Evaluation of isavuconazole MIC strips for susceptibility testing of Aspergillus and Scedosporium species.
Isavuconazole is a new triazole with an expanded-spectrum and potent activity against moulds and yeasts. It has been authorized for use in adults for the treatment of invasive aspergillosis and for mucormycosis. The only commercially available isavuconazole susceptibility test is the minimum inhibitory concentration (MIC) strip isavuconazole test. The objective of this study was to assess the in vitro activity of isavuconazole using gradient concentration MIC strips, compared with the EUCAST broth microdilution reference method. A total of 147 clinically relevant fungal isolates comprising 120 Aspergillus sp. and 27 Scedosporium apiospermum complex were tested for susceptibility to isavuconazole using the EUCAST broth microdilution method and by the MIC strip isavuconazole test. The percent essential agreement between the two methods was calculated within a 1-fold dilution. The geometric means for the MICs using the EUCAST reference methods and the strip test were respectively: 0.60 mg/l and 0.65 mg/l for A. fumigatus, 0.70 mg/l and 0.77 mg/l for A. flavus, 1.50 mg/l and 1.25 mg/l for A. niger, 0.41 mg/l and 0.38 mg/l for A. terreus, 1.22 mg/l and 1.08 mg/l for S. apiospermum complex. The isavuconazole MIC strips showed good agreement with the EUCAST reference method. Isavuconazole MIC strips could be useful for susceptibility testing of Aspergillus sp. and S. apiospermum complex.


Screening billions of candidates for solid lithium-ion conductors: A transfer learning approach for small data.
Machine learning (ML) methods have the potential to revolutionize materials design, due to their ability to screen materials efficiently. Unlike other popular applications such as image recognition or language processing, large volumes of data are not available for materials design applications. Here, we first show that a standard learning approach using generic descriptors does not work for small data, unless it is guided by insights from physical equations. We then propose a novel method for transferring such physical insights onto more generic descriptors, allowing us to screen billions of unknown compositions for Li-ion conductivity, a scale which was previously unfeasible. This is accomplished by using the accurate model trained with physical insights to create a large database, on which we train a new ML model using the generic descriptors. Unlike previous applications of ML, this approach allows us to screen materials which have not necessarily been tested before (i.e., not on ICSD or Materials Project). Our method can be applied to any materials design application where a small amount of data is available, combined with high details of physical understanding.


Analysis of transcription asymmetries along the tRNAE-COB operon: evidence for transcription attenuation and rapid RNA degradation between coding sequences.
Mitochondrial gene expression in yeast is believed to be regulated predominantly at the post-transcriptional level. However, the contribution of mitochondrial transcription and RNA-turnover rates to differential gene regulation is still largely unknown. Mitochondrial run-on transcription and hybrid selection assays showed that some of the multigenic transcription units of the mitochondrial genome are transcribed evenly, whereas others are transcribed asymmetrically, with higher transcription rates for promoter-proximal genes, than for promoter-distal genes. The tRNA(E)-cytochrome b (COB) operon was analyzed in detail to investigate the mechanisms underlying transcription rate asymmetries in yeast mitochondria. We showed that a drop in transcription rates occurs in a particular region between the coding sequences and is independent of the coding sequence of the downstream COB gene. Deletion of the region between tRNA(E) and COB coding sequences decreases the drop in transcription rates. Deletion of the nuclear gene encoding the Pet 127 protein, which is involved in mitochondrial RNA 5' processing and degradation, also partially relieves transcriptional asymmetry. Therefore, asymmetry is probably due to a combination of attenuated transcription at specific sites between the coding sequences and very rapid RNA degradation.


Pulmonary hypertension in interstitial lung disease: prevalence, prognosis and 6 min walk test.
Pulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the prevalence and impact of PH on prognosis and exercise capacity in ILD patients. 212 ILD patients were screened for PH by echocardiography. Criteria for PH were either a tricuspid pressure regurgitation gradient >40 mmHg, a tricuspid annular plane systolic excursion <1.8 cm or right ventricular dilatation. If possible, PH was confirmed by right heart catheterisation. Pulmonary function tests and 6 min walk tests (6MWT) were performed. 29 patients (14%) had PH, 16 (8%) had mild and 13 (6%) had severe PH (mean pulmonary artery pressure ≥ 35 mmHg). Compared to patients without PH, lung function parameters were lower in PH patients, a larger proportion had idiopathic pulmonary fibrosis (IPF) (41 vs 21%, p = 0.006), and the hazard ratio for death was 8.5 (95% CI: 4-17). After correction for lung function parameters and the presence of IPF, 6MWT was significantly lower in patients with PH compared to non-PH patients (difference ± SEM: 58 ± 22 m, p = 0.01). PH occurred in 14% of a cohort of patients with ILD and was associated to IPF and lower lung function parameters. Mortality was markedly higher in PH patients, and the presence of PH reduced 6MWT independently of lung function and the presence of IPF. The present results emphasize the need for intensified treatment of patients with ILD and PH.


Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties.
Individuals with major depressive disorder (MDD) are characterized by maladaptive responses to both positive and negative outcomes, which have been linked to localized abnormal activations in cortical and striatal brain regions. However, the exact neural circuitry implicated in such abnormalities remains largely unexplored. In this study 26 unmedicated adults with MDD and 29 matched healthy controls (HCs) completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Psychophysiological interaction (PPI) analyses probed group differences in connectivity separately in response to positive and negative outcomes (i.e. monetary gains and penalties). Relative to HCs, MDD subjects displayed decreased connectivity between the caudate and dorsal anterior cingulate cortex (dACC) in response to monetary gains, yet increased connectivity between the caudate and a different, more rostral, dACC subregion in response to monetary penalties. Moreover, exploratory analyses of 14 MDD patients who completed a 12-week, double-blind, placebo-controlled clinical trial after the baseline fMRI scans indicated that a more normative pattern of cortico-striatal connectivity pre-treatment was associated with greater improvement in symptoms 12 weeks later. These results identify the caudate as a region with dissociable incentive-dependent dACC connectivity abnormalities in MDD, and provide initial evidence that cortico-striatal circuitry may play a role in MDD treatment response. Given the role of cortico-striatal circuitry in encoding action-outcome contingencies, such dysregulated connectivity may relate to the prominent disruptions in goal-directed behavior that characterize MDD.


Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice.
Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers' upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes' downregulation, thus causing hypoglycemia. This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue.


Use of Questionnaire-Based Research in Hand Surgery.
Questionnaire-based research is ubiquitous, and careful survey design is paramount to obtaining meaningful results. This study characterizes the use of questionnaire-based studies in the current hand surgery literature. We conducted a systematic review of questionnaire-based studies published between 2010 and 2020 in 4 major American journals. We included studies in which questionnaire results represented a primary outcome. Validation status of the survey instruments was assessed, and topics of study were categorized. Nonvalidated instruments were assessed for reporting of parameters to limit bias. Three hundred fifty-four studies were identified, including 186 (52.5%) using validated instruments, 98 (27.7%) using nonvalidated instruments, 64 (18.1%) using a combination, and 6 (1.7%) that sought to validate an instrument. Of the studies that used validated instruments, 84.9% focused on patient-reported outcomes and 15.1% focused on other patient-centered topics. In contrast, of studies that used nonvalidated instruments, 44.9% focused on physician practice, 30.6% were patient centered, and 13.3% focused on education. Among nonvalidated questionnaires, 74.5% did not report predistribution testing, 49.0% did not publish full survey questions, and 33.3% did not report response rates. Survey research is common in the hand surgery literature. Forty-six percent of examined studies included at least some nonvalidated elements. Techniques to limit bias in the design and reporting of studies based on nonvalidated surveys were not uniformly disclosed. Identified areas for improvement include (1) pilot testing to assess for question clarity; (2) publication of full texts to improve transparency; and (3) better reporting on sample selection, respondents, and nonrespondents.


Increased hematopoietic cells in the mertk-/- mouse peritoneal cavity: a result of augmented migration.
The peritoneal cavity is recognized as an important site for autoreactive B cells prior to their transit to other immune tissues; however, little is known of the genes that may regulate this process. Mice lacking the receptor tyrosine kinase, Mertk, display a lupus-like autoimmune phenotype with splenomegaly and high autoantibodies titers. In this study, we investigate whether Mertk regulates the composition of peritoneal cells that favor an autoimmune phenotype. We found an increase in the number of macrophages, dendritic cells (DCs), plasmacytoid DCs, T cells, and B cells in the peritoneal cavity of mertk-/- mice when compared with wild-type mice. This disparity in cell numbers was not due to changes in cell proliferation or cell death. In adoptive transfer experiments, we showed an increase in migration of labeled donor cells into the mertk-/- peritoneal cavity. In addition, bone marrow chimeric mice showed hematopoietic-derived factors were also critical for T cell migration. Consistent with this migration and the increase in the number of cells, we identified elevated expression of CXCL9, its receptor CXCR3, and IL-7R on peritoneal cells from mertk-/- mice. To corroborate the migratory function of CXCR3 on cells, the depletion of CXCR3 donor cells significantly reduced the number of adoptively transferred cells that entered into the peritoneum of mertk-/- mice. This control of peritoneal cells numbers correlated with autoantibody production and was exclusively attributed to Mertk because mice lacking other family members, Axl or Tyro 3, did not display dysregulation in peritoneal cell numbers or the autoimmune phenotype.


