Bidirectional effects of Internet-specific parenting practices and compulsive social media and Internet game use.
This two-wave prospective study investigated the bidirectional relation between Internet-specific parenting (reactive restrictions, Internet-specific rules, and frequency and quality of communication about Internet) and adolescents' symptoms of social media disorder (SMD) and Internet gaming disorder (IGD). In addition, we investigated whether this relation was different for boys and girls. A sample of 352 adolescents (48.9% boys, Mage = 13.9, SDage = 0.74, range: 11-15) completed questionnaires at two waves. Zero-inflated cross-lagged analyses in Mplus were performed to predict the level of IGD and SMD symptoms by Internet-specific parenting practices and vice versa, while controlling for age, level of education, and outcome at T1. More frequent parent-adolescent communication about Internet predicted more IGD (β = 0.26, p = .03) and SMD symptoms among boys, and more restrictive rules predicted fewer SMD symptoms among girls (β = -0.23, p = .08). More IGD symptoms predicted more reactive rules (β = 0.20, p = .08) among boys and girls and a higher frequency (β = 0.16, p = .02) and lower quality of communication (β = -0.24, p < .001) among boys and girls, respectively. This study demonstrates bidirectional relations between Internet-specific parenting and IGD symptoms, but not SMD symptoms. Displaying IGD symptoms seems to elicit ineffective parental responses, which may further exacerbate problematic involvement in gaming. With respect to problematic social use media among girls, this study suggests that parents should set strict rules regarding Internet use, prior to problematic use of social media. Longitudinal studies on the role of parenting in development of Internet-related disorders would be promising in enhancing our understanding of how parents can effectively prevent problematic involvement in online behaviors among their children.


Pharmacometabolomics of response to sertraline and to placebo in major depressive disorder - possible role for methoxyindole pathway.
Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ(2)(1) = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.


The Effective Dynamic Ranges for Glaucomatous Visual Field Progression With Standard Automated Perimetry and Stimulus Sizes III and V.
It has been shown that threshold estimates below approximately 20 dB have little effect on the ability to detect visual field progression in glaucoma. We aimed to compare stimulus size V to stimulus size III, in areas of visual damage, to confirm these findings by using (1) a different dataset, (2) different techniques of progression analysis, and (3) an analysis to evaluate the effect of censoring on mean deviation (MD). In the Iowa Variability in Perimetry Study, 120 glaucoma subjects were tested every 6 months for 4 years with size III SITA Standard and size V Full Threshold. Progression was determined with three complementary techniques: pointwise linear regression (PLR), permutation of PLR, and linear regression of the MD index. All analyses were repeated on "censored'' datasets in which threshold estimates below a given criterion value were set to equal the criterion value. Our analyses confirmed previous observations that threshold estimates below 20 dB contribute much less to visual field progression than estimates above this range. These findings were broadly similar with stimulus sizes III and V. Censoring of threshold values < 20 dB has relatively little impact on the rates of visual field progression in patients with mild to moderate glaucoma. Size V, which has lower retest variability, performs at least as well as size III for longitudinal glaucoma progression analysis and appears to have a larger useful dynamic range owing to the upper sensitivity limit being higher.


How linear tension converts to curvature: geometric control of bone tissue growth.
This study investigated how substrate geometry influences in-vitro tissue formation at length scales much larger than a single cell. Two-millimetre thick hydroxyapatite plates containing circular pores and semi-circular channels of 0.5 mm radius, mimicking osteons and hemi-osteons respectively, were incubated with MC3T3-E1 cells for 4 weeks. The amount and shape of the tissue formed in the pores, as measured using phase contrast microscopy, depended on the substrate geometry. It was further demonstrated, using a simple geometric model, that the observed curvature-controlled growth can be derived from the assembly of tensile elements on a curved substrate. These tensile elements are cells anchored on distant points of the curved surface, thus creating an actin "chord" by generating tension between the adhesion sites. Such a chord model was used to link the shape of the substrate to cell organisation and tissue patterning. In a pore with a circular cross-section, tissue growth increases the average curvature of the surface, whereas a semi-circular channel tends to be flattened out. Thereby, a single mechanism could describe new tissue growth in both cortical and trabecular bone after resorption due to remodelling. These similarities between in-vitro and in-vivo patterns suggest geometry as an important signal for bone remodelling.


NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures.
Loss-of-function mutations in genes generating reactive oxygen species (ROS), such as NOX1, are associated with IBD. Mechanisms whereby loss of ROS drive IBD are incompletely defined. ROS measurements and single-cell transcriptomics were performed on colonoids stratified by NOX1 genotype and TNFα stimulation. Clustering of epithelial cells from human UC (inflamed and uninflamed) scRNASeq was performed. Validation of M cell induction was performed by immunohistochemistry using UEA1 (ulex europaeus agglutin-1 lectin) and in vivo with DSS injury. TNFα induces ROS production more in NOX1-WT versus NOX1-deficient murine colonoids under a range of Wnt-mediated and Notch-mediated conditions. scRNASeq from inflamed and uninflamed human colitis versus TNFα stimulated, in vitro colonoids defines substantially shared, induced transcription factors; NOX1-deficient colonoids express substantially lower levels of STAT3 (signal transducer and activator of transcription 3), CEBPD (CCAAT enhancer-binding protein delta), DNMT1 (DNA methyltransferase) and HIF1A (hypoxia-inducible factor) baseline. Subclustering unexpectedly showed marked TNFα-mediated induction of M cells (sentinel cells overlying lymphoid aggregates) in NOX1-deficient colonoids. M cell induction by UEA1 staining is rescued with H2O2 and paraquat, defining extra- and intracellular ROS roles in maintenance of LGR5+ stem cells. DSS injury demonstrated GP2 (glycoprotein-2), basal lymphoplasmacytosis and UEA1 induction in NOX1-deficiency. Principal components analyses of M cell genes and decreased DNMT1 RNA velocity correlate with UC inflammation. NOX1 deficiency plus TNFα stimulation contribute to colitis through dysregulation of the stem cell niche and altered cell differentiation, enhancing basal lymphoplasmacytosis. Our findings prioritise ROS modulation for future therapies.


Intracranial Hemangiopericytoma in a Child: A Case Report with Magnetic Resonance Spectroscopy Findings.
Hemangiopericytoma is a hypervascular soft tissue sarcoma with a predilection for the extremities. It has two clinical types according to the age of presentation: Infantile hemangiopericytoma ( < 1 years) and adult type hemangiopericytoma ( > 1 years). The intracranial location is very rare and accounts for only 0.4-1% of all primary brain tumors, with only 10% detected in the pediatric age group. The differential diagnosis of this rare tumor from other extra-axial masses plays an important role in proper treatment planning. There are few case reports in adult patients indicating that magnetic resonance spectroscopy (MRS) can play a role in the differential diagnosis. Here, we present imaging findings of this rare tumor, including MRS at 3.0T of an intracranial hemangiopericytoma in a 4.5 year old boy.


Green, catalytic oxidation of alcohols in water
Alcohol oxidations are typically performed with stoichiometric reagents that generate heavy-metal waste and are usually run in chlorinated solvents. A water-soluble palladium(II) bathophenanthroline complex is a stable recyclable catalyst for the selective aerobic oxidation of a wide range of alcohols to aldehydes, ketones, and carboxylic acids in a biphasic water-alcohol system. The use of water as a solvent and air as the oxidant makes the reaction interesting from both an economic and environmental point of view.


X-ray phase-contrast imaging of the breast--advances towards clinical implementation.
Breast cancer constitutes about one-quarter of all cancers and is the leading cause of cancer death in women. To reduce breast cancer mortality, mammographic screening programmes have been implemented in many Western countries. However, these programmes remain controversial because of the associated radiation exposure and the need for improvement in terms of diagnostic accuracy. Phase-contrast imaging is a new X-ray-based technology that has been shown to provide enhanced soft-tissue contrast and improved visualization of cancerous structures. Furthermore, there is some indication that these improvements of image quality can be maintained at reduced radiation doses. Thus, X-ray phase-contrast mammography may significantly contribute to advancements in early breast cancer diagnosis. Feasibility studies of X-ray phase-contrast breast CT have provided images that allow resolution of the fine structure of tissue that can otherwise only be obtained by histology. This implies that X-ray phase-contrast imaging may also lead to the development of entirely new (micro-) radiological applications. This review provides a brief overview of the physical characteristics of this new technology and describes recent developments towards clinical implementation of X-ray phase-contrast imaging of the breast.


On the precision of time-of-flight shear wave speed estimation in homogeneous soft solids: initial results using a matrix array transducer.
A system capable of tracking radiation-force-induced shear wave propagation in a 3-D volume using ultrasound is presented. In contrast to existing systems, which use 1-D array transducers, a 2-D matrix array is used for tracking shear wave displacements. A separate single-element transducer is used for radiation force excitation. This system allows shear wave propagation in all directions away from the push to be observed. It is shown that for a limit of 64 tracking beams, by placing the beams at the edges of the measurement region of interest (ROI) at multiple directions from the push, time-of- flight (TOF) shear wave speed (SWS) measurement uncertainty can theoretically be reduced by 40% compared with equally spacing the tracking beams within the ROI along a single plane, as is typical when using a 1-D array for tracking. This was verified by simulation, and a reduction of 30% was experimentally observed on a homogeneous phantom. Analytical expressions are presented for the relationship between TOF SWS measurement uncertainty and various shear wave imaging parameters. It is shown that TOF SWS uncertainty is inversely proportional to ROI size, and inversely proportional to the square root of the number of tracking locations for a given distribution of beam locations relative to the push. TOF SWS uncertainty is shown to increase with the square of the SWS, indicating that TOF SWS measurements are intrinsically less precise for stiffer materials.


