relationship between coffee consumption and atrial fibrillation with regard to spontaneous conversion of arrhythmia. A group of 600 patients presenting with a first known episode of AF was investigated, and we identified 247 hypertensive patients. The prevalence of nutritional parameters was assessed with a food frequency questionnaire. Coffee and caffeine intake were specifically estimated. Left ventricular hypertrophy was evaluated by electrocardiogram (ECG) and echocardiogram. Coffee consumption was higher in normotensive patients. High coffee consumers were more frequent in normotensive patients compared with hypertensive patients. On the other hand, the intake of caffeine was similar in hypertensive and normotensive patients, owing to a higher intake in hypertensive patients from sources other than coffee. Within normotensive patients, we report that non-habitual and low coffee consumers showed the highest probability of spontaneous conversion (OR 1.93 95%CI 0.88-3.23; p=0.001), whereas, within hypertensive patients, moderate but not high coffee consumers had the lowest probability of spontaneous conversion (OR 1.13 95%CI 0.67-1.99; p=0.05). Coffee and caffeine consumption influence spontaneous conversion of atrial fibrillation. Normotensive non-habitual coffee consumers are more likely to convert arrhythmia within 48h from the onset of symptoms. Hypertensive patients showed a U-shaped relationship between coffee consumption and spontaneous conversion of AF, moderate coffee consumers were less likely to show spontaneous conversion of arrhythmia. Patients with left ventricular hypertrophy showed a reduced rate of spontaneous conversion of arrhythmia.


Caudal epidural anesthesia during intracavitary brachytherapy for cervical cancer.
It has been suggested that pain control during intracavitary brachytherapy for cervical cancer is insufficient in most hospitals in Japan. Our hospital began using caudal epidural anesthesia during high-dose-rate (HDR) intracavitary brachytherapy in 2011. The purpose of the present study was to retrospectively investigate the effects of caudal epidural anesthesia during HDR intracavitary brachytherapy for cervical cancer patients. Caudal epidural anesthesia for 34 cervical cancer patients was performed during HDR intracavitary brachytherapy between October 2011 and August 2013. We used the patients' self-reported Numeric Rating Scale (NRS) score at the first session of HDR intracavitary brachytherapy as a subjective evaluation of pain. We compared NRS scores of the patients with anesthesia with those of 30 patients who underwent HDR intracavitary brachytherapy without sacral epidural anesthesia at our hospital between May 2010 and August 2011. Caudal epidural anesthesia succeeded in 33 patients (97%), and the NRS score was recorded in 30 patients. The mean NRS score of the anesthesia group was 5.17 ± 2.97, significantly lower than that of the control group's 6.80 ± 2.59 (P = 0.035). The caudal epidural block resulted in no side-effects. Caudal epidural anesthesia is an effective and safe anesthesia option during HDR intracavitary brachytherapy for cervical cancer.


Quantitative proteome analysis of detergent-resistant membranes identifies the differential regulation of protein kinase C isoforms in apoptotic T cells.
Several lines of evidence suggest that detergent-resistant membranes (DRMs) (also known as lipid rafts and glycosphingolipid-enriched microdomains) may have a role in signaling pathways of apoptosis. Here, we developed a method that combines DRMs isolation and methanol/chloroform extraction with stable isotope labeling with amino acids in cell culture-based quantitative proteome analysis of DRMs from control and cisplatin-induced apoptotic Jurkat T cells. This approach enabled us to enrich proteins with a pivotal role in cell signaling of which several were found with increased or decreased amounts in DRMs upon induction of apoptosis. Specifically, we show that three isoforms of protein kinase C (PKC) are regulated differently upon apoptosis. Although PKC alpha which belongs to the group of conventional PKCs is highly up-regulated in DRMs, the levels of two novel PKCs, PKC eta and PKC theta, are significantly reduced. These alterations/differences in PKC regulation are verified by immunoblotting and confocal microscopy. In addition, a specific enrichment of PKC alpha in apoptotic blebs and buds is shown. Furthermore, we observe an increased expression of ecto-PKC alpha as a result of exposure to cisplatin using flow cytometry. Our results demonstrate that in-depth proteomic analysis of DRMs provides a tool to study differential localization and regulation of signaling molecules important in health and disease.


Cannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders.
The G-protein coupled receptors for Δ⁹-tetrahydrocannabinol, the major psychoactive principle of marijuana, are known as cannabinoid receptors of type 1 (CB₁) and 2 (CB₂) and play important functions in degenerative and inflammatory disorders of the central nervous system. Whilst CB₁ receptors are mostly expressed in neurons, where they regulate neurotransmitter release and synaptic strength, CB₂ receptors are found mostly in glial cells and microglia, which become activated and over-express these receptors during disorders such as Alzheimer's disease, multiple sclerosis, amyotropic lateral sclerosis, Parkinson's disease, and Huntington's chorea. The neuromodulatory actions at CB₁ receptors by endogenous agonists ('endocannabinoids'), of which anandamide and 2-arachidonoylglycerol are the two most studied representatives, allows them to counteract the neurochemical unbalances arising during these disorders. In contrast, the immunomodulatory effects of these lipophilic mediators at CB₂ receptors regulate the activity and function of glia and microglia. Indeed, the level of expression of CB₁ and CB₂ receptors or of enzymes controlling endocannabinoid levels, and hence the concentrations of endocannabinoids, undergo time- and brain region-specific changes during neurodegenerative and neuroinflammatory disorders, with the initial attempt to counteract excitotoxicity and inflammation. Here we discuss this plasticity of the endocannabinoid system during the aforementioned central nervous system disorders, as well as its dysregulation, both of which have opened the way to the use of either direct and indirect activators or blockers of CB₁ and CB₂ receptors for the treatment of the symptoms or progression of these diseases.


[Comparative study of the performance of different cohorts evaluating whether they have entered university with or without admissibility course].
The present paper analyses the overall performance of different cohorts which graduated the same year, taking into account whether or not they had an admissibility course to the School of Medicine. To evaluate that with the implementation of the entrance exam, the following two variables improved considerably: average mark during the course of studies and duration of the course of studies. The graduation rates corresponding to the years 1999-2003 were analyzed, differentiating those students entering university before the year 1991--without entrance exam--and those entering it as from 1992--with entrance exam. Analyzing the graduation years corresponding to the periods 1999-2003 for those students who entered university in the year 1991 and the previous years (without entrance selection) we have found that the average mark during the course of studies (including failed exams) is 5,64. If we apply the same analysis to those students who entered university in the year 1992--when the Admissibility Course to the Course of Studies begins--and the following years. and with the same years of graduation, we found that the average mark (including failed exams) is 7.09. In the case of the students entering university in the year 1991 and the previous years, the duration of the course of studies is 13.22 years. In the case of the students entering university in the years 1992 and the following years this figure goes down to 7.95 years. We can say that both the average marks in the final exams of each subject in the course of studies and the attendance to classes improves considerably when the admissibility course has been attended..


Caring for older adults: practice guided by Watson's caring-healing model.
Caring for older people and listening attentively to what they say about themselves and their varied health situations, especially in relation to quality of life and peace of mind, body, and soul, are important matters to nurses aligned with Watson's caring-healing theory. Assumptions and key concepts of Watson's framework are described with examples that illustrate how a nursing framework has shaped the author's advanced nursing practice. Some of the key concepts discussed include intersubjectivity, transpersonal caring, spirituality, and caring moments. Watson's framework of caring-healing is shown to inform practice, education, and research.


[The effect of the immunostimulating agent trimezon on the cells of the mononuclear phagocytosing system].
The effect of the immunostimulator trimeson of the 8-aza-gomogonan series on the cells of the mononuclear monocyte system was studied in C3H and ICR mice in vitro. Intraperitoneal injection of trimeson (50 mg/kg 1 x 10(-7)-1 x 10(6) M) inhibits, as a rule, the initial stages of the phagocytizing process but stimulates the bactericidal properties of the peritoneal phagocytes and their mechanisms of processing and destruction of the antigen material. In the system of adaptive transfer of donor splenocytes and peritoneal macrophages to recipients exposed to lethal radiation, trimeson (20 mg/kg intravenously, 50 mg/kg per os) increases the immunogenic function of the mononuclear phagocytes in formation of the primary immune response to sheep erythrocytes.


Inference of modules associated to eQTLs.
Cataloging the association of transcripts to genetic variants in recent years holds the promise for functional dissection of regulatory structure of human transcription. Here, we present a novel approach, which aims at elucidating the joint relationships between transcripts and single-nucleotide polymorphisms (SNPs). This entails detection and analysis of modules of transcripts, each weakly associated to a single genetic variant, together exposing a high-confidence association signal between the module and this 'main' SNP. To explore how transcripts in a module are related to causative loci for that module, we represent such dependencies by a graphical model. We applied our method to the existing data on genetics of gene expression in the liver. The modules are significantly more, larger and denser than found in permuted data. Quantification of the confidence in a module as a likelihood score, allows us to detect transcripts that do not reach genome-wide significance level. Topological analysis of each module identifies novel insights regarding the flow of causality between the main SNP and transcripts. We observe similar annotations of modules from two sources of information: the enrichment of a module in gene subsets and locus annotation of the genetic variants. This and further phenotypic analysis provide a validation for our methodology.