Phylogeny of Agrodiaetus Hübner 1822 (Lepidoptera: Lycaenidae) inferred from mtDNA sequences of COI and COII and nuclear sequences of EF1-alpha: karyotype diversification and species radiation.
Butterflies in the large Palearctic genus Agrodiaetus (Lepidoptera: Lycaenidae) are extremely uniform and exhibit few distinguishing morphological characters. However, these insects are distinctive in one respect: as a group they possess among the greatest interspecific karyotype diversity in the animal kingdom, with chromosome numbers (n) ranging from 10 to 125. The monophyly of Agrodiaetus and its systematic position relative to other groups within the section Polyommatus have been controversial. Characters from the mitochondrial genes for cytochrome oxidases I and II and from the nuclear gene for elongation factor 1 alpha were used to reconstruct the phylogeny of Agrodiaetus using maximum parsimony and Bayesian phylogenetic methods. Ninety-one individuals, encompassing most of the taxonomic diversity of Agrodiaetus, and representatives of 14 related genera were included in this analysis. Our data indicate that Agrodiaetus is monophyletic. Representatives of the genus Polyommatus (sensu stricto) are the closest relatives. The sequences of the Agrodiaetus taxa in this analysis are tentatively arranged into 12 clades, only 1 of which corresponds to a species group traditionally recognized in Agrodiaetus. Heterogeneous substitution rates across a recovered topology were homogenized with a nonparametric rate-smoothing algorithm before the application of a molecular clock. Two published estimates of substitution rates dated the origin of Agrodiaetus between 2.51 and 3.85 million years ago. During this time, there was heterogeneity in the rate and direction of karyotype evolution among lineages within the genus. Karyotype instability has evolved independently three times in the section Polyommatus, within the lineages Agrodiaetus, Lysandra, and Plebicula. Rapid karyotype diversification may have played a significant role in the radiation of the genus Agrodiaetus.


[Etiopathogenesis and pathophysiology of type 2 diabetes].
Etiopathogenesis of type 2 diabetes is complex and still partially unknown. Its etiology is determined by the interaction of genetic and environmental factors. The genetic contribution is important, but has a polygenic origin. Obesity, especially when fat mass is preferably located in the abdomen, is the main predisposing factor for type 2 diabetes, and almost 80% of diabetic patients are overweight or obese. The diabetogenic effect of obesity is due to the capacity of excessive fat mass to induce or aggravate insulin resistance. Increasing lack of physical activity is also a contributing factor as it increases insulin resistance. As far as pathophysiology is concerned, the development of type 2 diabetes results from the coexistence of abnormalities of insulin secretion and insulin action. Insulin secretory dysfunction, whose underlying mechanism remains poorly understood, is characterized by a relative defect in circulating insulin levels of variable severity. Resistance to insulin action is located in the liver (increased hepatic glucose production), in the skeletal muscle (decreased muscular glucose uptake) and in the adipose tissue (exaggerated lipolysis with elevated plasma free fatty acids). Changes in life-style habits (weight reduction, regular physical activity) are able to prevent or delay the development of type 2 diabetes.


Glucagon-like peptide-1 receptor agonist Liraglutide has anabolic bone effects in ovariectomized rats without diabetes.
Recently, a number of studies have demonstrated the potential beneficial role for novel anti-diabetic GLP-1 receptor agonists (GLP-1RAs) in the skeleton metabolism in diabetic rodents and patients. In this study, we evaluated the impacts of the synthetic GLP-1RA Liraglutide on bone mass and quality in osteoporotic rats induced by ovariectomy (OVX) but without diabetes, as well as its effect on the adipogenic and osteoblastogenic differentiation of bone marrow stromal cells (BMSCs). Three months after sham surgery or bilateral OVX, eighteen 5-month old female Wistar rats were randomly divided into three groups to receive the following treatments for 2 months: (1) Sham + normal saline; (2) OVX + normal saline; and (3) OVX + Liraglutide (0.6 mg/day). As revealed by micro-CT analysis, Liraglutide improved trabecular volume, thickness and number, increased BMD, and reduced trabecular spacing in the femurs in OVX rats; similar results were observed in the lumbar vertebrae of OVX rats treated with Liraglutide. Following in vitro treatment of rat and human BMSCs with 10 nM Liraglutide, there was a significant increase in the mRNA expression of osteoblast-specific transcriptional factor Runx2 and the osteoblast markers alkaline phosphatase (ALP) and collagen α1 (Col-1), but a significant decrease in peroxisome proliferator-activated receptor γ (PPARγ). In conclusion, our results indicate that the anti-diabetic drug Liraglutide can exert a bone protective effect even in non-diabetic osteoporotic OVX rats. This protective effect is likely attributable to the impact of Liraglutide on the lineage fate determination of BMSCs.