EnzymeDetector: an integrated enzyme function prediction tool and database.
The ability to accurately predict enzymatic functions is an essential prerequisite for the interpretation of cellular functions, and the reconstruction and analysis of metabolic models. Several biological databases exist that provide such information. However, in many cases these databases provide partly different and inconsistent genome annotations. We analysed nine prokaryotic genomes and found about 70% inconsistencies in the enzyme predictions of the main annotation resources. Therefore, we implemented the annotation pipeline EnzymeDetector. This tool automatically compares and evaluates the assigned enzyme functions from the main annotation databases and supplements them with its own function prediction. This is based on a sequence similarity analysis, on manually created organism-specific enzyme information from BRENDA (Braunschweig Enzyme Database), and on sequence pattern searches. EnzymeDetector provides a fast and comprehensive overview of the available enzyme function annotations for a genome of interest. The web interface allows the user to work with customisable weighting schemes and cut-offs for the different prediction methods. These customised quality criteria can easily be applied, and the resulting annotation can be downloaded. The summarised view of all used annotation sources provides up-to-date information. Annotation errors that occur in only one of the databases can be recognised (because of their low relevance score). The results are stored in a database and can be accessed at http://enzymedetector.tu-bs.de.


Chronic post thoracotomy pain.
Chronic post-thoracotomy pain (CPP) is a vexing clinical problem whose management has received scant attention. In order to identify the risk factors associated with CPP and determine the optimal treatment, the records of 238 consecutive patients who underwent thoracotomy were reviewed. CPP was defined as discomfort requiring the regular administration of analgesics that continued more than three months following surgery. CPP was present in 25 (11%) patients: 10/20 (50%) chest wall resections, 5/25 (20%) pleurectomies, 10/193 (5%) pulmonary resections. Among the 23 patients who required preoperative narcotics, 12 (52%) developed CPP. Improved pain control and decreased narcotic use was achieved via the administration of nonsteroidal anti-inflammatory medication and tricyclic anti-depressants. In addition, 10/25 patients required 11 pain procedures: trigger-point injection, intercostal blocks, injections of epidural steroids, stellate ganglion block. Recurrent pain occurred in 20 patients following initial control. All were found to have tumor regrowth. We conclude that CPP occurs more commonly following chest-wall resection and pleurectomy, and that preoperative narcotic use is a predictor of CPP. Worsening pain following initial relief should prompt a vigorous search for recurrent cancer.


An antibiotic-responsive mouse model of fulminant ulcerative colitis.
The constellation of human inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn's disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn's disease. We generated a novel mouse line (dnKO) that possessed defects in both TGFbetaRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNgamma and TNFalpha and was completely inhibited by a combination of broad-spectrum antibiotics. Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting disease is sensitive to both anticytokine therapy and broad-spectrum antibiotics. These findings indicated the IL-10 and TGFbeta pathways synergize to inhibit microbially induced production of proinflammatory cytokines, including IFNgamma and TNFalpha, which are known to play a role in the pathogenesis of human ulcerative colitis. Our findings also provide evidence that broad-spectrum antibiotics may have an application in the treatment of patients with ulcerative colitis. This model system will be useful in the future to explore the microbial factors that induce immune activation and characterize how these interactions produce disease.


Ribonucleocapsid formation of severe acute respiratory syndrome coronavirus through molecular action of the N-terminal domain of N protein.
Conserved among all coronaviruses are four structural proteins: the matrix (M), small envelope (E), and spike (S) proteins that are embedded in the viral membrane and the nucleocapsid phosphoprotein (N), which exists in a ribonucleoprotein complex in the lumen. The N-terminal domain of coronaviral N proteins (N-NTD) provides a scaffold for RNA binding, while the C-terminal domain (N-CTD) mainly acts as oligomerization modules during assembly. The C terminus of the N protein anchors it to the viral membrane by associating with M protein. We characterized the structures of N-NTD from severe acute respiratory syndrome coronavirus (SARS-CoV) in two crystal forms, at 1.17 A (monoclinic) and at 1.85 A (cubic), respectively, resolved by molecular replacement using the homologous avian infectious bronchitis virus (IBV) structure. Flexible loops in the solution structure of SARS-CoV N-NTD are now shown to be well ordered around the beta-sheet core. The functionally important positively charged beta-hairpin protrudes out of the core, is oriented similarly to that in the IBV N-NTD, and is involved in crystal packing in the monoclinic form. In the cubic form, the monomers form trimeric units that stack in a helical array. Comparison of crystal packing of SARS-CoV and IBV N-NTDs suggests a common mode of RNA recognition, but they probably associate differently in vivo during the formation of the ribonucleoprotein complex. Electrostatic potential distribution on the surface of homology models of related coronaviral N-NTDs suggests that they use different modes of both RNA recognition and oligomeric assembly, perhaps explaining why their nucleocapsids have different morphologies.


Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis.
Microsatellite instability (MSI) has been associated with colitic cancer. However, reported frequency of MSI was varied and the association of MSI with mismatch repair (MMR) deficiency was unclear. In addition, the occurrence of genetic alterations in stromal cells within ulcerative colitis (UC) is still controversial. We therefore sampled 164 microareas in various pathological lesions of UC with or without colitic cancer and studied the MSI status in relation to the DNA repair protein expressions. A total of 129 microfoci from colorectal tissue of 5 colitic cancer patients and 35 microfoci of 7 UC patients (without neoplasm) were carefully sampled by laser-capture microdissection. MSI was analyzed in each microsamples. The protein expression of MMR genes (MLH1, MSH2, MSH6), O(6)-methylguanine-DNA methyltransferase and p53 were assessed by immunohistochemical analysis. Variety of di-nulcleotide microsatellite markers was altered in individual microfoci from different morphological epithelial lesions, in full range of nonneoplastic epithelium to colitic cancer. Interestingly, MSI was not observed in stromal cells at any sites, including those within colitic cancer/dysplasia lesions. Expression of the MMR proteins was not lost in any of the lesions examined. Microsatellite alterations rather seem to be related to the initiation than to the progression of colitic cancer.


Adaptation of short-term plasticity parameters via error-driven learning may explain the correlation between activity-dependent synaptic properties, connectivity motifs and target specificity.
The anatomical connectivity among neurons has been experimentally found to be largely non-random across brain areas. This means that certain connectivity motifs occur at a higher frequency than would be expected by chance. Of particular interest, short-term synaptic plasticity properties were found to colocalize with specific motifs: an over-expression of bidirectional motifs has been found in neuronal pairs where short-term facilitation dominates synaptic transmission among the neurons, whereas an over-expression of unidirectional motifs has been observed in neuronal pairs where short-term depression dominates. In previous work we found that, given a network with fixed short-term properties, the interaction between short- and long-term plasticity of synaptic transmission is sufficient for the emergence of specific motifs. Here, we introduce an error-driven learning mechanism for short-term plasticity that may explain how such observed correspondences develop from randomly initialized dynamic synapses. By allowing synapses to change their properties, neurons are able to adapt their own activity depending on an error signal. This results in more rich dynamics and also, provided that the learning mechanism is target-specific, leads to specialized groups of synapses projecting onto functionally different targets, qualitatively replicating the experimental results of Wang and collaborators.


Survival responses of human embryonic stem cells to DNA damage.
Pluripotent human embryonic stem (hES) cells require mechanisms to maintain genomic integrity in response to DNA damage that could compromise competency for lineage-commitment, development, and tissue-renewal. The mechanisms that protect the genome in rapidly proliferating hES cells are minimally understood. Human ES cells have an abbreviated cell cycle with a very brief G1 period suggesting that mechanisms mediating responsiveness to DNA damage may deviate from those in somatic cells. Here, we investigated how hES cells react to DNA damage induced by ionizing radiation (IR) and whether genomic insult evokes DNA repair pathways and/or cell death. We find that hES cells respond to DNA damage by rapidly inducing Caspase-3 and -8, phospho-H2AX foci, phosphorylation of p53 on Ser15 and p21 mRNA levels, as well as concomitant cell cycle arrest in G2 based on Ki67 staining and FACS analysis. Unlike normal somatic cells, hES cells and cancer cells robustly express the anti-apoptotic protein Survivin, consistent with the immortal growth phenotype. SiRNA depletion of Survivin diminishes hES survival post-irradiation. Thus, our findings provide insight into pathways and processes that are activated in human embryonic stem cells upon DNA insult to support development and tissue regeneration.


Patterns of temporal and enemy niche use by a community of leaf cone moths (Caloptilia) coexisting on maples (Acer) as revealed by metabarcoding.
The diversity of herbivorous insects is often considered a function of host plant diversity. However, recent research has uncovered many examples of closely related herbivores using the same host plant(s), suggesting that partitioning of host plants is not the only mechanism generating diversity. Herbivores sharing hosts may utilize different parts of the same plant, but such resource partitioning is often not apparent; hence, the factors that allow closely related herbivores to coexist are still largely undetermined. We examined whether partitioning of phenology or natural enemies may explain the coexistence of leaf cone moths (Caloptilia; Gracillariidae) associated with maples (Acer; Sapindaceae). Larval activity of 10 sympatric Caloptilia species found on nine maple species was monitored every 2-3 weeks for a total of 13 sampling events, and an exhaustive search for internal parasitoid wasps was conducted using high-throughput sequencing. Blocking primers were used to facilitate the detection of wasp larvae inside moth tissue. We found considerable phenological overlap among Caloptilia species, with two clear peaks in July and September-October. Coexisting Caloptilia species also had largely overlapping parasitoid communities; a total of 13 chalcid and ichneumon wasp species attacked Caloptilia in a nonspecific fashion at an overall parasitism rate of 46.4%. Although coexistence may be facilitated by factors not accounted for in this study, it appears that niche partitioning is not necessary for closely related herbivores to stably coexist on shared hosts. Co-occurrence without resource partitioning may provide an additional axis along which herbivorous insects attain increased species richness.