Human papillomavirus in the male patient.
Human papillomavirus is a double-stranded DNA virus associated with a broad spectrum of clinical states including condylomata acuminata, latent and subclinical infection (acetowhitening), Bowen's disease, and carcinoma of the penis and anus. The virus is transmitted by direct contact with site-subtype specificity; additional studies are needed to elucidate the exact transmissibility and disease course of HPV infection. The association of HPV-16 and HPV-18 with anogenital malignancy increases the importance of treating such infections and raises questions about the role of HPV in oncogenesis. Treatment modalities for HPV include cytotoxic agents, surgical excision, immunotherapy, and laser ablation. Success rates appear best for laser ablation of evident disease. No therapeutic modality appears superior for treating latent disease. The public health ramifications of HPV are vast and warrant investigation to further our scientific and clinical understanding of oncogenesis and its prevention.


Acute liver failure: mechanisms of hepatocyte injury and regeneration.
Acute liver failure (ALF) occurs when the extent of hepatocyte death exceeds the liver's regenerative capacity. Despite vast differences in causes, the mode of cell death typically follows one of two patterns: necrosis or apoptosis. Necrosis and apoptosis have traditionally been considered separate entities within various etiologies of ALF; however, there is increasing evidence that they are alternative outcomes of the same initiating factors and signaling pathways, a process known as necroapoptosis. Here we review mechanisms of liver cell injury in ALF, including evolving knowledge of pathways leading to apoptosis, necrosis, and necroapoptosis, as well as how these pathways are potential therapeutic targets in ALF. We also discuss hepatic regeneration and the cytokines and growth factors involved in both the replication of differentiated hepatocytes as well as activation of intrahepatic progenitor cells, two pathways of hepatocyte regeneration that are dependent on the type and extent of hepatic insult in ALF.


Placebo neural systems: nitric oxide, morphine and the dopamine brain reward and motivation circuitries.
Evidence suggests that the placebo response is related to the tonic effects of constitutive nitric oxide in neural, vascular and immune tissues. Constitutive nitric oxide levels play a role in the modulation of dopamine outflow in the nigrostriatal movement and the mesolimbic and mesocortical reward and motivation circuitries. Endogenous morphine, which stimulates constitutive nitric oxide, may be an important signal molecule working at mu receptors on gamma aminobutyric acid B interneurons to disinhibit nigral and tegmental dopamine output. We surmise that placebo induced belief will activate the prefrontal cortex with downstream stimulatory effects on these dopamine systems as well as on periaqueductal grey opioid output neurons. Placebo responses in Parkinson's disease, depression and pain disorder may result. In addition, mesolimbic/mesocortical control of the stress response systems may provide a way for the placebo response to benefit other medical conditions.


Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms.
Recent studies have shown that macrophages play an important part in both tumor initiation and various key steps in growth and metastasis. These cells show a remarkable degree of plasticity during tumor development with a "switch" in macrophage phenotypes occurring during the course of tumor progression. During chronic inflammation they appear to predispose a given tissue to tumor initiation by the release of factors that promote neoplastic transformation. Following this, their phenotype shifts more toward one that is immunosuppressive and supports tumor growth, angiogenesis, and metastasis. In this review, we discuss the evidence for this plasticity of macrophage functions, the specific signaling mechanisms that may be regulating it, and the new targets for anticancer therapies highlighted by these findings.


Refractive error in underserved adults: causes and potential solutions.
To evaluate the epidemiology of uncorrected refractive errors (URE) in adults both in the United States and globally, health outcomes impacted by URE, common barriers to treatment, and propose potential interventions. URE is the main cause of visual impairment and the second leading cause of blindness globally. Rates of URE are rising, and cause disability that reduces productivity, economic earnings, and the quality of life of affected individuals. Economic barriers, healthcare access, and sociocultural constraints are among the most fundamental barriers to correcting URE. However, innovative approaches are poised to lower rates of URE. URE is a leading cause of preventable visual impairment with serious health consequences. Numerous social and financial barriers are associated with the high prevalence of URE in low-income adults. Novel delivery programs for eyeglasses and programs to provide refractive surgery to correct refractive error could decrease rates of URE.


Germanium-on-silicon mid-infrared grating couplers with low-reflectivity inverse taper excitation.
A broad transparency range of its constituent materials and compatibility with standard fabrication processes make germanium-on-silicon (Ge-on-Si) an excellent platform for the realization of mid-infrared photonic circuits. However, the comparatively large Ge waveguide thickness and its moderate refractive index contrast with the Si substrate hinder the implementation of efficient fiber-chip grating couplers. We report for the first time, to the best of our knowledge, a single-etch Ge-on-Si grating coupler with an inversely tapered access stage, operating at a 3.8 μm wavelength. Optimized grating excitation yields a coupling efficiency of -11 dB (7.9%), the highest value reported for a mid-infrared Ge-on-Si grating coupler, with reflectivity below -15 dB (3.2%). The large periodicity of our higher-order grating design substantially relaxes the fabrication constraints. We also demonstrate that a focusing geometry allows a 10-fold reduction in inverse taper length, from 500 to 50 μm.


Brain activation predicts treatment improvement in patients with major depressive disorder.
Major depressive disorder (MDD) is associated with alterations in brain function that might be useful for therapy evaluation. The current study aimed to identify predictors for therapy improvement and to track functional brain changes during therapy. Twenty-one drug-free patients with MDD underwent functional MRI twice during performance of an emotional perception task: once before and once after 4 weeks of antidepressant treatment (mirtazapine or venlafaxine). Twelve healthy controls were investigated once with the same methods. A significant difference between groups was a relative greater activation of the right dorsolateral prefrontal cortex (dlPFC) in the patients vs. controls. Before treatment, patients responding better to pharmacological treatment showed greater activation in the dorsomedial PFC (dmPFC), posterior cingulate cortex (pCC) and superior frontal gyrus (SFG) when viewing of negative emotional pictures was compared with the resting condition. Activations in the caudate nucleus and insula contrasted for emotional compared to neutral stimuli were also associated with successful treatment. Responders had also significantly higher levels of activation, compared to non-responders, in a range of other brain regions. Brain activation related to treatment success might be related to altered self-referential processes and a differential response to external emotional stimuli, suggesting differences in the processing of emotionally salient stimuli between those who are likely to respond to pharmacological treatment and those who will not. The present investigation suggests the pCC, dmPFC, SFG, caudate nucleus and insula may have a key role as a biological marker for treatment response and predictor for therapeutic success.


Characterization of a putative Drosophila GTP-binding protein.
We generated a set of monoclonal antibodies raised against Drosophila antigen eluted from a lectin affinity column. One antibody, mAb 13D5 recognizes an antigen found in the most dorsal regions of the ventral midline of Drosophila embryos at stages prior to and during axonogenesis. 13D5 recognizes cells dorsal to the ectoderm in the extended germ band beginning approximately 7 hours after fertilization and in the peripheral nervous system (PNS) at about 13 hours. In addition, 24-hour-old cultures of isolated embryonic neuroblasts possess a number of cells that express the 13D5 antigen and are not recognized by horseradish peroxidase antisera. These cells extend ramified processes with multiple growth cone-like structures or large individual processes with a broad growth cone structure. 13D5 immunoprecipitates a single band with an apparent molecular mass of 58 kDa and isolated a 1.9 kb EcoRI fragment from the lambda gt11 expression libraries. In situ hybridization to staged embryos using the digoxygenin-labeled probe reveals a pattern of expression in cells just lateral to the dorsal-most regions (mesectoderm) of the ventral midline in 8- to 9-hour embryos. In situ hybridization to cultured cells derived from whole embryos reveals several cell types with differing morphologies that express transcript recognized by the digoxygenin-labeled probe. These cells may possess either broad processes containing detectable transcript, or long thin processes with no detectable transcript. Northern analysis reveals a 2.1 kb RNA transcript detectable in all embryonic stages. Nucleotide sequence obtained from the 1.9 kb insert reveals homology with the GTP-binding regions of two signal recognition particle receptors (SNRP) isolated from canine and human tissues.


Rayleigh-Brillouin scattering of carbon dioxide.
The spectral line shape of spontaneous Rayleigh-Brillouin scattering in CO2 is studied in a range of pressures. The spectrum is influenced by the bulk viscosity η(b), which is a relaxation phenomenon involving the internal degrees of freedom of the molecule. The associated relaxation rates can be compared to the frequency shift of the scattered light, which demands precise measurements of the spectral line shape. We find η(b)=(5.7±0.6)×10(-6) kg m(-1) s(-1) for the range of pressures p=2-4 bar and for room temperature conditions.