The acute exposure effects of inhaled nickel nanoparticles on murine endothelial progenitor cells.
The discovery of endothelial progenitor cells (EPCs) may help to explain observed cardiovascular effects associated with inhaled nickel nanoparticle exposures, such as increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone and potentiated atherosclerosis in murine species. Following an acute whole body inhalation exposure to 500 µg/m(3) of nickel nanoparticles for 5 h, bone marrow EPCs from C57BL/6 mice were isolated. EPCs were harvested for their RNA or used in a variety of assays including chemotaxis, tube formation and proliferation. Gene expression was assessed for important receptors involved in EPC mobilization and homing using RT-PCR methods. EPCs, circulating endothelial progenitor cells (CEPCs), circulating endothelial cells (CECs) and endothelial microparticles (EMPs) were quantified on a BD FACSCalibur to examine endothelial damage and repair associated with the exposure. Acute exposure to inhaled nickel nanoparticles significantly increased both bone marrow EPCs as well as their levels in circulation (CEPCs). CECs were significantly elevated indicating that endothelial damage occurred due to the exposure. There was no significant difference in EMPs between the two groups. Tube formation and chemotaxis, but not proliferation, of bone marrow EPCs was impaired in the nickel nanoparticle exposed group. These results coincided with a decrease in the mRNA of receptors involved in EPC mobilization and homing. These data provide new insight into how an acute nickel nanoparticle exposure to half of the current Occupational Safety & Health Administration (OSHA) permissible exposure limit may adversely affect EPCs and exacerbate cardiovascular disease states.


Color categories are not universal: replications and new evidence from a stone-age culture.
The authors sought to replicate and extend the work of E. Rosch Heider (1972) on the Dani with a comparable group from Papua, New Guinea, who speak Berinmo, which has 5 basic color terms. Naming and memory for highly saturated focal, non-focal, and low-saturation stimuli from around the color space were investigated. Recognition of desaturated colors was affected by color vocabulary. When response bias was controlled, there was no recognition advantage for focal stimuli. Paired-associate learning also failed to show an advantage for focal stimuli. Categorical Perception effects for both English and Berinmo were found, but only at the boundaries of existing linguistic categories. It is concluded that possession of linguistic categories facilitates recognition and influences perceptual judgments.


Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects millions of patients worldwide. The current disease-modifying therapies (DMTs) that are widely used to treat MS only show modest effects. Because MS is a chronic disease, it is important to develop treatments that have better long-term efficacy. Recently, several new-generation DMTs have been developed, most of which target specific immune molecules based on the assumption that MS is an autoimmune disease. These DMTs are designed to inhibit inflammation that is thought to directly cause demyelination. Preliminary studies suggest that these new therapies are likely to show a greater effect in reducing relapses in early MS patients, although their long-term efficacy is still unknown. In contrast, it was recently reported that the initial course of MS does not significantly influence long-term disability and that disability increases approximately at the same rate despite variable relapse frequencies. Furthermore, new neuropathological evidence now argues against the autoimmune hypothesis and suggests that MS is a primary oligodendrogliopathy disease in which the inflammatory response may be a mere epiphenomenon. So can we be optimistic about the unproven long-term outcomes of new DMTs or should we reconsider the pathogenesis of MS when developing more disease-specific treatments?


Epilithonimonas xixisoli sp. nov., isolated from wetland bank-side soil.
A novel Gram-staining-negative, non-motile and rod-shaped bacterial strain containing flexirubin-type pigments, designated S31(T), was isolated from bank-side soil of the Xixi wetland in Zhejiang province, China. Growth occurred at 10-37 °C (optimum, 32 °C), pH 6-8 (optimum, pH 7) and with 0-2 % (w/v) NaCl (optimum, 1 %). Strain S31(T) shared highest 16S rRNA gene sequence similarities with Epilithonimonas lactis H1(T) (96.2 %) and Chryseobacterium molle DW3(T) (96.4 %). Phylogenetic analysis suggested that strain S31(T) was a member of the genus Epilithonimonas. The dominant respiratory quinone was MK-6 and the DNA G+C content was 33.3 mol%. The major fatty acids were iso-C15 : 0, summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1ω7c) and anteiso-C15 : 0. The major polar lipids of strain S31(T) were phosphatidylethanolamine, three unidentified aminolipids and four unidentified polar lipids. Based on its phenotypic and chemotaxonomic characteristics and phylogenetic data, strain S31(T) represents a novel species of the genus Epilithonimonas, for which the name Epilithonimonas xixisoli sp. nov. (type strain S31(T) = CGMCC 1.12802(T) = NBRC 110387(T)) is proposed.