Three subgroups of pain profiles identified in 227 women with arthritis: a latent class analysis.
The objectives were to identify subgroups of women with arthritis based upon the multi-dimensional nature of their pain experience and to compare health and socio-demographic variables between subgroups. A latent class analysis of 227 women with self-reported arthritis was used to identify clusters of women based upon the sensory, affective, and cognitive dimensions of the pain experience. Multivariate multinomial logistic regression analysis was used to determine the relationship between cluster membership and health and sociodemographic characteristics. A three-class cluster model was most parsimonious. 39.5 % of women had a unidimensional pain profile; 38.6 % of women had moderate multidimensional pain profile that included additional pain symptomatology such as sensory qualities and pain catastrophizing; and 21.9 % of women had severe multidimensional pain profile that included prominent pain symptomatology such as sensory and affective qualities of pain, pain catastrophizing, and neuropathic pain. Women with severe multidimensional pain profile have a 30.5 % higher risk of poorer quality of life and a 7.3 % higher risk of suffering depression, and women with moderate multidimensional pain profile have a 6.4 % higher risk of poorer quality of life when compared to women with unidimensional pain. This study identified three distinct subgroups of pain profiles in older women with arthritis. Women had very different experiences of pain, and cluster membership impacted significantly on health-related quality of life. These preliminary findings provide a stronger understanding of profiles of pain and may contribute to the development of tailored treatment options in arthritis.


Dysfunctional nitric oxide signalling increases risk of myocardial infarction.
Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.


T cell dependence of the "natural" autoreactive B cell activation in the spleen of normal mice.
A high frequency of clonal precursor B cells producing lytic antibodies to syngeneic erythrocytes treated with bromelain (BMRC) is revealed in normal mouse spleen cells by lipopolysaccharide-driven limiting dilution analysis. All such specificities are recovered as activated blasts after density gradient fractionation, the "small lymphocyte" pool being depleted of anti-BMRC reactivities. In contrast, the spleens of athymic (nude) mice contain undetectably low frequencies of these specificities in either lymphocyte compartment. Transfer of relatively low numbers of normal syngeneic splenic T lymphocytes to adult nude mice restores the high frequency of anti-BMRC clonal precursor B cells, again in the activated, but not in the resting spleen cell fractions. Large total T cells are more than tenfold better than resting T cells in reconstitution potential, as are enriched CD4+ as compared to CD8+ cells which are practically devoid of activity in this respect. These results apply exclusively to B cells at a differentiative stage that allows for extensive clonal expansion, since there is a marked difference between the frequency of clonal precursors determined by limiting dilution analysis and the frequency of Ig-secreting plaque-forming cells of the same specificity, and induced by the same mitogen in short-term cultures. The implications of these findings for the physiology of autoreactivity and repertoire selection in the compartment of perinatal B cells are discussed.


Sex differences in common childhood infections in Taiwan.
Sex differences in childhood infections are commonly reported in case-only studies. In this population-based study of 278000 Taiwanese children followed from 3 months to 18 years of age during the period 2000-2012, age-trajectories of monthly numbers of all-cause healthcare visits and monthly rates of infection-specific healthcare visits were compared between boys and girls. For all-cause healthcare visits and for healthcare visits related to conjunctivitis, respiratory tract infections, enteritis, hand, foot, and mouth disease, and herpangina, there was good resemblance of age trajectories between boys and girls. Despite this resemblance, there was evidence of a slightly higher rate in boys than in girls under age 6 years (i.e., a male tendency, or male-to-female ratio >1.0) across all diagnoses except herpangina. For urinary tract infection, where an age-specific sex difference is well reported in case-only studies, this population-based study confirmed that there was a much higher rate of kidney infection among boys than among girls during infancy, and a higher rate of kidney and bladder infection among girls than among boys after this period. The age-specific sex difference in urinary tract infections was so strong that the age trajectories in boys and girls were qualitatively different. This report confirms previously reported sex differences in other countries, whilst placing this in the context of age dynamics in childhood infection.


Anatomy of a live invertebrate revealed by manganese-enhanced Magnetic Resonance Imaging.
Non-invasive imaging technologies such as Magnetic Resonance Imaging (MRI) are increasingly in demand by researchers in many biological disciplines. However, when imaging small animals such as invertebrates, not only is the use of high-field magnets necessary to gain satisfactory spatial resolution, but the achievement of adequate contrast between tissues also requires the identification of applicable imaging parameters by means of expensive and time-consuming procedures. Here we report that systemically administered manganese can act as an effective MRI contrast agent for quick and non-invasive imaging of the nervous system and other complex anatomical structures in a small aquatic animal. Due to the tendency of manganese ions to differentially accumulate in most soft tissues, higher overall signal intensity and strongly improved contrast between structures yield data well suited for digital post-processing into three-dimensional models. Within a few hours this technique can efficiently generate anatomical images that are not obtainable with conventional methods, thus demonstrating a new and exciting approach to invertebrate research.


A primary school outbreak of pandemic 2009 influenza A (H1N1) in China.
We investigated the first known outbreak of pandemic 2009 influenza A (H1N1) at a primary school in China. To describe epidemiologic findings, identify risk factors associated with 2009 H1N1 illness, and inform national policy including school outbreak control and surveillance strategies. We conducted retrospective case finding by reviewing the school's absentee log and retrieving medical records. Enhanced surveillance was implemented by requiring physicians to report any influenza-like illness (ILI) cases to public health authorities. A case-control study was conducted to detect potential risk factors for 2009 H1N1 illness. A questionnaire was administered to 50 confirmed cases and 197 age-, gender-, and location-matched controls randomly selected from student and population registries. The attack rate was 4% (50/1314), and children from all grades were affected. When compared with controls, confirmed cases were more likely to have been exposed to persons with respiratory illness either in the home or classroom within 7 days of symptom onset (OR, 4.5, 95% CI: 1.9-10.7). No cases reported travel or contact with persons who had traveled outside of the country. Findings in this outbreak investigation, including risk of illness associated with contacting persons with respiratory illness, are consistent with those reported by others for seasonal influenza and 2009 H1N1 outbreaks in school. The outbreak confirmed that community-level transmission of 2009 H1N1 virus was occurring in China and helped lead to changes in the national pandemic policy from containment to mitigation.


Use of follow-up imaging in isolated perimesencephalic subarachnoid hemorrhage: a meta-analysis.
Multiple studies have shown that negative computed tomographic angiograms (CTAs) are reliable in excluding aneurysms in patients with isolated perimesencephalic subarachnoid hemorrhage (pSAH). We evaluate the use of digital subtraction angiography versus CTA for initial diagnosis and of angiographic follow-ups in patients with pSAH by performing an institutional analysis and a meta-analysis of literature. Retrospective institutional analysis of patients with pSAH was performed from 2008 to 2014. The number and types of follow-up imaging studies were tabulated. Initial and follow-up studies were evaluated by an experienced neuroradiologist for intracranial aneurysm. Meta-analysis of literature was performed to assess the use of initial digital subtraction angiography and of follow-up imaging. Our institutional review revealed no additional use of initial digital subtraction angiography or of any angiographic follow-up after initial negative CTA in patients with pSAH on noncontrast CT. Meta-analysis of 40 studies yielded a total of 1031 patients. Only 8 aneurysms were first diagnosed on follow-ups (0.78%). Careful review showed that some of these aneurysms reported on follow-up are of questionable validity. Initial digital subtraction angiography and follow-up imaging after a negative initial CTA showed no statistically significant benefits. In patients meeting the strict imaging criteria of pSAH, initial negative CTA is reliable in excluding aneurysms. A critical review of the literature through meta-analysis shows no foundation for multiple follow-up studies in patients with pSAH.


Progesterone-Dependent Induction of Phospholipase C-Related Catalytically Inactive Protein 1 (PRIP-1) in Decidualizing Human Endometrial Stromal Cells.
Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells. In pregnancy, decidual cells form a protective matrix around the implanting embryo, enabling coordinated trophoblast invasion and formation of a functional placenta. Continuous progesterone (P4) signaling renders decidual cells resistant to various environmental stressors, whereas withdrawal inevitably triggers tissue breakdown and menstruation or miscarriage. Here, we show that PLCL1, coding phospholipase C (PLC)-related catalytically inactive protein 1 (PRIP-1), is highly induced in response to P4 signaling in decidualizing human endometrial stromal cells (HESCs). Knockdown experiments in undifferentiated HESCs revealed that PRIP-1 maintains basal phosphoinositide 3-kinase/Protein kinase B activity, which in turn prevents illicit nuclear translocation of the transcription factor forkhead box protein O1 and induction of the apoptotic activator BIM. By contrast, loss of this scaffold protein did not compromise survival of decidual cells. PRIP-1 knockdown did also not interfere with the responsiveness of HESCs to deciduogenic cues, although the overall expression of differentiation markers, such as PRL, IGFBP1, and WNT4, was blunted. Finally, we show that PRIP-1 in decidual cells uncouples PLC activation from intracellular Ca(2+) release by attenuating inositol 1,4,5-trisphosphate signaling. In summary, PRIP-1 is a multifaceted P4-inducible scaffold protein that gates the activity of major signal transduction pathways in the endometrium. It prevents apoptosis of proliferating stromal cells and contributes to the relative autonomy of decidual cells by silencing PLC signaling downstream of Gq protein-coupled receptors.