Brain regions of marine medaka activated by acute and short-term ocean acidification.
Altered behaviors have been reported in many marine fish following exposure to high CO2 concentrations. However, the mechanistic link between elevated CO2 and activation of brain regions in fish is unknown. Herein, we examined the relative quantification and location of c-Fos expression in marine medaka following acute (360 min) and short-term (7 d) exposure to CO2-enriched water (1000 ppm and 1800 ppm CO2). In the control and two treatment groups, pH was stable at 8.21, 7.92 and 7.64, respectively. After acute exposure to seawater acidified by enrichment with CO2, there was a clear upregulation of c-Fos protein in the medaka brain (P < 0.05). c-Fos protein expression peaked after 120 min exposure in the two treatment groups and thereafter began to decline. There were marked increases in c-Fos-labeling in the ventricular and periventricular zones of the cerebral hemispheres and the medulla oblongata. After 1800 ppm CO2 exposure for 7 d, medaka showed significant preference for dark zones during the initial 2 min period. c-Fos protein expression in the ventricular and periventricular zones of the diencephalon in medaka exposed to 1000 ppm and 1800 ppm CO2 were 0.51 ± 0.10 and 1.34 ± 0.30, respectively, which were significantly higher than controls (P < 0.05). Highest doublecortin protein expression occurred in theventricular zones of the diencephalon and mesencephalon. These findings suggest that the ventricular and periventricular zones of the cerebral hemispheres and the medulla oblongata of marine medaka are involved in rapid acid-base regulation. Prolonged ocean acidification may induce cell mitosis and differentiation in the adult medaka brain.


Disruption of the putative vascular leak peptide sequence in the stabilized ricin vaccine candidate RTA1-33/44-198.
Vitetta and colleagues identified and characterized a putative vascular leak peptide (VLP) consensus sequence in recombinant ricin toxin A-chain (RTA) that contributed to dose-limiting human toxicity when RTA was administered intravenously in large quantities during chemotherapy. We disrupted this potentially toxic site within the more stable RTA1-33/44-198 vaccine immunogen and determined the impact of these mutations on protein stability, structure and protective immunogenicity using an experimental intranasal ricin challenge model in BALB/c mice to determine if the mutations were compatible. Single amino acid substitutions at the positions corresponding with RTA D75 (to A, or N) and V76 (to I, or M) had minor effects on the apparent protein melting temperature of RTA1-33/44-198 but all four variants retained greater apparent stability than the parent RTA. Moreover, each VLP(-) variant tested provided protection comparable with that of RTA1-33/44-198 against supralethal intranasal ricin challenge as judged by animal survival and several biomarkers. To understand better how VLP substitutions and mutations near the VLP site impact epitope structure, we introduced a previously described thermal stabilizing disulfide bond (R48C/T77C) along with the D75N or V76I substitutions in RTA1-33/44-198. The D75N mutation was compatible with the adjacent stabilizing R48C/T77C disulfide bond and the T(m) was unaffected, whereas the V76I mutation was less compatible with the adjacent disulfide bond involving C77. A crystal structure of the RTA1-33/44-198 R48C/T77C/D75N variant showed that the structural integrity of the immunogen was largely conserved and that a stable immunogen could be produced from E. coli. We conclude that it is feasible to disrupt the VLP site in RTA1-33/44-198 with little or no impact on apparent protein stability or protective efficacy in mice and such variants can be stabilized further by introduction of a disulfide bond.


Landscape associations of the sand fly, Lutzomyia (Heleocyrtomyia) apache (Diptera: Psychodidae), in the southwestern United States: a geographic information system analysis.
Landscape associations of the sand fly, Lutzomyia apache, Young and Perkins, in the southwestern U.S. were investigated by light/suction trap sampling and the development of a GIS-generated distribution map. In the mid-Rio Grande River valley, N.M., female and male L. apache were captured in updraft light/suction traps set in desert shrubland, irrigation levee, and bosque vegetation communities. Small numbers of flies were captured, but the presence of males and females in spatially separate and diverse plant communities at two locations suggest that L. apache are dispersed among available vegetation types. These data, along with 22 previously published collection site records, were used with a suite of physiographic features to characterize the biogeographic conditions suitable for L. apache. Suitable conditions encompass three life zones: the Rocky Mountain steppe province, the Colorado semi-plateau province, and the American semi-desert province, all within the dry domain region of the western U.S. The potential range of L. apache was then estimated based on elevation, mean and max - min temperature, precipitation, wet days, and relative humidity. The estimated range includes large contiguous areas in north-central Colorado, east-central New Mexico and west Texas, the lower mid-Rio Grande River valley, and southern Arizona, along with smaller, patchy, areas in northern Arizona, California, Nevada, Utah, and central Idaho. The spatial relationship between the estimated distribution of L. apache and the location of livestock exposed to vesicular stomatitis virus at the onset of recent outbreaks is presented.


Comparative Assessment of Phenolic Content and in Vitro Antioxidant Capacity in the Pulp and Peel of Mango Cultivars.
Mango (Mangifera indica L.), also called "the king of fruits", is one of the most popular fruits in tropical regions. Pulp and peel samples of mango cultivars were analyzed to estimate total phenolic, total flavonoid and total anthocyanin contents. Phenolic acids, hydrophilic peroxyl radical scavenging capacity (hydro-PSC) and oxygen radical scavenging capacity (ORAC) in vitro were also determined. Total phenolics and flavonoid contents were found maximum in the peel of Xiao Tainang and Da Tainang cultivars, respectively, whereas Xiao Tainang also exhibited significant antioxidant capacity. Noteworthy, concentrations of gallic acid, protocatechuic acid, ferulic acid, chlorogenic acid and caffeic acids at 79.15, 64.33, 33.75, 27.19 and 13.62 mg/100 g fresh weight (FW) were quantified for Da Tainang, Xiao Tainang and of Jidan cultivars, respectively. Comparatively, a higher level of phenolics and significant antioxidant capacity in mango peel indicated that it might be useful as a functional food and value-added ingredient to promote human health.


A Josephson junction withh-BN tunnel barrier: observation of low critical current noise.
Decoherence in quantum bits (qubits) is a major challenge for realizing scalable quantum computing. One of the primary causes of decoherence in qubits and quantum circuits based on superconducting Josephson junctions is the critical current fluctuation. Many efforts have been devoted to suppressing the critical current fluctuation in Josephson junctions. Nonetheless, the efforts have been hindered by the defect-induced trapping states in oxide-based tunnel barriers and the interfaces with superconductors in the traditional Josephson junctions. Motivated by this, along with the recent demonstration of 2D insulatorh-BN with exceptional crystallinity and low defect density, we fabricated a vertical NbSe2/h-BN/Nb Josephson junction consisting of a bottom NbSe2superconductor thin layer and a top Nb superconductor spaced by an atomically thinh-BN layer. We further characterized the superconducting current and voltage (I-V) relationships and Fraunhofer pattern of the NbSe2/h-BN/Nb junction. Notably, we demonstrated the critical current noise (1/fnoise power) in theh-BN-based Josephson device is at least a factor of four lower than that of the previously studied aluminum oxide-based Josephson junctions. Our work offers a strong promise ofh-BN as a novel tunnel barrier for high-quality Josephson junctions and qubit applications.


Effect of adenosine 3',5'-monophosphate on neuronal pacemaker activity: a voltage clamp analysis.
Bursting pacemaker activity in nerve cells can be modified for long periods by synaptic input of short duration. There is evidence that cyclic nucleotides may play a role in these modifications. The predominant effect of elevated levels of adenosine 3',5'-monophosphate in Aplysia neurons was an increased slope conductance to hyperpolarizing pulses, evident in voltage clamp records. A similar increase in slope conductance was seen as one component of maximum strength synaptic stimulation, which is consistent with the idea that cyclic nucleotides are important in the expression of synaptic alteration of bursting pacemaker activity.


Dynamically Crosslinked Poly(ethylene-glycol) Hydrogels Reveal a Critical Role of Viscoelasticity in Modulating Glioblastoma Fates and Drug Responses in 3D.
Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor in adults. Hydrogels have been employed as 3D in vitro culture models to elucidate how matrix cues such as stiffness and degradation drive GBM progression and drug responses. Recently, viscoelasticity has been identified as an important niche cue in regulating stem cell differentiation and morphogenesis in 3D. Brain is a viscoelastic tissue, yet how viscoelasticity modulates GBM fate and drug response remains largely unknown. Using dynamic hydrazone crosslinking chemistry, a poly(ethylene-glycol)-based hydrogel system with brain-mimicking stiffness and tunable stress relaxation is reported to interrogate the role of viscoelasticity on GBM fates in 3D. The hydrogel design allows tuning stress relaxation without changing stiffness, biochemical ligand density, or diffusion. The results reveal that increasing stress relaxation promotes invasive GBM behavior, such as cell spreading, migration, and GBM stem-like cell marker expression. Furthermore, increasing stress relaxation enhances GBM proliferation and drug sensitivity. Stress-relaxation induced changes on GBM fates and drug response are found to be mediated through the cytoskeleton and transient receptor potential vanilloid-type 4. These results highlight the importance of incorporating viscoelasticity into 3D in vitro GBM models and provide novel insights into how viscoelasticity modulates GBM cell fates.