Mechanistic insights in charge-transfer-induced luminescence of 1,2-dioxetanones with a substituent of low oxidation potential.
We have investigated the decomposition pathway of dioxetanones 1c with a phenoxide anion group by the B3LYP/6-31+G(d) method together with the second-order multireference Møller-Plesset perturbation (MRMP) theory and propose charge-transfer-induced luminescence (CTIL) with polarization-induced branching excitation processes. In the gas phase, the thermal decomposition of 1c occurs by an asynchronous two-stage pathway without a discrete intermediate; that is, the initial O-O bond breaking to generate a charge-transfer (CT) diradical species is immediately followed by the subsequent C-C bond breaking with simultaneous back CT, which is responsible for the surface crossing at the avoided crossing. The activation energy is dramatically reduced from 19.4 to 3.8 kcal mol(-)(1) by the deprotonation of phenol meta-1d to its anion meta-1c, showing an important role of the endothermic CT. The odd/even selection rule for the chemiluminescence efficiency can be explained by the orbital interaction for the back CT between the carbonyl pi orbital and either a HOMO or a LUMO of the generated light emitters. To examine the accessibility of the chemically initiated electron exchange luminescence (CIEEL) route, we considered the solvent effects on the free-energy change of meta-1c by using continuum solvent models. The bending vibration mode of the CO(2) fragment is specifically considered. Borderline features emerges from the solution-phase CT reaction of meta-1c, which depends on the solvent polarity: one is a nonadiabatic or adiabatic back CT process (polarization-induced concerted CTIL), and the other is a radical dissociation, i.e., complete one-electron-transfer process (CIEEL).


An iron-dependent 5'-nucleotide phosphoribohydrolase activity in the venom of Crotalus atrox and its effect upon the determination of mammalian ribonucleotide reductase.
There is an iron-dependent activity in the venom of Crotalus atrox which appears to hydrolyze the N-glycosidic sugar-base bond of pyrimidine and purine nucleotides. Maximal activation of this activity occurred at 1.0 mmol/l and 0.8 mmol/l FeCl3 for cytidine diphosphate (CDP) and ADP substrates, respectively. The release of free base affects the background values of control experiments carried out during nucleotide-labelled assays of ribonucleotide reductase which require the conversion of nucleotides to nucleosides by snake venom treatment. When the reductase is examined in intact cells, a situation closely resembling normal physiological conditions for the enzyme, FeCl3 was found to be an inhibitor of ADP reductions and varied from a mild stimulator to a significant inhibitor of CDP reductions depending upon FeCl3 concentration. Possible explanations for previously observed variability in ribonucleotide reductase activity in the presence of iron are suggested.


Soccer heading is associated with white matter microstructural and cognitive abnormalities.
To investigate the association of soccer heading with subclinical evidence of traumatic brain injury. With institutional review board approval and compliance with HIPAA guidelines, 37 amateur soccer players (mean age, 30.9 years; 78% [29] men, 22% [eight] women) gave written informed consent and completed a questionnaire to quantify heading in the prior 12 months and lifetime concussions. Diffusion-tensor magnetic resonance (MR) imaging at 3.0 T was performed (32 directions; b value, 800 sec/mm(2); 2 × 2 × 2-mm voxels). Cognitive function was measured by using a computerized battery of tests. Voxelwise linear regression (heading vs fractional anisotropy [FA]) was applied to identify significant regional associations. FA at each location and cognition were tested for a nonlinear relationship to heading by using an inverse logit model that incorporated demographic covariates and history of concussion. Participants had headed 32-5400 times (median, 432 times) over the previous year. Heading was associated with lower FA at three locations in temporo-occipital white matter with a threshold that varied according to location (885-1550 headings per year) (P < .00001). Lower levels of FA were also associated with poorer memory scores (P < .00001), with a threshold of 1800 headings per year. Lifetime concussion history and demographic features were not significantly associated with either FA or cognitive performance. Heading is associated with abnormal white matter microstructure and with poorer neurocognitive performance. This relationship is not explained by a history of concussion.


[Synthesis of thieno[2,3-d]pyrimidines from 6-imino-6H-1,3-thiazine hydroperchlorates].
Mechanism of ring transformation reactions starting from substituted 6-imino-6H-1,3-thiazine hydroperchlorates is depending upon the substituent in position 5 of the thiazine nucleus. Starting from 4-methylthio-2-phenyl-6-imino-6H-1,3-thiazin-5-carbonitrile hydroperchlorat various 6-substituted 5-amino-4-methylthio-2-phenylthieno[2,3-d]pyrimidines can be obtained by reaction with acceptor substituted halogenmethanes under basic conditions in an one pot synthesis.