Nonlinear least squares analysis of atmospheric absorption spectra.
The essential elements of practical nonlinear least squares analysis of atmospheric absorption spectra are discussed. These include speed of analysis, flexibility of spectrum type, and stability in the presence of noise. A computer program which embodies these elements is described, and two types of results are presented. The first is a series of least squares analyses of synthetic spectra, both noise free and noisy. The second is a summary of results from analyses of high resolution solar spectra. Among the parameters which have been fit are trace gas mixing ratios, temperatures, spectral background, instrument resolution, phase error and channel spectrum parameters, line shifts, intensities, and broadening coefficients.


Salvage Islet Auto Transplantation After Relaparatomy.
To assess feasibility, safety, and metabolic outcome of islet auto transplantation (IAT) in patients undergoing completion pancreatectomy because of sepsis or bleeding after pancreatic surgery. From November 2008 to October 2016, approximately 22 patients were candidates to salvage IAT during emergency relaparotomy because of postpancreatectomy sepsis (n = 11) or bleeding (n = 11). Feasibility, efficacy, and safety of salvage IAT were compared with those documented in a cohort of 36 patients who were candidate to simultaneous IAT during nonemergency preemptive completion pancreatectomy through the pancreaticoduodenectomy. The percentage of candidates that received the infusion of islets was significantly lower in salvage IAT than simultaneous IAT (59.1% vs 88.9%, P = 0.008), mainly because of a higher rate of inadequate islet preparations. Even if microbial contamination of islet preparation was significantly higher in candidates to salvage IAT than in those to simultaneous IAT (78.9% vs 20%, P < 0.001), there was no evidence of a higher rate of complications related to the procedure. Median follow-up was 5.45 ± 0.52 years. Four (36%) of 11 patients reached insulin independence, 6 patients (56%) had partial graft function, and 1 patient (9%) had primary graft nonfunction. At the last follow-up visit, median fasting C-peptide was 0.43 (0.19-0.93) ng/mL; median insulin requirement was 0.38 (0.04-0.5) U/kg per day, and median HbA1c was 6.6% (5.9%-8.1%). Overall mortality, in-hospital mortality, metabolic outcome, graft survival, and insulin-free survival after salvage IAT were not different from those documented after simultaneous IAT. Our data demonstrate the feasibility, efficacy, and safety of salvage IAT after relaparotomy.


Longevity of frictional telescopic crowns in the severely reduced dentition: 3-year results of a longitudinal prospective clinical study.
The longevity of frictional telescopic crowns (FTC) in severely reduced dentitions with 1 to 3 remaining teeth per jaw has not yet been studied prospectively and exclusively. Aims of this study were to estimate risks of telescope loss and abutment tooth loss and to determine abutment tooth mobility over time. A total of 74 patients with severely reduced dentitions received 82 telescopic removable partial dentures (TRPDs) retained with 173 FTCs. Dentures were reexamined after 1 week and 3, 6, 12, 18, 24, 30, and 36 months. Tooth mobility was monitored with Periotest values. Adjuvant therapies were carried out if necessary. Survival probabilities of telescopes and abutment teeth as well as the influence of clinical factors (age, sex, jaw, vitality, opposing dentition, axis inclination, end Periotest value, crown length, crown margin quality, wearing mode, tooth types, abutment distribution, number of telescopes) were calculated with Kaplan-Meier estimators. The relative risks for telescope loss were calculated with Cox regression. The survival rate was 93.9% for abutment teeth and 87.5% for telescopes. Number of telescopes, abutment distribution, vitality, and gender as factors influenced the survival rates (Kaplan-Meier). In combination with the jaw as a factor, these affected the risk for telescope loss (Cox regression). Periotest values (mean of abutment teeth per examination) decreased significantly (P < .0001). Altogether, 11% of teeth fractured and 4.6% of teeth were extracted. Patients were mostly very satisfied. TRPDs proved to be a favorable treatment concept for severely reduced dentitions. FTCs can be considered as elements with a good benefit-maintenance relation. A general increase of abutment tooth mobility could not be verified.


Effects of music on pain in patients with fibromyalgia.
Fibromyalgia syndrome (FMS) is a chronic syndrome characterized by diffuse musculoskeletal system pain and painful tender points in certain areas of the body. The aim of the investigation was to determine the effects of music on pain in fibromyalgia patients. This randomized clinical trial was carried out with 37 fibromyalgia outpatients as an experimental group (n = 21) and control group (n = 16) at a University Hospital Internal Medicine and Rheumatology Clinic between 1 June and 1 December 2014. The research instruments used were descriptive characteristics questionnaire, Visual Analogue Scale (VAS), music CD which includes water and wave sounds recommended by the Turkish Psychological Association for psychological relaxation, and pain evaluation form. According to the findings, the average age of patients was 43.59 years ± 10.30, 94.6 % were women and 81.1 % were married. The fibromyalgia patients had the disease ranged from 1 month to 20 years, the average of disease duration was 23.6 ± 45.5 months, and the average of pain intensity was 6.89 ± 1.64 on the VAS. Average pain was reported in the experimental group in VAS on day 1 (5.45 ± 2.73), day 7 (4.57 ± 2.71), and day 14 (4.14 ± 2.45), and significant reduction in pain in the listening music group was seen (p = 0.026). A repeated measure analysis of variance controlling for differences between days demonstrated a significant decrease in pain between day 1 and day 14 (p = 0.022). There was no significant decrease in pain among control group participants. The effect of music has been found to control pain in fibromyalgia patients. Music therapy should be suggested in pain management for fibromyalgia patients as an non-pharmacologic nursing intervention.


Three new species of Pseudodactylogyrus (Monogenea: Pseudodactylogyridae) from Australian eels.
Three species of Pseudodactylogyrus Gusev, 1965 (Monogenea: Pseudodactylogyridae) were collected from the gills of Anguilla reinhardtii Steindachner and A. australis Richardson from several localities in Australia and eels imported to Japan from Australia. Pseudodactylogyrus gusevi sp. n. from A. reinhardtii (type host) and A. australis in Queensland, Australia is most similar to P. bini (Kikuchi, 1929), but can be differentiated by the shorter male copulatory tube, heavy sclerotisation of the vaginal tube and the presence of a small projection of the supplementary piece of the hamulus. Pseudodactylogyrus rohdei sp. n. from A. australis (type host) in Queensland, Australia is most similar to P. anguillae (Yin et Sproston, 1948), but differs in the possession of a longer cement gland and the presence of a small projection on the supplementary piece of the hamulus. Pseudodactylogyrus bini sensu Gusev, 1965 and P. anguillae sensu Gusev, 1965 are synonymised with P. gusevi sp. n. and P. rohdei sp. n., respectively. Pseudodactylogyrus mundayi sp. n. from A. australis, originating in Tasmania, Australia and sent alive to Japan, is most similar to P. kamegaii Iwashita, Hirata et Ogawa, 2002, from which it can be discriminated by the shorter male copulatory tube and the shorter vaginal tube. Dactylogyrus bialatus Wu, Wang et Jian, 1988 from Synechogobius ommaturus (Richardson) (Gobiidae) is transferred to Pseudodactylogyrus as P. bialatus comb. n. A phylogenetic tree based on the ITS2 region of six species of Pseudodactylogyrus including P. gusevi and P. mundayi shows that P. haze from a goby diverged first, and that species from eels are monophyletic, forming three lineages differing by their zoogeographical distribution. With the three new species and one new combination proposed in this paper, Pseudodactylogyrus is now comprised of eight species infecting anguillid and gobiid fish, and a key to species is presented.


Prediction of in vivo drug clearance from in vitro data. II: potential inter-ethnic differences.
Potential differences in drug clearance between Japanese and Caucasians were investigated by integrating data on demography, liver size, the abundance of the major cytochromes P450 and in vitro metabolic parameters. Eleven drugs (alprazolam, caffeine, chlorzoxazone, cyclosporine, midazolam, omeprazole, sildenafil, tolbutamide, triazolam, S-warfarin and zolpidem) fulfilled the entry criteria of the study (i.e. the necessary in vitro metabolism data were available and clearance values had been reported both in Caucasians and Japanese). Values of relevant biological variables were obtained from the literature, and clearance predictions were made using the Simcyp Population-Based ADME Simulator. The ratios of observed oral clearance (CLp.o.) values in Caucasians compared with Japanese ranged from 0.6 to 2.8 (integrating data from 82 sources). The CLp.o. values for alprazolam, caffeine and zolpidem were not statistically different between Caucasian and Japanese (p>0.05), whereas those for chorzoxazone, cyclosporine, omeprazole, tolbutamide and triazolam were higher in Caucasians (p<0.05), and those for midazolam, sildenafil and S-warfarin were higher in Japanese (p<0.05). CLp.o. values, predicted from in vitro data, were within 3-fold of observed in vivo values for seven of the 11 drugs in Japanese. Values for the predicted ratios ranged from 1.6 to 4.9. The predicted ratios were not significantly different from observed ratios for cyclosporine, omeprazole, tolbutamide and triazolam. Only partial success in predicting ethnic differences in clearance indicates the need for larger and more reliable databases on relevant variables. With such information, in silico predictions might be used with more confidence to decrease the need for repeating pharmacokinetic studies in different ethnic groups.