Shear stress enhances human endothelial cell wound closure in vitro.
Repair of the endothelium occurs in the presence of continued blood flow, yet the mechanisms by which shear forces affect endothelial wound closure remain elusive. Therefore, we tested the hypothesis that shear stress enhances endothelial cell wound closure. Human umbilical vein endothelial cells (HUVEC) or human coronary artery endothelial cells (HCAEC) were cultured on type I collagen-coated coverslips. Cell monolayers were sheared for 18 h in a parallel-plate flow chamber at 12 dyn/cm(2) to attain cellular alignment and then wounded by scraping with a metal spatula. Subsequently, the monolayers were exposed to a laminar shear stress of 3, 12, or 20 dyn/cm(2) under shear-wound-shear (S-W-sH) or shear-wound-static (S-W-sT) conditions for 6 h. Wound closure was measured as a percentage of original wound width. Cell area, centroid-to-centroid distance, and cell velocity were also measured. HUVEC wounds in the S-W-sH group exposed to 3, 12, or 20 dyn/cm(2) closed to 21, 39, or 50%, respectively, compared with only 59% in the S-W-sT cells. Similarly, HCAEC wounds closed to 29, 49, or 33% (S-W-sH) compared with 58% in the S-W-sT cells. Cell spreading and migration, but not proliferation, were the major mechanisms accounting for the increases in wound closure rate. These results suggest that physiological levels of shear stress enhance endothelial repair.


[Immune response and the formation of immunologic memory to Staphylococcus in mice of different genotypes].
The time course of changes in the number of antibody-forming cells in the spleen in the primary and secondary immune response to staphylococcal corpuscular antigen was studied in experiments on mice. C3H mice were found to be highly responsive, while A/Sn mice showed low response, the opposite character of immune responsiveness to this antigen in the animals of the above-mentioned genotypes increasing after the second immunization. C57BL/6, CBA, DBA/2, BALB/c and (CBA X C57BL/6) F1 mice showed comparatively moderate antibody formation in response to staphylococci. The formation of immunological memory to this antigen depended on the genotype of mice and was determined by the intensity of antigenic action: high priming doses of staphylococci proved to be most effective; low doses of the antigen were not effective or produced only short-term immunological memory to staphylococci in mice.


Cost Analysis of Vaginal Anti-incontinence Procedures at a Tertiary Care Center.
To compare the cost of 3 vaginal procedures used in the surgical management of stress urinary incontinence (SUI) at 1 tertiary institution. The costs of autologous fascial sling (AFS), synthetic mid-urethral sling (MUS), and anterior vaginal wall suspension (AVWS) were analyzed from a prospective long-term database, with follow-up to 5 years after these procedures. Original costing data were obtained for operating room, medical and surgical supplies, pharmacy, anesthesia supplies, and room and bed over 2 consecutive years. Included were complete cost data provided by our institution from Medicare (2012) and private payer insurance. For the year 2013, the AVWS, AFS, and MUS had total median costs of $4513, $5721, and $3311, respectively. Total cost and all subcosts except for pharmacy costs were significantly different for each procedure. AVWS and MUS placement differed from each other regarding the cost of anesthesia and hospital stay, which was higher for AVWS. Compared to AFS, AVWS had significantly lower total costs due to decreased costs associated with operating time, hospital stay, and surgical supplies (P <.0001). At 5 years after these procedures, synthetic slings had less frequent follow-up visits. The most common revision for SUI failure was a bulking agent injection. Initial costs of vaginal SUI procedures at our institution fared favorably compared to SUI procedures reported in the contemporary US literature. Long-term costs can vary based on physician preference in follow-up routine and etiology of SUI.


Postdiagnostic Calcium Channel Blocker Use and Breast Cancer Mortality: A Population-based Cohort Study.
There have long been concerns that calcium channel blockers (CCBs), widely used to treat hypertension, may contribute to malignant growth through the evasion of apoptosis and proliferation of cancer cells. Worryingly, a recent cohort study found breast cancer patients who used CCBs had higher death rates, but interpreting these results was difficult as they were based on all-cause mortality and medication use before cancer diagnosis. We used UK population-based data to more robustly investigate the association between CCB use and cancer-specific mortality. We selected a cohort of patients with breast cancer diagnosed between 1998 and 2012 from English cancer registries. We linked to prescription and clinical records from the Clinical Practice Research Datalink, and to death records from the Office for National Statistics. We used adjusted, time-dependent Cox regression models to calculate hazard ratios (HRs) comparing breast cancer-specific and all-cause mortality between postdiagnostic CCB users and nonusers. Our cohort included 23,669 breast cancer patients, of whom 5,141 used CCBs and 3,053 died due to their breast cancer during follow-up. After adjustment, CCB users had similar breast cancer-specific mortality to nonusers (HR = 0.98, 95% confidence interval [CI] = 0.88, 1.08). There was no evidence of a dose-response relationship. We found similar associations for specific CCBs, and for all-cause mortality. In this large population-based breast cancer cohort, we did not find any evidence that CCB use is associated with increased mortality.


Agent-based simulations for protecting nursing homes with prevention and vaccination strategies.
Due to its high lethality among older people, the safety of nursing homes has been of central importance during the COVID-19 pandemic. With test procedures and vaccines becoming available at scale, nursing homes might relax prohibitory measures while controlling the spread of infections. By control we mean that each index case infects less than one other person on average. Here, we develop an agent-based epidemiological model for the spread of SARS-CoV-2 calibrated to Austrian nursing homes to identify optimal prevention strategies. We find that the effectiveness of mitigation testing depends critically on test turnover time (time until test result), the detection threshold of tests and mitigation testing frequencies. Under realistic conditions and in absence of vaccinations, we find that mitigation testing of employees only might be sufficient to control outbreaks if tests have low turnover times and detection thresholds. If vaccines that are 60% effective against high viral load and transmission are available, control is achieved if 80% or more of the residents are vaccinated, even without mitigation testing and if residents are allowed to have visitors. Since these results strongly depend on vaccine efficacy against infection, retention of testing infrastructures, regular testing and sequencing of virus genomes is advised to enable early identification of new variants of concern.


Loss of Rab27 function results in abnormal lung epithelium structure in mice.
Rab27 small GTPases regulate secretion and movement of lysosome-related organelles such as T cell cytolytic granules and platelet-dense granules. Previous studies indicated that Rab27a and Rab27b are expressed in the murine lung suggesting that they regulate secretory processes in the lung. Consistent with those studies, we found that Rab27a and Rab27b are expressed in cell types that contain secretory granules: alveolar epithelial type II (AEII) and Clara cells. We then used Rab27a/Rab27b double knockout (DKO) mice to examine the functional consequence of loss of Rab27 proteins in the murine lung. Light and electron microscopy revealed a number of morphological changes in lungs from DKO mice when compared with those in control animals. In aged DKO mice we observed atrophy of the bronchiolar and alveolar epithelium with reduction of cells numbers, thinning of the bronchiolar epithelium and alveolar walls, and enlargement of alveolar airspaces. In these samples we also observed increased numbers of activated foamy alveolar macrophages and granulocyte containing infiltrates together with reduction in the numbers of Clara cells and AEII cells compared with control. At the ultrastructural level we observed accumulation of cytoplasmic membranes and vesicles in Clara cells. Meanwhile, AEII cells in DKO accumulated large mature lamellar bodies and lacked immature/precursor lamellar bodies. We hypothesize that the morphological changes observed at the ultrastructural level in DKO samples result from secretory defects in AEII and Clara cells and that over time these defects lead to atrophy of the epithelium.


Intraoperative unfolding and postoperative pruning of the pituitary gland after transsphenoidal surgery for pituitary adenoma: A volumetric and endocrinological evaluation.
To describe the volumetric changes that the pituitary gland (PG) undergoes during and after transsphenoidal surgery (TSS), and to evaluate if unfolding and/or pruning are related to endocrinological outcome measures. Retrospective evaluation of data prospectively collected of a cohort of patients undergoing TSS for a pituitary adenoma with the adjunctive use of high field 3 Tesla intraoperative MRI. All patients underwent a full endocrinological workup preoperatively, as well as at 6 weeks and 1 year postoperatively. A decrease in PG volume ≥15% between the intraoperative and 3-month, or between the 3-month and 12-month measurements, was considered early and late pruning, respectively. The PG unfolds significantly during TSS, and subsequently undergoes pruning up until 1 year postoperatively, in most cases returning to the preoperatively measured PG volume. A smaller baseline PG volume predicts intraoperative unfolding. Early pruning of the PG after surgery was associated with new functional deficits. Baseline pituitary compression also correlated to newly occurring deficits after surgery. A larger 1-year pituitary volume was associated with biochemical remission in secreting adenomas. The PG shows dynamic change during and after TSS for pituitary adenoma. Small baseline and 3-month PG volumes, as well as early pruning were independently associated with new deficits. Our findings warrant prospective validation in a larger cohort with higher statistical power.