Neuropsychological profile in early Parkinson's disease: Comparison between patients with right side onset versus left side onset of motor symptoms.
Though impaired cognition in Parkinson's disease (PD) is well known, data in early PD is sparse. This study was designed to assess the cognitive profile in patients with early PD (motor symptoms <5 years and Hoehn and Yahr stage <2), and to compare the cognitive profile between these patients with right versus left side onset of motor symptoms. National Institute of National Health and Neurosciences (NIMHANS) neuropsychological battery was used to assess the cognitive profile in 50 patients with early PD and compared with 50 age-, education-, and gender-matched healthy controls. Within the PD group, the cognitive profile was also compared between patients with right side onset motor symptoms (RPD) versus those with left side onset (LPD). The neuropsychological tests assessed the executive functions, memory, attention, visuospatial functions, and psychomotor speed. Among the 50 patients, 25 each were RPD and LPD. The two subgroups were matched for age, gender, education, age at disease onset, disease duration, and degree of motor disability. There was no significant difference between the groups on Hoehn and Yahr staging or Unified Parkinson Disease Rating Scale (UPDRS) motor score. Patients with early PD performed significantly worse in the tasks involving memory, executive functions, and attention compared to controls. However, there was no difference in the cognitive profile between RPD and LPD subgroups. Patients with early PD have cognitive dysfunction with predominant involvement of frontal and temporal lobes. Side of onset of motor symptoms probably does not have significant role in future development or profile of cognitive dysfunction in PD.


Endothelial activation biomarkers increase after HIV-1 acquisition: plasma vascular cell adhesion molecule-1 predicts disease progression.
We aimed to determine whether endothelial activation biomarkers increase after HIV-1 acquisition, and whether biomarker levels measured in chronic infection would predict disease progression and death in HIV-1 seroconverters. HIV-1-seronegative Kenyan women were monitored monthly for seroconversion, and followed prospectively after HIV-1 acquisition. Plasma levels of angiopoietin-1 and angiopoietin-2 (ANG-1, ANG-2) and soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin were tested in stored samples from pre-infection, acute infection, and two chronic infection time points. We used nonparametric tests to compare biomarkers before and after HIV-1 acquisition, and Cox proportional-hazards regression to analyze associations with disease progression (CD4 < 200 cells/μl, stage IV disease, or antiretroviral therapy initiation) or death. Soluble ICAM-1 and VCAM-1 were elevated relative to baseline in all postinfection periods assessed (P < 0.0001). Soluble E-selectin and the ANG-2:ANG-1 ratio increased in acute infection (P = 0.0001), and ANG-1 decreased in chronic infection (P = 0.0004). Among 228 participants followed over 1028 person-years, 115 experienced disease progression or death. Plasma VCAM-1 levels measured during chronic infection were independently associated with time to HIV progression or death (adjusted hazard ratio 5.36, 95% confidence interval 1.99-14.44 per log10 increase), after adjustment for set point plasma viral load, age at infection, and soluble ICAM-1 levels. HIV-1 acquisition was associated with endothelial activation, with sustained elevations of soluble ICAM-1 and VCAM-1 postinfection. Soluble VCAM-1 may be an informative biomarker for predicting the risk of HIV-1 disease progression, morbidity, and mortality.


Effect of transcranial direct-current stimulation combined with treadmill training on balance and functional performance in children with cerebral palsy: a double-blind randomized controlled trial.
Cerebral palsy refers to permanent, mutable motor development disorders stemming from a primary brain lesion, causing secondary musculoskeletal problems and limitations in activities of daily living. The aim of the present study was to determine the effects of gait training combined with transcranial direct-current stimulation over the primary motor cortex on balance and functional performance in children with cerebral palsy. A double-blind randomized controlled study was carried out with 24 children aged five to 12 years with cerebral palsy randomly allocated to two intervention groups (blocks of six and stratified based on GMFCS level (levels I-II or level III).The experimental group (12 children) was submitted to treadmill training and anodal stimulation of the primary motor cortex. The control group (12 children) was submitted to treadmill training and placebo transcranial direct-current stimulation. Training was performed in five weekly sessions for 2 weeks. Evaluations consisted of stabilometric analysis as well as the administration of the Pediatric Balance Scale and Pediatric Evaluation of Disability Inventory one week before the intervention, one week after the completion of the intervention and one month after the completion of the intervention. All patients and two examiners were blinded to the allocation of the children to the different groups. The experimental group exhibited better results in comparison to the control group with regard to anteroposterior sway (eyes open and closed; p<0.05), mediolateral sway (eyes closed; p<0.05) and the Pediatric Balance Scale both one week and one month after the completion of the protocol. Gait training on a treadmill combined with anodal stimulation of the primary motor cortex led to improvements in static balance and functional performance in children with cerebral palsy. Ensaiosclinicos.gov.br/RBR-9B5DH7.