A systematic review of hospitalization resulting from medicine-related problems in adult patients.
Medicine-related problems (MRPs) represent a major issue leading to hospitalization, especially in adult and elderly patients. The aims of this review are to investigate the prevalence, causes and major risk factors for MRPs leading to hospitalization in adult patients and to identify the main medicine classes involved. Studies were identified through electronic searches of Medline, Embase, Scopus and International Pharmaceutical Abstracts between January 2000 and May 2013. A systematic review was conducted of both retrospective and prospective studies. Studies included were those involving hospitalization resulting from MRPs in adults (≥18 years old), whereas studies excluded were those investigating drug misuse and abuse and studies investigating MRPs in hospitalized patients. Data analysis was performed using SPSS version 20. Forty-five studies were identified, including 21 that investigated hospitalization resulting from adverse drug reactions, six studies that investigated hospitalization due to adverse drug events and 18 studies that investigated hospitalization due to MRPs. The median prevalence rates of hospitalization resulting from adverse drug reactions, adverse drug events and MRPs were 7% (interquartile range, 2.4-14.9%), 4.6% (interquartile range, 2.85-16.6%) and 12.1% (interquartile range, 6.43-22.2%), respectively. The major causes contributing to MRPs were adverse drug reactions and noncompliance. In addition, the major risk factors associated with MRPs were old age, polypharmacy and comorbidities. Moreover, the main classes of medicines implicated were medicines used to treat cardiovascular diseases and diabetes. Hospitalization due to MRPs had a high prevalence, in the range of 4.6-12.1%. Most MRPs encountered were prevalent among adult patients taking medicines for cardiovascular diseases and diabetes.


GPCRs Direct Germline Development and Somatic Gonad Function in Planarians.
Planarians display remarkable plasticity in maintenance of their germline, with the ability to develop or dismantle reproductive tissues in response to systemic and environmental cues. Here, we investigated the role of G protein-coupled receptors (GPCRs) in this dynamic germline regulation. By genome-enabled receptor mining, we identified 566 putative planarian GPCRs and classified them into conserved and phylum-specific subfamilies. We performed a functional screen to identify NPYR-1 as the cognate receptor for NPY-8, a neuropeptide required for sexual maturation and germ cell differentiation. Similar to NPY-8, knockdown of this receptor results in loss of differentiated germ cells and sexual maturity. NPYR-1 is expressed in neuroendocrine cells of the central nervous system and can be activated specifically by NPY-8 in cell-based assays. Additionally, we screened the complement of GPCRs with expression enriched in sexually reproducing planarians, and identified an orphan chemoreceptor family member, ophis, that controls differentiation of germline stem cells (GSCs). ophis is expressed in somatic cells of male and female gonads, as well as in accessory reproductive tissues. We have previously shown that somatic gonadal cells are required for male GSC specification and maintenance in planarians. However, ophis is not essential for GSC specification or maintenance and, therefore, defines a secondary role for planarian gonadal niche cells in promoting GSC differentiation. Our studies uncover the complement of planarian GPCRs and reveal previously unappreciated roles for these receptors in systemic and local (i.e., niche) regulation of germ cell development.


A randomized clinical trial of adjuvant chemotherapy for radically resected locoregional relapse of breast cancer: IBCSG 27-02, BIG 1-02, and NSABP B-37.
In this phase III, multinational, randomized trial, the International Breast Cancer Study Group, Breast International Group, and the National Surgical Adjuvant Breast and Bowel Project will attempt to define the effectiveness of cytotoxic therapy for patients with locoregional recurrence of breast cancer. We will evaluate whether chemotherapy prolongs disease-free survival and, secondarily, whether its use improves overall survival and systemic disease-free survival. Quality of life measurements will be monitored during the first 12 months of the study. Women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery and who have undergone complete surgical excision of all macroscopic disease but who subsequently develop isolated local and/or regional ipsilateral invasive recurrence are eligible. Patients are randomized to observation/no adjuvant chemotherapy or to adjuvant chemotherapy; all suitable patients receive radiation, hormonal, and trastuzumab therapy. Radiation therapy is recommended for patients who have not received previous adjuvant radiation therapy but is required for those with microscopically positive margins. The radiation field must encompass the tumor bed plus a surrounding margin to a dose of >or= 40 Gy. Radiation therapy will be administered before, during, or after chemotherapy. All women with estrogen receptor-positive and/or progesterone receptor-positive recurrence must receive hormonal therapy, with the agent and duration to be determined by the patient's investigator. Adjuvant trastuzumab therapy is permitted for those with HER2- positive tumors, provided that intent to treat is declared before randomization. Although multidrug regimens are preferred, the agents, doses, and use of supportive therapy are at the discretion of the investigator.


Homo naledi and Pleistocene hominin evolution in subequatorial Africa.
New discoveries and dating of fossil remains from the Rising Star cave system, Cradle of Humankind, South Africa, have strong implications for our understanding of Pleistocene human evolution in Africa. Direct dating of Homo naledi fossils from the Dinaledi Chamber (Berger et al., 2015) shows that they were deposited between about 236 ka and 335 ka (Dirks et al., 2017), placing H. naledi in the later Middle Pleistocene. Hawks and colleagues (Hawks et al., 2017) report the discovery of a second chamber within the Rising Star system (Dirks et al., 2015) that contains H. naledi remains. Previously, only large-brained modern humans or their close relatives had been demonstrated to exist at this late time in Africa, but the fossil evidence for any hominins in subequatorial Africa was very sparse. It is now evident that a diversity of hominin lineages existed in this region, with some divergent lineages contributing DNA to living humans and at least H. naledi representing a survivor from the earliest stages of diversification within Homo. The existence of a diverse array of hominins in subequatorial comports with our present knowledge of diversity across other savanna-adapted species, as well as with palaeoclimate and paleoenvironmental data. H. naledi casts the fossil and archaeological records into a new light, as we cannot exclude that this lineage was responsible for the production of Acheulean or Middle Stone Age tool industries.


Small-conductance, calcium-activated potassium channels from mammalian brain.
Members of a previously unidentified family of potassium channel subunits were cloned from rat and human brain. The messenger RNAs encoding these subunits were widely expressed in brain with distinct yet overlapping patterns, as well as in several peripheral tissues. Expression of the messenger RNAs in Xenopus oocytes resulted in calcium-activated, voltage-independent potassium channels. The channels that formed from the various subunits displayed differential sensitivity to apamin and tubocurare. The distribution, function, and pharmacology of these channels are consistent with the SK class of small-conductance, calcium-activated potassium channels, which contribute to the afterhyperpolarization in central neurons and other cell types.


Pilot Study Assessing the Impact of Intrathecal Administration of Variants AAV-PHP.B and AAV-PHP.eB on Brain Transduction in Adult Rhesus Macaques.
Adeno-associated virus (AAV) vectors are increasingly used as an effective and safe approach to deliver genetic material to the central nervous system (CNS). The AAV9-derived variants, AAV-PHP. B and AAV-PHP.eB, reportedly broadly transduce cells throughout the CNS compared to the original serotype 9, AAV9. As non-human primate data are scarce, we here evaluated the CNS transduction efficiencies after lumbar intrathecal bolus delivery of identical doses of either AAV-PHP. B:CAG-EGFP or AAV-PHP. eB:CAG-EGFP in rhesus macaque monkeys. AAV-PHP.eB achieved a more efficient and widespread CNS transduction compared to AAV-PHP.B. We report a strong neuronal and oligodendroglial tropism for both variants in the putamen and in the hippocampus. This proof-of-concept experiment highlights the potential value of intrathecal infusions of AAV-PHP.eB to distribute genetic material in the CNS with cell-type specificity and introduces a new opportunity to model brain diseases in rhesus macaque monkeys and further develop gene therapies targeting the CNS in humans.


Factors underlying the early limb muscle weakness in acute quadriplegic myopathy using an experimental ICU porcine model.
The basic mechanisms underlying acquired generalized muscle weakness and paralysis in critically ill patients remain poorly understood and may be related to prolonged mechanical ventilation/immobilization (MV) or to other triggering factors such as sepsis, systemic corticosteroid (CS) treatment and administration of neuromuscular blocking agents (NMBA). The present study aims at exploring the relative importance of these factors by using a unique porcine model. Piglets were all exposed to MV together with different combinations of endotoxin-induced sepsis, CS and NMBA for five days. Peroneal motor nerve conduction velocity and amplitude of the compound muscle action potential (CMAP) as well as biceps femoris muscle biopsy specimens were obtained immediately after anesthesia on the first day and at the end of the 5-day experimental period. Results showed that peroneal nerve motor conduction velocity is unaffected whereas the size of the CMAP decreases independently of the type of intervention, in all groups after 5 days. Otherwise, despite a preserved size, muscle fibre specific force (maximum force normalized to cross-sectional area) decreased dramatically for animals exposed to MV in combination with CS or/and sepsis. These results suggest that the rapid declines in CMAP amplitude and in force generation capacity are triggered by independent mechanisms with significant clinical and therapeutic implications.


Profile of Reported Alcohol, Tobacco, and Recreational Drug Use in Nulliparous Women.
To estimate alcohol, tobacco, and recreational drug use during pregnancy among nulliparous women. In a cohort of nulliparous women followed through pregnancy from the first-trimester nuMoM2b (Nulliparous Outcomes in Pregnancy: Monitoring Mothers to be) study, self-reported use of alcohol, tobacco, and drugs was chronicled longitudinally at four study visits in this secondary analysis. Rates of use before pregnancy, in each trimester (visit 1, visit 2, visit 3, approximating each trimester), and at the time of delivery (visit 4) were recorded. The amount of alcohol, tobacco, and drug exposure were recorded using validated measures, and trends across pregnancy were analyzed. Of the 10,038 study participants, 10,028 had information regarding alcohol, tobacco, and drug use at visit 1, 9,412 at visit 2, 9,217 at visit 3, and 7,167 at visit 4. The rates of drinking alcohol, which had been 64.6% in the 3 months before pregnancy, were lower in pregnancy (3.9% at visit 1, 5.6% at visit 2, 7.0% at visit 3, and 6.1% at visit 4, P<.001 for all). Rates later in pregnancy were all greater than in the first trimester (P<.01). The rate of smoking in the 3 months before pregnancy, which was 17.8%, also declined at visit 1 (5.9%), and continued to decline through pregnancy (5.3% at visit 2, 4.7% at visit 3, and 3.9% at visit 4, with all rates lower than that of visit 1 [P<.01]). Although recreational drug use was relatively common in the months before pregnancy (33.8%), it also declined during pregnancy (1.1% at visit 2, 0.7% at visit 3, 0.4% at visit 4). In this geographically and ethnically diverse cohort of nulliparous women, rates of self-reported alcohol, smoking, and recreational drug use were all significantly lower during than before pregnancy. Nonetheless, rates of alcohol use rose as pregnancy progressed, highlighting the need for continued counseling throughout all trimesters of pregnancy. ClinicalTrials.gov, NCT01322529.