Environmental risk factors associated with West Nile virus clinical disease in Florida horses.
The objective of this study was to examine the extrinsic risk factors of West Nile virus (WNV) clinical disease in Florida horses as established from confirmed and negative horses tested within the state from 2001 to 2003. An Arboviral Case Information Form (ACF) was submitted by a referring veterinarian at the time of testing to the Florida Department of Agriculture and Consumer Services on every horse suspected of a viral encephalitis in Florida. A follow-up survey that focused on arbovirus prevention and farm ecology was created and mailed to the owner of each tested horse. Data from the follow-up survey indicated peak WNV prevalence in the late summer months in Florida. Quarter horses were the most commonly affected breed. The WNV vaccine was highly protective and natural water on the property also had a protective association. Factors that increased the risk of WNV to horses were the use of fans and a stable construction of solid wood or cement. Some risk indicators were dead birds on the property and other ill animals on the property. Data from this retrospective study have helped identify factors associated with WNV transmission in equines in Florida. Horses that have not been vaccinated and show clinical signs of arboviral infection from June to November should be tested for WNV. Horses that have been vaccinated and show clinical signs should be tested when the vaccination was administered within 1 month or greater than 6 months prior to the onset of clinical symptoms associated with WN infection.


Identification of all classes of spin-trapped carbon-centered radicals in soybean lipoxygenase-dependent lipid peroxidations of omega-6 polyunsaturated fatty acids via LC/ESR, LC/MS, and tandem MS.
Using the combined techniques of on-line high performance liquid chromatography/electron spin resonance (LC/ESR) and mass spectrometry (MS), we previously identified spin-trapped adducts of all expected carbon-centered lipid-derived radicals ((*)L(d)) formed in linoleic acid peroxidation. In the present study, spin trapped lipid-derived carbon-centered radicals formed from the reactions of two omega-6 polyunsaturated fatty acids (PUFAs: linoleic and arachidonic acids) with soybean lipoxygenase in the presence of alpha-[4-pyridyl 1-oxide]-N-tert-butyl nitrone (POBN) were identified using a combination of LC/ESR and LC/MS. All expected lipid-derived carbon-centered radicals in lipoxygenase-dependent peroxidations of linoleic acid and arachidonic acid were detected and identified by the combination of LC/ESR and LC/MS with confirmation by tandem mass spectrometry (MS/MS). The five classes of (*)L(d) formed from both omega-6 PUFAs including lipid alkyl radicals (L(*)), epoxyallyic radicals (OL(*)), dihydroxyallyic radicals ((*)L(OH)(2)), and a variety of R(*) and (*)RCOOH from beta-scission of lipid alkoxyl radicals, gave distinct retention times: POBN/(*)L(OH)(2) approximately 4-6 min, POBN/R(*) and POBN/(*)RCOOH approximately 8-22 min, POBN/L(*) and PBON/OL(*) approximately 25-36 min. The major beta-scission products in peroxidations of omega-6 PUFAs were the pentyl radicals. The ratio of beta-scission products, however, varied significantly depending on pH, [PUFA], as well as [O(2)].


Evidence in favor of a calcium-sensing receptor in arterial endothelial cells: studies with calindol and Calhex 231.
Small increases in extracellular Ca2+ dilate isolated blood vessels. In the present study, the possibility that a vascular, extracellular Ca2+-sensing receptor (CaSR) could mediate these vasodilator actions was investigated. Novel ligands that interact with the CaSR were used in microelectrode recordings from rat isolated mesenteric and porcine coronary arteries. The major findings were that (1) raising extracellular Ca2+ or adding calindol, a CaSR agonist, produced concentration-dependent hyperpolarizations of vascular myocytes, actions attenuated by Calhex 231, a negative allosteric modulator of CaSR. (2) Calindol-induced hyperpolarizations were inhibited by the intermediate conductance, Ca2+-sensitive K+ (IKCa) channel inhibitors, TRAM-34, and TRAM-39. (3) The effects of calindol were not observed in the absence of endothelium. (4) CaSR mRNA and protein were present in rat mesenteric arteries and in porcine coronary artery endothelial cells. (5) CaSR and IKCa proteins were restricted to caveolin-poor membrane fractions. We conclude that activation of vascular endothelial CaSRs opens endothelial cell IKCa channels with subsequent myocyte hyperpolarization. The endothelial cell CaSR may have a physiological role in the control of arterial blood pressure.


Depressed expression of adipocyte beta-adrenergic receptors is a common feature of congenital and diet-induced obesity in rodents.
To determine whether the dramatic reduction in expression and functional activity of the beta3-adrenergic receptor (AR) and beta1AR subtypes originally observed in adipose tissue of the C57BL/6J Lep(ob)/Lep(ob) ('obese') mouse are general features of all models of obesity, and whether obesity-related differences in betaAR subtype expression occur between adipose depots. Survey of adipose tissue betaAR expression from four mouse models of congenital obesity: the 'obese' mouse (C57BL/6J Lep(ob)/Lep(ob)), the 'diabetic' mouse (C57BL/KsJ LepRdb/LepRdb), the 'tubby' mouse (C57BL/6J tub/tub) and the 'fat' mouse (C57BL/KsJ Cpe(fat)/Cpe(fat)), and in a model of high-fat diet-induced obesity in C57BL/6J mice. Expression of the betaAR subtypes was measured by Northern blot hybridization in white and brown adipose depots. In the severely obese Lep(ob) and LepRdb mice, mRNA concentrations of beta3AR and beta1AR in white adipose tissue (WAT) were decreased by > 99% and by > 70%, respectively. More modest effects on beta3AR expression were observed in brown adipose tissue (BAT, decreased by 20 - 30%). In less severe forms of obesity, as found in the tubby and carboxypeptidase (Cpe)fat mice, and in diet-induced obese B6 mice, beta3AR expression was decreased in WAT by up to 90%, with more modest decreases in interscapular BAT (IBAT). Changes in beta1AR mRNA concentrations were more variable. Beta2AR mRNA levels did not differ in most cases, with the exception that there was a 3-5-fold increase in BAT for both Lep(ob) and LepRdb mice. Impaired expression of adipocyte betaAR subtypes is a general feature of both genetic and dietary obesity in mice. The degree of obesity is correlated with the extent of loss of beta3AR and beta1AR expression in WAT. The distinct endocrine abnormalities associated with these obesity models may be responsible for the degree of impaired adipocyte betaAR expression.


[Aerobic 12-week training reduces cardiovascular risk factors in overweight teenagers].
Obesity and low cardiorespiratory fitness are risk factors for cardiovascular diseases and type 2 diabetes. To examine changes in cardiorespiratory fitness and cardiovascular risk factors after an exercise program without any dietary change in sedentary overweight teenagers. Fifteen obese young males (15.5 ± 0.8 years, 31.5 BMI ± 5.9 kg/m2) participated in this study. Subjects underwent anthropometric and metabolic measurements, peak oxygen consumption (VO2peak), and lipid profile before and after training. Exercise training consisted of treadmill exercise at 70-80% of heart rate maximal (HRmax) during 50 min, 3 days/week for 12 weeks. Before and after training 24-hour recall was recorded and caloric intake was calculated. Participants did not change their dietary habits during the intervention. Aerobic training diminished the abdominal circumference (p < 0.05), body fat percentage (p < 0.01), and increased VO2peak (p < 0.001). No significant change in body weight, lipid profile, or blood glucose was observed after training. Our study shows that 12 weeks of aerobic training improved cardiorespiratory fitness and decreased body fat percentage in overweight male teenagers.


[Serological diagnosis of Staphylococcus aureus infections using anti-A beta telchoic acid antibodies assay (author's transl)].
225 contol subjects, 12 hospitalized staphylococcus free (34 sera) and 16 S. aureus infected patients (79 sera) were tested for anti-A beta teichoic acid antibodies, using counter-immunoelectrophoresis. Anti-alpha and gamma haemolysins antibodies were dosed in parallel in 164 sera. Less than 5 per cent of control sera (3,11 per cent) have an antibody titre higher than 1/8; this titre is therefore selected as threshold level of positivity. Ten of the 12 hospitalized patients without staphylococcal infections are below this level. 31,6 per cent of staphylococcus infected patients have higher serum titers; only 3,7 per cent have no antibodies. In the others, a significant rise in titres is observed. There is no correlation between anti-alpha and gamma staphylolysin and anti-teichoic acid antibodies titres. The method suggested, both easy and rapid, could be used in association with anti-staphylolysin dosage for serological diagnosis of staphylococcal infections.