Effect of sprouting on nutritional quality of pulses.
In order to investigate the nutritional quality of industrial-scale sprouted versus unsprouted chickpeas and green peas, before and after cooking, the ultrastructure, chemical composition, antioxidant capacity, starch digestibility, mineral content and accessibility were analysed. Sprouting did not deeply affect raw seed structure, although after cooking starch granules appeared more porous and swelled. Chemical composition of raw sprouted seeds was not strongly affected, excepting an increase in protein (both pulses), and in free sugars (in peas; +10% and +80%, respectively, p < .05). The industrial sprouting favoured phytic acid leaching in cooking water (-35% in seeds, compared to unsprouted cooked ones, p < .05), and promoted antioxidant capacity reductions in raw and cooked seeds (-10% and -37%, respectively, p < .05). In conclusion, sprouting on an industrial-scale induced mild structural modifications in chickpeas and peas, sufficient to reduce antinutritional factors, without strongly influencing their nutritional quality. These products could represent nutritionally interesting ingredients for different dietary patterns as well as for enriched cereal-based foods.


[Magnetic resonance cholangiography: our first experience].
Magnetic resonance cholangiography is a new field of clinical application within MR imaging, enabling high-quality imaging on disorders of the pancreaticobiliary system. This cross-sectional imaging technique is, by means of postprocessing, suitable for the production of reconstruction images appropriate for comparison with endoscopic retrograde cholangiography. The quality of the images thus obtained is dependent upon the level of development of the technology and software available. Observations arising from authors initial examinations using 2D fast spin echo sequence are summarised.


Treatment of intracranial aneurysms associated with other entities.
Considering the current state of surgery for intracranial aneurysm, a philosophy for treating intracranial aneurysms associated with other entities is presented. The premise is based on a comprehensive review of the literature relative to the risk factors applied to intracranial aneurysms and personal experience in dealing with the combination of problems of aneurysms diagnosed in association with other intracranial aneurysms, vascular malformations, neoplasms, trauma, and inflammatory diseases. A patient's problem must be considered individually and comprehensively, using all known prognostic factors and the specific features of the case for an appropriate therapeutic regimen to be designed. Current mortality and morbidity rates warrant the surgical intervention for the incidentally diagnosed aneurysm, but the occurrence of an aneurysm in conjunction with another serious entity demands careful, comprehensive evaluation. The surgical challenge of these complex problems should take second priority to a careful therapeutic deliberation to promote the best final outcome.


Serum neuroleptic levels and extrapyramidal side effects in patients treated with amoxapine.
Serum neuroleptic levels were measured by radioreceptor assay in patients treated with the antidepressant amoxapine. When compared to standard neuroleptics, amoxapine produced relatively weak neuroleptic activity. Amoxapine dose correlated significantly with serum neuroleptic level. Three of eight patients developed significant extrapyramidal side effects. Neither dose of amoxapine nor neuroleptic level correlated with the presence or severity of EPS.


Postpartum Depression and Subsequent Autoimmune Diseases in Taiwan.
Postpartum depression (PPD) is one of the most common examples of postnatal morbidity, but the subsequent risks of autoimmune diseases in patients with PPD have yet to be fully investigated. This nationwide population-based study utilized data of the National Health Insurance Research Database of Taiwan for the period from 1996 to 2013. In total, 45,451 women with primiparity were identified. Among them, 542 patients with PPD were enrolled as a study group while 2165 matched patients without PPD were enrolled as a control group. The demographic characteristics and comorbidities of the patients were analyzed, and Cox regression analysis was applied to calculate the hazard ratios for the risk of autoimmune diseases. Of the 2707 women enrolled in this study, 469 (17.3%) patients with newly diagnosed autoimmune diseases were identified, including 123 (22.7%) in the PPD group and 346 (16%) in the non-PPD group. After adjusting for confounding factors, it was determined that the patients with PPD had a significantly higher risk of subsequent autoimmune diseases (adjusted hazard ratio (aHR): 1.61, 95% confidence interval (CI): 1.30⁻1.99; p < 0.001). Specifically, increased risks of pernicious anemia (aHR: 3.85, 95% CI: 2.06⁻7.22), rheumatoid arthritis (aHR: 2.62, 95% CI: 1.28⁻5.39), and Graves' disease (aHR: 1.57, 95% CI: 1.05⁻2.33) were observed in the PPD group. This study demonstrated that patients with PPD have higher risks of subsequent autoimmune diseases, especially pernicious anemia, rheumatoid arthritis, and Graves' disease. This useful information provides physicians with clues regarding the associations between autoimmune diseases and PPD.