Empirical study of self-rated defense styles.
A self-administered questionnaire that would indicate a person's perception of his or her habitual defensive style was constructed and tested. The hypotheses assessed were that defenses cluster so as to constitute "styles" and that these styles can be ranked as more or less adaptive. The sample comprised 98 psychiatric patients and 111 nonpatients. The tools used were (1) a questionnaire measure of self-appraisal of defensive style, (2) a questionnaire measure of ego adaptation, and (3) a sentence completion measure of ego development. The results, which argued strongly for the validity of a questionnaire measure of perceived defensive style, also showed that such defenses tend to cluster into styles that can be ranked on a developmental continuum, from "maladaptive action patterns," through "image-distorting" defenses, "self-sacrificing" defenses, and "adaptive" defenses.


Effects of switchgrass (Panicum virgatum) rotations with peanut (Arachis hypogaea L.) on nematode populations and soil microflora.
A 3-year field rotation study was conducted to assess the potential of switchgrass (Panicum virgatum) to suppress root-knot nematodes (Meloidogyne arenaria), southern blight (Sclerotium rolfsii), and aflatoxigenic fungi (Aspergillus sp.) in peanut (Arachis hypogaea L.) and to assess shifts in microbial populations following crop rotation. Switchgrass did not support populations of root-knot nematodes but supported high populations of nonparasitic nematodes. Peanut with no nematicide applied and following 2 years of switchgrass had the same nematode populations as continuous peanut plus nematicide. Neither previous crop nor nematicide significantly reduced the incidence of pods infected with Aspergillus. However, pod invasion by A. flavus was highest in plots previously planted with peanut and not treated with nematicide. Peanut with nematicide applied at planting following 2 years of switchgrass had significantly less incidence of southern blight than either continuous peanut without nematicide application or peanut without nematicide following 2 years of cotton. Peanut yield did not differ among rotations in either sample year. Effects of crop rotation on the microbial community structure associated with peanut were examined using indices for diversity, richness, and similarity derived from culture-based analyses. Continuous peanut supported a distinctly different rhizosphere bacterial microflora compared to peanut following 1 year of switchgrass, or continuous switchgrass. Richness and diversity indices for continuous peanut rhizosphere and geocarposphere were not consistently different from peanut following switchgrass, but always differed in the specific genera present. These shifts in community structure were associated with changes in parasitic nematode populations.


The Impact of COVID-19 Pandemic on Spine Surgeons Worldwide: A One Year Prospective Comparative Study.
Survey. In March of 2020, an original study by Louie et al investigated the impact of COVID-19 on 902 spine surgeons internationally. Since then, due to varying government responses and public health initiatives to the pandemic, individual countries and regions of the world have been affected differently. Therefore, this follow-up study aimed to assess how the COVID-19 impact on spine surgeons has changed 1 year later. A repeat, multi-dimensional, 90-item survey written in English was distributed to spine surgeons worldwide via email to the AO Spine membership who agreed to receive surveys. Questions were categorized into the following domains: demographics, COVID-19 observations, preparedness, personal impact, patient care, and future perceptions. Basic respondent demographics, such as gender, age, home demographics, medical comorbidities, practice type, and years since training completion, were similar to those of the original 2020 survey. Significant differences between groups included reasons for COVID testing, opinions of media coverage, hospital unemployment, likelihood to be performing elective surgery, percentage of cases cancelled, percentage of personal income, sick leave, personal time allocation, stress coping mechanisms, and the belief that future guidelines were needed (P<.05). Compared to baseline results collected at the beginning of the COVID-19 pandemic in 2020, significant differences in various domains related to COVID-19 perceptions, hospital preparedness, practice impact, personal impact, and future perceptions have developed. Follow-up assessment of spine surgeons has further indicated that telemedicine and virtual education are mainstays. Such findings may help to inform and manage expectations and responses to any future outbreaks.


Candidate gene polymorphisms and risk of psoriasis: A pilot study.
Psoriasis is a complex genetic disease, which has previously been associated with numerous single nucleotide polymorphisms (SNPs) that are implicated in various processes, including skin barrier functions and in the regulation of inflammatory and immune responses. The present study aimed to investigate the genotypic and allelic frequencies of 32 SNPs at 24 genetic loci, and their association with psoriasis in a Mexican population. These SNPs, which were associated with psoriasis in previous studies, included the following genes: Major histocompatibility complex class I-C (HLA-C), interleukin (IL)-12B, IL-23R, IL-23A, IL-28RA, tumor necrosis factor (TNF)-α, ring finger protein-114 (RNF114), cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1, late cornified envelope 3B/3C, signal transducer and activator of transcription 4, LINC01185, interferon induced with helicase C domain 1, IL-13, TNF-α-induced protein 3 (TNFAIP3), TNFAIP3 interacting protein 1, endoplasmic reticulum aminopeptidase 1, TNF receptor-associated factor interacting protein 2, Leptin, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha, F-box and leucine-rich repeat protein 19, nitric oxide synthase 2, cluster of differentiation 40, nuclear receptor coactivator 5, and ADAM metallopeptidase domain 33. A total of 32 male and 14 female subjects with a clinical diagnosis of chronic plaque psoriasis, as well as 103 control subjects, were analyzed. Molecular analyses were performed using TaqMan® assays in a TaqMan® OpenArray® Genotyping system. Results were analyzed using the Golden Helix SNP and Variation Suite 7 program. Of the 32 SNPs, six were associated with an increased risk of developing psoriasis, including: HLA-C rs10484554 [allele T: odds ratio (OR) 3.51], IL-12B rs3212227 (allele T: OR 1.88), IL-12B rs3213094 (allele C: OR 1.94), HLA complex group 27 rs1265181 (allele C: OR 2.83), annexin A6 rs17728338 (allele A: OR 2.41), and RNF114 rs6125829 (allele G: OR 1.98). Fisher's exact test detected statistical significance; however, following false discovery rate and Bonferroni correction, this association was no longer significant (threshold for genome-wide significance, P<1.56×10-3). SNPs that were associated with an increased risk of psoriasis in the present study have previously been associated with psoriasis in European, American, and Asian populations. In order to establish genome-wide significance, future studies must analyze a greater sample size. To the best of our knowledge, the present pilot study is the first to investigate the association between these 32 SNPs and psoriasis in a Mexican Mestizo population.


The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module.
The catalytic activities of eukaryotic protein kinases (EPKs) are regulated by movement of the C-helix, movement of the N and C lobes upon ATP binding, and movement of the activation loop upon phosphorylation. Statistical analysis of the selective constraints associated with AGC kinase functional divergence reveals conserved interactions between these regulatory regions and three regions of the C-terminal tail (C-tail): the N-lobe tether (NLT), the active-site tether (AST), and the C-lobe tether (CLT). The NLT serves as a docking site for an upstream kinase PDK1 and, upon activation, positions the C-helix within the ATP binding pocket. The AST directly interacts with the ATP binding pocket, and the CLT interacts with the interlobe linker and the alphaC-beta4 loop, which appears to serve as a hinge for C-helix movement. The C-tail is a hallmark of AGC functional divergence inasmuch as most of the conserved core residues that distinguish AGC kinases from other EPKs are associated with the NLT, AST, or CLT. Moreover, several AGC catalytic core conserved residues that interact with the C-tail strikingly diverge from the canonical residues observed at corresponding positions in nearly all other EPKs, suggesting that the catalytic core may have coevolved with the C-tail in AGC kinases. These observations, along with the fact that the C-tail is needed for catalytic activity suggests that the C-tail is a cis-acting regulatory module that can also serve as a regulatory "handle," to which trans-acting cellular components can bind to modulate activity.


Strength training effects on bone mineral content and density in premenopausal women.
Mechanical loading, such as that seen with physical activity, is thought to be the primary factor influencing bone strength. Previous randomized studies that assessed the effect of strength training on bone in premenopausal women report inconsistent results. The analysis herein examines the effect of a strength training program following published guidelines (US Department of Health and Human Services) on bone mineral content (BMC) and areal bone mineral content (aBMD) in the proximal femur and lumbar spine in premenopausal women. One hundred and forty-eight overweight, sedentary, premenopausal women aged 25-44 were randomized to progressive strength training (ST, n = 72) or standard care (CO, n = 76) for 2 yr. Measurements occurred at baseline, 1 yr, and 2 yr. Proximal femur and lumbar spine BMC and aBMD were measured by dual energy x-ray absorptiometry. Intention-to-treat analyses were completed, and repeated-measures ANCOVA adjusted for baseline height and weight was used to assess the effect of strength training on bone. aBMD showed little change and did not differ between groups at any site. Femoral neck BMC showed a significant difference in the slopes between ST and CO (P = 0.04) with no change in the ST group and a 1.5% decrease in the CO. There were no significant between-group differences at any other measurement site. Strength training had no effect on aBMD after 2 yr of strength training. Femoral neck BMC decreased in CO and had no change in ST. Because there was no change in aBMD, strength training may have influenced bone size. Research to better understand changes in bone dimensions and geometry with strength training in premenopausal women is warranted.