Pineal-adrenal interactions in domestic male pigeon exposed to variable circadian light regimes and exogenous melatonin.
This study was aimed to see the histophysiological changes of the pineal and adrenal glands under altered photoperiodic conditions due to the administration of melatonin in the male domestic pigeon, Columba livia Gmelin. Young adult male domestic pigeons were exposed to long photoperiod (LP; 20 hr light: 4 hr dark), short photoperiod (SP; 4 hr light: 20 hr dark) exogenous melatonin (MEL; 20 microg/100 g body weight/day) was administered for 60 days in the primary breeding and regressive phase. At the end of experiment, adrenal and pineal glands were quickly dissected and processed for histology, ultrastructure study, biochemical, histochemical and immunohistochemical analysis. In the primary breeding phase, the number of mitochondria and rough endoplasmic reticulum were increased in the adrenal gland in MEL-LP group, while lipid granules were also increased in the subcapsular zone. In MEL-SP treated group, however, the number of mitochondria decreased. Pinealocytes were increased in size and well-developed Golgi complexes were present near the cell nucleus after induction with MEL-LP treatment during the primary breeding phase. No remarkable changes were noticed in the number of mitochondria. In the regressive phase-I, the adrenocortical cytoplasm showed similar morphological features both in MEL-LP treatment and control groups. In pinealocytes, few rough endoplasmic reticulum and lipid droplets and moderate number of mitochondria were present. In MEL-SP treatment, increased number of mitochondria in the adrenocortical cells and decreased nuclear diameter of the pinealocytes were noticed. Few mitochondria were observed within the pinealocyte cytoplasm. Side chain cleavage enzyme (immunocytochemical) activity was increased in the subcapsular zone in MEL-LP treated group. The present data indicates that the changes in pineal and adrenocortical tissue histophysiology might be due to melatonin rhythm and light/dark regime which act as a modulator in the male domestic pigeon.


Social Risk Factor Associations With Presenting Visual Acuity in Patients With Microbial Keratitis.
Neighborhood-level social risk factors may contribute to health disparities in microbial keratitis (MK) disease presentation. Understanding neighborhood-level factors may identify areas for revised health policies to address inequities that impact eye health. To investigate if social risk factors were associated with presenting best-corrected visual acuity (BCVA) for patients with MK. This was a cross-sectional study of patients with a diagnosis of MK. Patients presenting to the University of Michigan with a diagnosis of MK between August 1, 2012, and February 28, 2021, were included in the study. Patient data were obtained from the University of Michigan electronic health record. Individual-level characteristics (age, self-reported sex, self-reported race and ethnicity), presenting log of the minimum angle of resolution (logMAR) BCVA, and neighborhood-level factors, including measures on deprivation, inequity, housing burden, and transportation at the census block group, were obtained. Univariate associations of presenting BCVA (< 20/40 vs ≥20/40) with individual-level characteristics were assessed with 2-sample t, Wilcoxon, and χ2 tests. Logistic regression was used to test associations of neighborhood-level characteristics with the probability of presenting BCVA worse than 20/40 after adjustment for patient demographics. A total of 2990 patients with MK were identified and included in the study. Patients had a mean (SD) age of 48.6 (21.3) years, and 1723 were female (57.6%). Patients self-identified with the following race and ethnicity categories: 132 Asian (4.5%), 228 Black (7.8%), 99 Hispanic (3.5%), 2763 non-Hispanic (96.5%), 2463 White (84.4%), and 95 other (3.3%; included any race not previously listed). Presenting BCVA had a median (IQR) value of 0.40 (0.10-1.48) logMAR units (Snellen equivalent, 20/50 [20/25-20/600]), and 1508 of 2798 patients (53.9%) presented with BCVA worse than 20/40. Patients presenting with logMAR BCVA less than 20/40 were older than those who presented with 20/40 or higher (mean difference, 14.7 years; 95% CI, 13.3-16.1; P < .001). Furthermore, a larger percentage of male vs female sex patients presented with logMAR BCVA less than 20/40 (difference, 5.2%; 95% CI, 1.5-8.9; P = .04), as well as Black race (difference, 25.7%; 95% CI, 15.0%-36.5%;P < .001) and White race (difference, 22.6%; 95% CI, 13.9%-31.3%; P < .001) vs Asian race, and non-Hispanic vs Hispanic ethnicity (difference, 14.6%; 95% CI, 4.5%-24.8%; P = .04). After adjusting for age, self-reported sex, and self-reported race and ethnicity, worse Area Deprivation Index (odds ratio [OR], 1.30 per 10-unit increase; 95% CI, 1.25-1.35; P < .001), increased segregation (OR, 1.44 per 0.1-unit increase in Theil H index; 95% CI, 1.30-1.61; P < .001), higher percentage of households with no car (OR, 1.25 per 1 percentage point increase; 95% CI, 1.12-1.40; P = .001), and lower average number of cars per household (OR, 1.56 per 1 less car; 95% CI, 1.21-2.02; P = .003) were associated with increased odds of presenting BCVA worse than 20/40. Findings of this cross-sectional study suggest that in a sample of patients with MK, patient characteristics and where they live were associated with disease severity at presentation. These findings may inform future research on social risk factors and patients with MK.


Inequalities in educational outcomes in individuals with childhood experience of out-of-home care: What are driving the differences?
Prior research has shown that individuals with experience of out-of-home care (foster family care or residential care) in childhood are educationally disadvantaged compared to their peers. In order to be better equipped to design interventions aimed at improving the educational outcomes of children for whom society has assumed responsibility, this study seeks to further our understanding about which factors that contribute to the educational disparities throughout the life course. Using longitudinal data from a cohort of more than 13,000 Swedes, of which around 7% have childhood experience of out-of-home care, Peters-Belson decomposition is utilized to quantify the extent to which the gap in educational achievement in school (age 16) and midlife educational attainment (age 50) captures differences in the prevalence of factors influencing educational outcomes, and differences in the impacts between these factors. We find that the achievement and the attainment gap was around 13% and 9% respectively. These gaps were to a large extent explained by differences in the distribution of predictors. The major explanatory factor for placed children's lower achievement was a lower average cognitive ability. Yet there were some evidence that the rewards of cognitive ability in these children differed across the life course. While the lower returns of cognitive ability suggest that they were underperforming in compulsory school, the higher returns of cognitive ability on midlife attainment indicate that-given previous underperformance-their attainment at age 50 reflects their cognitive capacity more accurately than their achievement at age 16 do. The large influence of the unequal distribution of predictors suggests that policy efforts are needed to promote equity in the distribution of factors contributing to educational achievement and attainment. Since cognitive ability was found to be an important contributory factor, such efforts may include promoting cognitive and intellectual development among children in out-of-home care, preferably starting at a young age.


Mechanobiology of mesenchymal stem cells: Which interest for cell-based treatment?
Thanks to their immune properties, the mesenchymal stem cells (MSC) are a promising source for cell therapy. Current clinical trials show that MSC administrated to patients can treat different diseases (graft-versus-host disease (GVHD), liver cirrhosis, systemic lupus, erythematosus, rheumatoid arthritis, type I diabetes…). In this case, the most common mode of cell administration is the intravenous injection, and the hemodynamic environment of cells induced by blood circulation could interfere on their behavior during the migration and homing towards the injured site. After a brief review of the mechanobiology concept, this paper will help in understanding how the mechanical environment could interact with MSC behavior once they are injected to patient in cell-based treatment.


Empathy and Schadenfreude in Human-Robot Teams.
Intergroup dynamics shape the ways in which we interact with other people. We feel more empathy towards ingroup members compared to outgroup members, and can even feel pleasure when an outgroup member experiences misfortune, known as schadenfreude. Here, we test the extent to which these intergroup biases emerge during interactions with robots. We measured trial-by-trial fluctuations in emotional reactivity to the outcome of a competitive reaction time game to assess both empathy and schadenfreude in arbitrary human-human and human-robot teams. Across four experiments (total n = 361), we observed a consistent empathy and schadenfreude bias driven by team membership. People felt more empathy towards ingroup members than outgroup members and more schadenfreude towards outgroup members. The existence of an intergroup bias did not depend on the nature of the agent: the same effects were observed for human-human and human-robot teams. People reported similar levels of empathy and schadenfreude towards a human and robot player. The human likeness of the robot did not consistently influence this intergroup bias. In other words, similar empathy and schadenfreude biases were observed for both humanoid and mechanoid robots. For all teams, this bias was influenced by the level of team identification; individuals who identified more with their team showed stronger intergroup empathy and schadenfreude bias. Together, we show that similar intergroup dynamics that shape our interactions with people can also shape interactions with robots. Our results highlight the importance of taking intergroup biases into account when examining social dynamics of human-robot interactions.