Statistical anisotropy in free turbulence for mixing layers at high Reynolds numbers.
A lateral shearing interferometer was used to measure the slope of perturbed wave fronts after propagating through free turbulent mixing layers. Shearing interferometers provide a two-dimensional flow visualization that is nonintrusive. Slope measurements were used to reconstruct the phase of the turbulence-corrupted wave front. The random phase fluctuations induced by the mixing layer were captured in a large ensemble of wave-front measurements. Experiments were performed on an unbounded, plane shear mixing layer of helium and nitrogen gas at fixed velocities and high Reynolds numbers for six locations in the flow development. Statistical autocorrelation functions and structure functions were computed on the reconstructed phase maps. The autocorrelation function results indicated that the turbulence-induced phase fluctuations were not wide-sense stationary. The structure functions exhibited statistical homogeneity, indicating that the phase fluctuations were stationary in first increments. However, the turbulence-corrupted phase was not isotropic. A five-thirds power law is shown to fit orthogonal slices of the structure function, analogous to the Kolmogorov model for isotropic turbulence. Strehl ratios were computed from the phase structure functions and compared with classical estimates that assume isotropy. The isotropic models are shown to overestimate the optical degradation by nearly 3 orders of magnitude compared with the structure function calculations.


Punishment sustains large-scale cooperation in prestate warfare.
Understanding cooperation and punishment in small-scale societies is crucial for explaining the origins of human cooperation. We studied warfare among the Turkana, a politically uncentralized, egalitarian, nomadic pastoral society in East Africa. Based on a representative sample of 88 recent raids, we show that the Turkana sustain costly cooperation in combat at a remarkably large scale, at least in part, through punishment of free-riders. Raiding parties comprised several hundred warriors and participants are not kin or day-to-day interactants. Warriors incur substantial risk of death and produce collective benefits. Cowardice and desertions occur, and are punished by community-imposed sanctions, including collective corporal punishment and fines. Furthermore, Turkana norms governing warfare benefit the ethnolinguistic group, a population of a half-million people, at the expense of smaller social groupings. These results challenge current views that punishment is unimportant in small-scale societies and that human cooperation evolved in small groups of kin and familiar individuals. Instead, these results suggest that cooperation at the larger scale of ethnolinguistic units enforced by third-party sanctions could have a deep evolutionary history in the human species.


Plasma membrane Ca2+-ATPase 4 in murine epididymis: secretion of splice variants in the luminal fluid and a role in sperm maturation.
Plasma membrane Ca(2+)-ATPase isoform 4 (PMCA4) is the primary Ca(2+) efflux pump in murine sperm, where it regulates motility. In Pmca4 null sperm, motility loss results in infertility. We have shown that murine sperm PMCA4b interacts with Ca(2+)/CaM-dependent serine kinase (CASK) in regulating Ca(2+) homeostasis and motility. However, recent work indicated that the bovine PMCA4a splice variant (missing in testis) is epididymally expressed, along with 4b, and may be transferred to sperm. Here we show, via conventional and in situ RT-PCR, that both the splice variants of Pmca4 mRNA are expressed in murine testis and throughout the epididymis. Immunofluorescence localized PMCA4a to the apical membrane of the epididymal epithelium, and Western analysis not only confirmed its presence but showed for the first time that PMCA4a and PMCA4b are secreted in the epididymal luminal fluid (ELF), from which epididymosomes containing PMCA4a were isolated. Flow cytometry indicated the presence of PMCA4a on mature caudal sperm where it was increased ~5-fold compared to caput sperm (detected by Western blotting) and ~2-fold after incubation in ELF, revealing in vitro uptake and implicating PMCA4a in epididymal sperm maturation. Coimmunoprecipitation using pan-PMCA4 antibodies, revealed that both variants associate with CASK, suggesting their presence in a complex. Because they have different kinetic properties for Ca(2+) transport and different abilities to bind to CASK, our study suggests a mechanism for combining the functional attributes of both PMCA4 variants, leading to heightened efficiency of the pump in the maintenance of Ca(2+) homeostasis, which is crucial for normal motility and male fertility.


Basic proteins of plant nuclei during normal and pathological cell growth.
Histone proteins were studied by microphotometry of plant tissue sections stained with fast green at pH 8.1. For comparative purposes the Feulgen reaction was used for deoxyribose nuclei acid (DNA); the Sakaguchi reaction for arginine; and the Millon reaction for estimates of total protein. Analysis of Tradescantia tissues indicated that amounts of nuclear histone fell into approximate multiples of the gametic (egg or sperm) quantity except in dividing tissues, where amounts intermediate between multiples were found. In differentiated tissues of lily, corn, onion, and broad bean, histones occurred in constant amounts per nucleus, characteristic of the species, as was found also for DNA. Unlike the condition in several animal species, the basic proteins of sperm nuclei in these higher plants were of the histone type; no evidence of protamine was found. In a plant neoplasm, crown gall of broad bean, behavior of the basic nuclear proteins closely paralleled that of DNA. Thus, alterations of DNA levels in tumor tissues were accompanied by quantitatively similar changes in histone levels to maintain the same Feulgen/fast green ratios found in homologous normal tissues.


Chemokine levels in human liver homogenates: associations between GRO alpha and histopathological evidence of alcoholic hepatitis.
Alcoholic hepatitis is characterized by parenchymal neutrophil infiltration. Hepatic synthesis of the neutrophil chemokine interleukin-8 (IL-8) is highly elevated in alcoholic hepatitis and levels correlate with the degree of neutrophil infiltration. The aim of this study was to further determine the spectrum of synthesis of chemokines in liver tissue from patients with alcoholic liver disease and a range of disease control subjects. Subjects were composed of 24 patients with alcoholic liver disease of whom 15 had histopathological evidence of alcoholic hepatitis (10 cirrhotic) and 9 no evidence of alcoholic hepatitis (5 cirrhotic); other controls included; normal liver (n = 6), viral hepatitis (n = 16), primary biliary cirrhosis (n = 5), acute liver failure (n = 4), and miscellaneous liver disease (n = 13). Levels of the C-X-C neutrophil chemokine GRO alpha and the mononuclear cell C-C chemokines: macrophage inflammatory protein 1 alpha, macrophage chemotactic protein 1 and RANTES, were determined by ELISA in liver homogenates. Levels of the neutrophil chemokine GRO alpha were specifically elevated (mean 46 pg/mg, compared with normal liver 11 pg/mg) in patients with alcoholic hepatitis. GRO alpha levels correlated with IL-8 levels and were higher in patients with alcoholic liver disease and parenchymal neutrophil infiltration. Hepatic RANTES was elevated in diseased liver, with the highest levels found in viral hepatitis (mean 117 pg/mg, compared with 24 pg/mg in normal liver). No significant changes in hepatic levels of macrophage inflammatory protein 1 alpha (MIP-1 alpha) or macrophage chemotactic protein 1 (MCP-1) were found. These data provide further supportive evidence that parenchymal neutrophil infiltration in alcoholic hepatitis may be determined by selective upregulation of C-X-C chemokine synthesis.


Entorhinal transformations in abstract frames of reference.
Knowing how another's preferences relate to our own is a central aspect of everyday decision-making, yet how the brain performs this transformation is unclear. Here, we ask whether the putative role of the hippocampal-entorhinal system in transforming relative and absolute spatial coordinates during navigation extends to transformations in abstract decision spaces. During functional magnetic resonance imaging (fMRI), subjects learned a stranger's preference for an everyday activity-relative to one of three personally known individuals-and subsequently decided how the stranger's preference relates to the other two individuals' preferences. We observed entorhinal/subicular responses to the absolute distance between the ratings of the stranger and the familiar choice options. Notably, entorhinal/subicular signals were sensitive to which familiar individuals were being compared to the stranger. In contrast, striatal signals increased when accurately determining the ordinal position of choice options in relation to the stranger. Paralleling its role in navigation, these data implicate the entorhinal/subicular region in assimilating relatively coded knowledge within abstract metric spaces.


Improving depiction of benefits and harms: analyses of studies of well-known therapeutics and review of high-impact medical journals.
The issues of weighing benefits and harms and of shared decision-making have become increasingly important in recent years. There is limited knowledge and lack of adequate data on the most transparent method of communicating the information. In this article we discuss examples of communicating benefits and harms for well-known therapeutics, illustrating that relative risk estimates are not helpful for communicating the chance of experiencing adverse events. In addition, we show that asymmetric presentation of the data for benefits and harms is likely to bias toward showing greater benefits and diminishing the importance of the harms (or vice versa). We also present preliminary results of a brief review of high-impact medical journals that show limitations of current systematic reviews. In the review we found that every second published study does not discuss frequency data and 1 in 3 studies that report information on both benefits and harms does not report information in the same metric. We conclude that consistently depicting benefit and harm information in frequencies can substantially improve the communication of benefits and harms. Investigators should be requested to provide frequency data along with relative risk information in the publication of their scientific findings. Currently, even in the highest impact medical journals, evidence of benefits and harms is not consistently presented in ways that facilitate accurate interpretation.