The Clinical and Radiological Evaluation of Impacted Third Molar Position, Crown and Root Morphology.
This study aimed to analyze the crown and root morphology of maxillary and mandibular third molars, and assess their position in relation to adjacent anatomical structures using clinical examination and radiographic images. A total of 176 extracted impacted or partially impacted third molars were included in this study. Orthopantomogram images (OPG) were used to evaluate the number of roots, position, depth of impaction relative to the occlusal plane of the second molar, and angulation of maxillary and mandibular third molars. The extracted teeth were examined to determine the actual number of roots. The root morphology was classified using the Alavi classification system for maxillary third molars and the Machado classification for mandibular third molars. Additionally, the number of cusps, crown dimensions, and morphology were analyzed using digital and dental calipers. The extracted samples exhibited a significantly higher number of roots compared to the number assessed on OPG images (P<0.001). The majority of mandibular third molars had two fused roots (37.39%) and a five-cuspid crown (48.70%), while maxillary third molars had three fused roots (26.23%) and four cusps (42.62%). Both maxillary (60.66%) and mandibular third molars (61.74%) were predominantly vertically positioned. Regarding the depth of impaction, maxillary third molars were primarily classified as Class C (65.57%), while mandibular third molars were classified as Class B (47.83%). Differences in crown shape were observed, with maxillary crowns being mostly triangular (36.07%) and mandibular crowns being oval (38.26%). Maxillary third molars had shorter crowns compared to mandibular third molars (P<0.05). The root morphology of maxillary and mandibular third molars in the population of Bosnia and Herzegovina displays variability. Orthopantomogram imaging was found to be inadequate for accurate determination of the number of roots in third molars. The number of cusps on third molars cannot be relied upon as a predictor of the number of roots. The study's findings will have implications for dental practice, particularly for oral surgeons and restorative dentists.


Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism.
Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes. The disease may be undiagnosed in the absence of a history suggestive of FHPT. Young PHPT patients (≤45 years of age) are more likely to harbor occult FPHPT. A total of 1,161 (136 were ≤45 years of age) PHPT patients underwent parathyroidectomy from 2001 to 2009. Thirty-four patients declined participation. Sixteen patients were diagnosed in the clinical routine with FPHPT (11 MEN1, four MEN2A, and one HPT-JT) and were not included in the genetic analysis. Eighty-six young (≤45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis. Sanger sequencing of all coding regions of the MEN1, CASR, and the HRPT2/CDC73 genes was performed. Eight of 86 (9.3%) young patients with clinically non-familial PHPT displayed deleterious germ-line mutations in the susceptibility genes (4 MEN1, 3 CASR, and 1 HRPT2/CDC73). There was one insertion, one deletion, two nonsense, and four missense mutations, all predicted to be highly damaging to protein function and absent in 3,244 control chromosomes. Germ-line mutations in known susceptibility genes within young patients with PHPT, including those diagnosed in the clinical routine, was 24/102 (23.5%; 15 MEN1, four RET, three CASR, and two HRPT2/CDC73). We demonstrate that germ-line inactivating mutations in susceptibility genes are common in young patients with clinically non-familial PHPT. Thus, enhanced use of genetic analysis may be warranted in clinically non-familial young PHPT patients.


Clinical outcomes of patients with rheumatoid arthritis after switching from infliximab to etanercept.
To assess the efficacy and monitor serious adverse events in patients with rheumatoid arthritis (RA) switching treatment from infliximab to etanercept. Adult patients with active RA who were discontinuing treatment with infliximab were eligible to enroll in this prospective, 12-week, open label, single-arm, observational study. Four to 10 weeks after their last infusion of infliximab, patients began treatment with etanercept (twice weekly subcutaneous injections of 25 mg). Clinical assessments using the American College of Rheumatology (ACR) criteria for improvement were performed at baseline and at Weeks 6 and 12, and serious adverse events were monitored throughout the study. Twenty-five patients were enrolled, 18 of whom had discontinued infliximab because of lack of efficacy, and 22 completed 12 weeks of etanercept treatment. After 12 weeks, 14 of 22 patients (64%) achieved at least a 20% improvement in ACR criteria (ACR20), 13 (59%) experienced improvements in physical function that were considered clinically important (> or = 0.22 point decrease in overall Health Assessment Questionnaire score), and mean values of all individual components of the ACR criteria had improved. No serious adverse events were reported during the study and no patient discontinued because of lack of efficacy. Etanercept, a soluble tumor necrosis factor (TNF) receptor, provided a well tolerated and effective treatment option for some patients even when infliximab, a monoclonal antibody to TNF, had been ineffective.


Marine Sponges as Chloroflexi Hot Spots: Genomic Insights and High-Resolution Visualization of an Abundant and Diverse Symbiotic Clade.
Members of the widespread bacterial phylum Chloroflexi can dominate high-microbial-abundance (HMA) sponge microbiomes. In the Sponge Microbiome Project, Chloroflexi sequences amounted to 20 to 30% of the total microbiome of certain HMA sponge genera with the classes/clades SAR202, Caldilineae, and Anaerolineae being the most prominent. We performed metagenomic and single-cell genomic analyses to elucidate the functional gene repertoire of Chloroflexi symbionts of Aplysina aerophoba. Eighteen draft genomes were reconstructed and placed into phylogenetic context of which six were investigated in detail. Common genomic features of Chloroflexi sponge symbionts were related to central energy and carbon converting pathways, amino acid and fatty acid metabolism, and respiration. Clade-specific metabolic features included a massively expanded genomic repertoire for carbohydrate degradation in Anaerolineae and Caldilineae genomes, but only amino acid utilization by SAR202. While Anaerolineae and Caldilineae import cofactors and vitamins, SAR202 genomes harbor genes encoding components involved in cofactor biosynthesis. A number of features relevant to symbiosis were further identified, including CRISPR-Cas systems, eukaryote-like repeat proteins, and secondary metabolite gene clusters. Chloroflexi symbionts were visualized in the sponge extracellular matrix at ultrastructural resolution by the fluorescence in situ hybridization-correlative light and electron microscopy (FISH-CLEM) method. Carbohydrate degradation potential was reported previously for "Candidatus Poribacteria" and SAUL, typical symbionts of HMA sponges, and we propose here that HMA sponge symbionts collectively engage in degradation of dissolved organic matter, both labile and recalcitrant. Thus, sponge microbes may not only provide nutrients to the sponge host, but they may also contribute to dissolved organic matter (DOM) recycling and primary productivity in reef ecosystems via a pathway termed the sponge loop. IMPORTANCE Chloroflexi represent a widespread, yet enigmatic bacterial phylum with few cultivated members. We used metagenomic and single-cell genomic approaches to characterize the functional gene repertoire of Chloroflexi symbionts in marine sponges. The results of this study suggest clade-specific metabolic specialization and that Chloroflexi symbionts have the genomic potential for dissolved organic matter (DOM) degradation from seawater. Considering the abundance and dominance of sponges in many benthic environments, we predict that the role of sponge symbionts in biogeochemical cycles is larger than previously thought.


Paleocirculation of the deep north atlantic: 150,000-year record of benthic foraminifera and oxygen-18.
Benthic foraminiferal faunas in a piston core from 3331 meters at 44 degrees N on the Mid-Atlantic Ridge show striking variations in the relative abundance of species. Uvigerina peregrina, which is broadly distributed today in the South Atlantic and in the Pacific in water that has been long isolated from the surface, is absent in the North and Equatorial Atlantic at depths occupied by highly oxygenated North Atlantic deep water. This species dominated the fauna at this site for much of the past 150,000 years. It is suggested that North Atlantic deepwater production was much reduced or eliminated at times of Uvigerina peregrina abundance, as a result of cooling and stratification of the Norwegian Sea surface, coincident with the times of the southward migration of the polar front in the North Atlantic.


[Asymmetry of the cerebral hemispheres during comparison of paired visual stimuli].
In conditions of tachistoscopic presentation of visual stimuli, healthy (male and female) right-handed subjects carried out a paired comparison of the stimuli presented unilaterally and in the center of the visual field. In case of recognition of images of words and objects, the number of correct answers and motor reaction time usually did not significantly differ at two interstimuli intervals (1 and 10 s). In comparing images of faces, there also were no differences by the number of reactions, and the reaction time was less at the intervals of 1 s. The left hemisphere dominated at the identification of words and female faces, the right one--at the recognition of male faces. When the right visual field was stimulated images of various classes were recognized more differentially than at the stimulation of the left visual field. The male subjects had more prominent interhemispheric differences than the females. The increase of the interstimuli interval from 1 to 10 s brought to a weakening of the functional interhemispheric asymmetry and decreasing of the differences between the male and female subjects. The obtained data show that in the processes connected with short-time memory, functional interhemispheric asymmetry is basically formed at the initial stages of the information processing.