Weekend hospitalization and additional risk of death: an analysis of inpatient data.
To assess whether weekend admissions to hospital and/or already being an inpatient on weekend days were associated with any additional mortality risk. Retrospective observational survivorship study. We analysed all admissions to the English National Health Service (NHS) during the financial year 2009/10, following up all patients for 30 days after admission and accounting for risk of death associated with diagnosis, co-morbidities, admission history, age, sex, ethnicity, deprivation, seasonality, day of admission and hospital trust, including day of death as a time dependent covariate. The principal analysis was based on time to in-hospital death. National Health Service Hospitals in England. 30 day mortality (in or out of hospital). There were 14,217,640 admissions included in the principal analysis, with 187,337 in-hospital deaths reported within 30 days of admission. Admission on weekend days was associated with a considerable increase in risk of subsequent death compared with admission on weekdays, hazard ratio for Sunday versus Wednesday 1.16 (95% CI 1.14 to 1.18; P < .0001), and for Saturday versus Wednesday 1.11 (95% CI 1.09 to 1.13; P < .0001). Hospital stays on weekend days were associated with a lower risk of death than midweek days, hazard ratio for being in hospital on Sunday versus Wednesday 0.92 (95% CI 0.91 to 0.94; P < .0001), and for Saturday versus Wednesday 0.95 (95% CI 0.93 to 0.96; P < .0001). Similar findings were observed on a smaller US data set. Admission at the weekend is associated with increased risk of subsequent death within 30 days of admission. The likelihood of death actually occurring is less on a weekend day than on a mid-week day.


Hypoxia-inducible factor 1 contributes to N-acetylcysteine's protection in stroke.
Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model. Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90min middle cerebral artery occlusion (MCAO) and 24h reperfusion. Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC's neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC's neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction. We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant's neuroprotection in ischemic stroke.


Body mass index and its effect on serum cortisol level.
Cortisol measurement is indicated in suspected over or under production of cortisol by the adrenal cortex. The finding of low cortisol can create concern and initiate further investigations for the exclusion of adrenal insufficiency. Cushing's syndrome is frequently included in the differential diagnosis of obesity. Some literature describes reduced serum cortisol levels in obesity, however, this is not a well-recognized phenomenon. The aim of this study was to determine the relationship between body mass index (BMI) and serum cortisol levels. Seventy healthy participants agreed to take part in the study. The anthropometric measurements (weight, height, and waist and hip circumferences) were done. Exclusion criteria include those with a history of adrenal/pituitary disease or medications altering cortisol level. The basal cortisol (BC) sample was taken at 8 a.m. immediately before administration of an intravenous bolus injection of 250 μg adrenocorticotropic hormone (ACTH). BMI categories were defined as normal and high if BMI was 18.5-24.99 kg/m² and ≥ 25 kg/m², respectively. Forty (57.1%) participants had normal BMI while 30 (42.9%) participants had BMI ≥ 25 kg/m² (P0 = 0.053). The mean BC level was lower in participants with BMI ≥ 25 kg/m² but not significant. There was a negative correlation between BMI and BC level ( r = -0.205, P = 0.88) while a positive correlation existed between stimulated cortisol level and BMI (r = 0.009, P = 0.944). Persons with BMI above 25 kg/m² had lower BC level though not statistically significant, the trend was noticed. Subjecting people whose BMI is above 25 kg/m² to further stimulation with ACTH because of low BC is not advised because their response to ACTH stimulation was similar to those who have normal BMI.


[Cue exposure treatment and coping skills training as adjuvant therapies in the management of craving in a crack cocaine addict].
An increased prevalence of crack cocaine users has been observed in clinical samples over the past years, underscoring the need for conducting research and developing treatment strategies aimed at this population. The objective of this study was to describe the case of a crack cocaine addict (inpatient) submitted to cue exposure treatment (CET) and coping skills training (CS) as adjuvant approaches to the conventional addiction treatment. A male patient, 29 years old, single, with complete high school, was dependent on crack cocaine and marijuana and also had a diagnosis of harmful alcohol use. The patient had been hospitalized for 2 weeks and had undertaken a protocol comprising four motivational interview and relapse prevention sessions. Six sessions of CET and CS were carried out over 2 weeks, including both in vivo and imaginal exposure to stimuli evoking craving for crack cocaine, such as a crack pipe, a lighter, and simulated crack cocaine rocks (in vivo exposure), or remembering places and friends associated with drug use (imaginal exposure). The patient was also trained to use strategies for the management of craving. Three months after hospital discharge, toxicological screening was performed to assess abstinence. CET and CS were considered by the patient to be important techniques for the maintenance of abstinence and of a low level of craving 3 months after discharge. These findings suggest that the two techniques may be useful as adjuvant therapies in the treatment of crack cocaine dependents. CET and CS should be assessed in clinical trials in order to demonstrate their real benefits.


Down-regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets.
Hepatitis C virus (HCV) perturbs the host's lipid metabolism and often results in hepatic steatosis. In nonalcoholic fatty liver disease, the intrahepatic down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a critical mechanism leading to steatosis and its progression toward fibrosis and hepatocellular carcinoma. However, whether an HCV infection triggers the formation of large lipid droplets through PTEN-dependent mechanisms is unknown. We assessed PTEN expression in the livers of patients infected with HCV genotype 1 or 3 with or without steatosis. The role of PTEN in the HCV-induced biogenesis of lipid droplets was further investigated in vitro with hepatoma cells transduced with the HCV core protein of genotype 1b or 3a. Our data indicate that PTEN expression was down-regulated at the posttranscriptional level in steatotic patients infected with genotype 3a. Similarly, the in vitro expression of the HCV genotype 3a core protein (but not 1b), typically leading to the appearance of large lipid droplets, down-regulated PTEN expression by a mechanism involving a microRNA-dependent blockade of PTEN messenger RNA translation. PTEN down-regulation promoted in turn a reduction of insulin receptor substrate 1 (IRS1) expression. Interestingly, either PTEN or IRS1 overexpression prevented the development of large lipid droplets, and this indicates that the down-regulation of both PTEN and IRS1 is required to affect the biogenesis of lipid droplets. However, IRS1 knockdown per se did not alter the morphology of lipid droplets, and this suggests that other PTEN-dependent mechanisms are involved in this process. The down-regulation of PTEN and IRS1 is a critical event leading to the HCV genotype 3a-induced formation of large lipid droplets in hepatocytes.


Comparison of Petunia inflata S-Locus F-box protein (Pi SLF) with Pi SLF like proteins reveals its unique function in S-RNase based self-incompatibility.
Petunia inflata possesses S-RNase-based self-incompatibility (SI), which prevents inbreeding and promotes outcrossing. Two polymorphic genes at the S-locus, S-RNase and P. inflata S-locus F-box (Pi SLF), determine the pistil and pollen specificity, respectively. To understand how the interactions between Pi SLF and S-RNase result in SI responses, we identified four Pi SLF-like (Pi SLFL) genes and used them, along with two previously identified Pi SLFLs, for comparative studies with Pi SLF(2). We examined the in vivo functions of three of these Pi SLFLs and found that none functions in SI. These three Pi SLFLs and two other Pi SLFs either failed to interact with S(3)-RNase (a non-self S-RNase for all of them) or interacted much more weakly than did Pi SLF(2) in vitro. We divided Pi SLF(2) into FD1 (for Functional Domain1), FD2, and FD3, each containing one of the Pi SLF-specific regions, and used truncated Pi SLF(2), chimeric proteins between Pi SLF(2) and one of the Pi SLFLs that did not interact with S(3)-RNase, and chimeric proteins between Pi SLF(1) and Pi SLF(2) to address the biochemical roles of these three domains. The results suggest that FD2, conserved among three allelic variants of Pi SLF, plays a major role in the strong interaction with S-RNase; additionally, FD1 and FD3 (each containing one of the two variable regions of Pi SLF) together negatively modulate this interaction, with a greater effect on interactions with self S-RNase than with non-self S-RNases. A model for how an allelic product of Pi SLF determines the fate of its self and non-self S-RNases in the pollen tube is presented.


Wide wavelength tuning of optical antennas on graphene with nanosecond response time.
Graphene is emerging as a broadband optical material which can be dynamically tuned by electrostatic doping. However, the direct application of graphene sheets in optoelectronic devices is challenging due to graphene's small thickness and the resultant weak interaction with light. By combining metal and graphene in a hybrid plasmonic structure, it is possible to enhance graphene-light interaction and thus achieve in situ control of the optical response. We show that the effective mode index of the bonding plasmonic mode in metal-insulator-metal (MIM) waveguides is particularly sensitive to the change in the optical conductivity of a graphene layer in the gap. By incorporating such MIM structures in optic antenna designs, we demonstrate an electrically tunable coupled antenna array on graphene with a large tuning range (1100 nm, i.e., 250 cm(-1), nearly 20% of the resonance frequency) of the antenna resonance wavelength at the mid-infrared (MIR) region. Our device exhibits a 3 dB cutoff frequency of 30 MHz, which can be further increased into the gigahertz range. This study confirms that hybrid metal-graphene structures are promising elements for high-speed electrically controllable optical and optoelectronic devices.


Lysophospholipid metabolism facilitates Toll-like receptor 4 membrane translocation to regulate the inflammatory response.
Sepsis, an overwhelming inflammatory response to infection, is a major cause of morbidity and mortality worldwide and has no specific therapy. Phospholipid metabolites, such as lysophospholipids, have been shown to regulate inflammatory responses in sepsis, although their mechanism of action is not well understood. The phospholipid-metabolizing enzymes, lysophospholipid acyltransferases, control membrane phospholipid composition, function, and the inflammatory responses of innate immune cells. Here, we show that lysophosphatidylcholine acyltransferase (LPCAT) regulates inflammatory responses to LPS and other microbial stimuli. Specific inhibition of LPCAT down-regulated inflammatory cytokine production in monocytes and epithelial cells by preventing translocation of TLR4 into membrane lipid raft domains. Our observations demonstrate a new regulatory mechanism that facilitates the innate immune responses to microbial molecular patterns and provide a basis for the anti-inflammatory activity observed in many phospholipid metabolites. This provides the possibility of the development of new classes of anti-inflammatory and antisepsis agents.