Shared neural representations of tactile roughness intensities by somatosensation and touch observation using an associative learning method.
Previous human fMRI studies have reported activation of somatosensory areas not only during actual touch, but also during touch observation. However, it has remained unclear how the brain encodes visually evoked tactile intensities. Using an associative learning method, we investigated neural representations of roughness intensities evoked by (a) tactile explorations and (b) visual observation of tactile explorations. Moreover, we explored (c) modality-independent neural representations of roughness intensities using a cross-modal classification method. Case (a) showed significant decoding performance in the anterior cingulate cortex (ACC) and the supramarginal gyrus (SMG), while in the case (b), the bilateral posterior parietal cortices, the inferior occipital gyrus, and the primary motor cortex were identified. Case (c) observed shared neural activity patterns in the bilateral insula, the SMG, and the ACC. Interestingly, the insular cortices were identified only from the cross-modal classification, suggesting their potential role in modality-independent tactile processing. We further examined correlations of confusion patterns between behavioral and neural similarity matrices for each region. Significant correlations were found solely in the SMG, reflecting a close relationship between neural activities of SMG and roughness intensity perception. The present findings may deepen our understanding of the brain mechanisms underlying intensity perception of tactile roughness.


Establishing Chronic Toxicity Effect Levels for Zebrafish (Danio rerio) Exposed to Perfluorooctane Sulfonate.
Zebrafish (Danio rerio) are among the aquatic species most sensitive to perfluorooctane sulfonate (PFOS). Environmental regulatory agencies and researchers use effect benchmarks from laboratory zebrafish PFOS toxicity studies in PFOS-spiked water to calculate PFOS aquatic life criteria. Threshold values as low as 0.7 µg/L (identified in an early, limited scope study) have been used in criteria derivation and site-specific aquatic ecological risk assessments. The present study reviews PFOS effects benchmarks for lethality, growth, and reproduction endpoints from more than 20 zebrafish toxicity studies, including a recent multigenerational study conducted by the United States Army Corps of Engineers Engineer Research & Development Center. Our review of 12 key studies examining long-term, chronic exposures (including multigenerational exposures of 300 days or more) indicated that 0.7 µg/L should not be used as a conservative screening threshold given that effects could not be repeated at this concentration by the recent enhanced multigenerational study. Based on this finding and multiple chronic sublethal studies on PFOS in zebrafish, chronic effects on lethality, growth, and reproduction occur at concentrations two orders of magnitude higher than 0.7 µg/L. Overall, the present review indicates a no-effect screening level of 31 µg/L and a low-effect screening level of 96 µg/L should be used to develop PFOS aquatic life criteria and to inform site-specific ecological risk assessments that are charged with evaluating risks to freshwater fish. Environ Toxicol Chem 2023;00:1-12. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.


Vaccinations for healthcare personnel: update on influenza, hepatitis B, and pertussis.
Healthcare personnel (HCP) are at risk for exposure to and transmission of potentially life-threatening vaccine preventable diseases to patients and colleagues. The Centers for Disease Control and Advisory Committee on Immunization Practices (ACIP) recommend routine influenza immunization and maintenance of immunity to hepatitis B and pertussis, among others. In this article, we aim to review recently approved influenza vaccines, as well as address some of the issues regarding hepatitis B and pertussis vaccinations in HCP. Several new formulations of influenza vaccines are now available, including quadrivalent vaccines and non-egg-based vaccines; their use in HCP requires further study. An alarming rise in pertussis rates has led to a revision of ACIP guidelines recommending vaccination for women during each pregnancy. Persistent lack of immunity to hepatitis B after vaccine series remains a problem for many HCP. Inactivated trivalent influenza vaccines remain the safest and most widely studied influenza vaccinations for healthcare workers. A pertussis booster in the form of Tdap is now recommended for most HCP. More studies are needed regarding the issue of nonresponders in HCP who receive the three-dose hepatitis B vaccine series, as there are some promising strategies available that may boost immune responses.


Psychosocial impact of scars due to cutaneous leishmaniasis on high school students in Errachidia province, Morocco.
In Morocco, cutaneous leishmaniasis (CL) is usually known to be a slowly healing localized skin disease, but in some cases, it can lead to mutilating scars. The outbreak of CL due to Leishmania major in the Errachidia province in southeastern Morocco between 2008 and 2010 left many adolescents with permanent scar tissue on the face or other exposed body parts. We studied the psychosocial impact of CL on these young people. In 2015 we conducted a cross-sectional survey among high-school students living in boarding schools in two CL-endemic areas of Errachidia: Rissani and Tinejdad. A self-administered questionnaire elicited responses about general knowledge of CL and related scars. An open-ended question focused on the possible psychosocial effects associated with these scars. The quantitative data were analyzed with Epi Info™ and the text data with NVivo software. Almost 20% of 448 respondents reported they had experienced a CL lesion and 87% said it could possibly or definitely lead to psychological consequences. The text analysis showed that girls more often than boys expanded on the negative psychological effects of CL. The students considered CL as "dangerous", "serious", and "deathly", and said it sometimes led to extreme suicidal ideations. The burden of CL in this age group is not negligible. The indelible CL scars lead to self-stigma and social stigma, and the emergence of negative psychological effects in this age group. While some students accepted their CL scars and related suffering as their "destiny", others were eagerly demanding protective measures against CL and treatment for the scars.


Once Daily High Dose Tigecycline Is Optimal: Tigecycline PK/PD Parameters Predict Clinical Effectiveness.
The clinical effectiveness of tigecycline depends on appropriate use, and PK/PD (pharmacokinetic/pharmacodynamic) parameters related to dose and dosing interval. In our 600-bed university-affiliated teaching hospital, we conducted a tigecycline efficacy review over a three-month period in 34 evaluable patients. Parameters assessed included clinical response, cure or treatment failure, once daily as q12h dosing, maintenance dosing, high dose vs. standard loading regimens, adverse effects, and the effect of infectious disease consultation on outcomes. We found once daily high dose tigecycline (HDT) was highly effective in treating serious systemic infections due to MDR Gram-positive/negative pathogens as well as C. difficile colitis. Adverse effects were infrequent and limited to mild nausea/vomiting. Once daily HDT was highly effective, and the few treatment failures were related to suboptimal/split dosing regimens. Once daily HDT was highly effective when used to treat susceptible pathogens and when optimally dosed, i.e., 200-400 mg (IV) loading dose ×1, followed by a once daily maintenance dose of 100-200 mg (IV) q24h.


Up-regulation of DRP-3 long isoform during the induction of neural progenitor cells by glutamate treatment in the ex vivo rat retina.
Glutamate has been shown to induce neural progenitor cells in the adult vertebrate retina. However, protein dynamics during progenitor cell induction by glutamate are not fully understood. To identify specific proteins involved in the process, we employed two-dimensional electrophoresis-based proteomics on glutamate untreated and treated retinal ex vivo sections. Rat retinal tissues were incubated with 1 mM glutamate for 1 h, followed by incubation in glutamate-free media for a total of 24 h. Consistent with prior reports, it was found that mitotic cells appeared in the outer nuclear layer without any histological damage. Immunohistological evaluations and immunoblotting confirmed the emergence of neuronal progenitor cells in the mature retina treated with glutamate. Proteomic analysis revealed the up-regulation of dihydropyrimidinase-related protein 3 (DRP-3), DRP-2 and stress-induced-phosphoprotein 1 (STIP1) during neural progenitor cell induction by glutamate. Moreover, mRNA expression of DRP-3, especially, its long isoform, robustly increased in the treated retina compared to that in the untreated retina. These results may indicate that glutamate induces neural progenitor cells in the mature rat retina by up-regulating the proteins which mediate cell mitosis and neurite growth.


Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli.
Drosophila Suppressor of fused (Su(fu)) encodes a novel 468-amino-acid cytoplasmic protein which, by genetic analysis, functions as a negative regulator of the Hedgehog segment polarity pathway. Here we describe the primary structure, tissue distribution, biochemical and functional analyses of a human Su(fu) (hSu(fu)). Two alternatively spliced isoforms of hSu(fu) were identified, predicting proteins of 433 and 484 amino acids, with a calculated molecular mass of 48 and 54 kDa, respectively. The two proteins differ only by the inclusion or exclusion of a 52-amino-acid extension at the carboxy terminus. Both isoforms were expressed in multiple embryonic and adult tissues, and exhibited a developmental profile consistent with a role in Hedgehog signaling. The hSu(fu) contains a high-scoring PEST-domain, and exhibits an overall 37% sequence identity (63% similarity) with the Drosophila protein and 97% sequence identity with the mouse Su(fu). The hSu(fu) locus mapped to chromosome 10q24-q25, a region which is deleted in glioblastomas, prostate cancer, malignant melanoma and endometrial cancer. HSu(fu) was found to repress activity of the zinc-finger transcription factor Gli, which mediates Hedgehog signaling in vertebrates, and to physically interact with Gli, Gli2 and Gli3 as well as with Slimb, an F-box containing protein which, in the fly, suppresses the Hedgehog response, in part by stimulating the degradation of the fly Gli homologue. Coexpression of Slimb with Su(fu) potentiated the Su(fu)-mediated repression of Gli. Taken together, our data provide biochemical and functional evidence for the hypothesis that Su(fu) is a key negative regulator in the vertebrate Hedgehog signaling pathway. The data further suggest that Su(fu) can act by binding to Gli and inhibiting Gli-mediated transactivation as well as by serving as an adaptor protein, which links Gli to the Slimb-dependent proteasomal degradation pathway.