ANFIS-Net for automatic detection of COVID-19.
Among the most leading causes of mortality across the globe are infectious diseases which have cost tremendous lives with the latest being coronavirus (COVID-19) that has become the most recent challenging issue. The extreme nature of this infectious virus and its ability to spread without control has made it mandatory to find an efficient auto-diagnosis system to assist the people who work in touch with the patients. As fuzzy logic is considered a powerful technique for modeling vagueness in medical practice, an Adaptive Neuro-Fuzzy Inference System (ANFIS) was proposed in this paper as a key rule for automatic COVID-19 detection from chest X-ray images based on the characteristics derived by texture analysis using gray level co-occurrence matrix (GLCM) technique. Unlike the proposed method, especially deep learning-based approaches, the proposed ANFIS-based method can work on small datasets. The results were promising performance accuracy, and compared with the other state-of-the-art techniques, the proposed method gives the same performance as the deep learning with complex architectures using many backbone.


Possible link between right ventricular coronary sinusoids and noncompaction sinusoids in pulmonary atresia with intact ventricular septum patients that later develop left ventricular noncompaction.
Patients who have pulmonary atresia with intact ventricular septum have been shown to have a number of various myocardium anomalies like ischemia, fibrosis, infarction, rupture, disarray, spongious myocardium and ventricular endocardial fibroelastosis. Multiple connections have been found between right ventricular myocardial sinusoids and small branches of intramural coronary arteries. Noncompation of ventricular myocardium has been shown to be the result of myocardial ischemia or excessive pressure preventing the reduction of embryonic sinusoids. The persistence of intertrabecular recesses that are connected to both the ventricular cavity and coronary circulation is the result of this process. In this text, we describe a PA-IVS patient who underwent patent ductus arteriosus stenting and pulmonary valve perforation to create antegrade flow and later developed left ventricular noncompaction. We posit that there is a connection between right ventricular coronary sinusoids and noncompaction sinusoids. As our patient's RV outflow tract stenosis and RV pressure increased, the coronary circulation connected to coronary sinuses became sufficient and LV function improved, which further supports our hypothesis.


[Validation of a questionnaire of physical sensations in a French-Canadian population].
The objectives of this study are three-fold. The first objective is to present the aspects of reliability and validity of a self-reported questionnaire that evaluates a specific facet of Panic Disorder with Agoraphobia (PDA) for the francophone population of Quebec, mainly the fear of fear. The Body Sensations Questionnaire (17), translated as the Questionnaire des Sensations Physiques (QSP) evaluates the degree to which individuals fear somatic symptoms commonly associated with panic. A second objective is to determine the factorial validity of the QSP and to investigate the dimensionality of the construct as assessed by the questionnaire. The third objective is to establish a reference database for the agoraphobic (N = 141 and N = 70) and the non-clinical population (N = 223). Results suggest that both questionnaires have similar internal consistency, temporal stability, construct validity, and discriminative validity. While the factorial solution of the present study uncovered a three-factor model (somatic, cardiac, and psychosensorial), which points to the multidimensional nature of the construct evaluated by the QSP, it greatly differs from the one obtained by Arrindel's study (5). Nevertheless, the extraction of the three principal components is supported by the results of the screen test and by two different implementations of parallel analysis, i.e., the computation of random eigen values and the use of an interpolation table of eigen values. Finally, it can be concluded that the psychometric properties of the French-Canadian translation of the BSQ are indications that it is an appropriate instrument to use in clinical research and in clinical practice to assess the fear of bodily sensations associated with the fear of fear.


Scoria: a Python module for manipulating 3D molecular data.
Third-party packages have transformed the Python programming language into a powerful computational-biology tool. Package installation is easy for experienced users, but novices sometimes struggle with dependencies and compilers. This presents a barrier that can hinder the otherwise broad adoption of new tools. We present Scoria, a Python package for manipulating three-dimensional molecular data. Unlike similar packages, Scoria requires no dependencies, compilation, or system-wide installation. One can incorporate the Scoria source code directly into their own programs. But Scoria is not designed to compete with other similar packages. Rather, it complements them. Our package leverages others (e.g. NumPy, SciPy), if present, to speed and extend its own functionality. To show its utility, we use Scoria to analyze a molecular dynamics trajectory. Our FootPrint script colors the atoms of one chain by the frequency of their contacts with a second chain. We are hopeful that Scoria will be a useful tool for the computational-biology community. A copy is available for download free of charge (Apache License 2.0) at http://durrantlab.com/scoria/ . Graphical abstract .


Signaling events triggered by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL): caspase-8 is required for TRAIL-induced apoptosis.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a TNF family member and potent apoptosis inducer. In contrast to TNF-alpha or Fas ligand, relatively little is known about the signaling events activated by TRAIL. In particular, the initial caspase(s) required for TRAIL-induced apoptosis remains to be determined Caspase-3-like protease but not caspase-1-like protease (YVADase) activity rapidly increased in HeLa cells in response to TRAIL treatment. The increase in protease activity correlated with the profile of apoptotic cell death that was inhibited by the pan-caspase inhibitor Z-VAD-fmk. In response to TRAIL, caspase-8, an initiator caspase in death receptor-mediated apoptosis, was activated within 1 h in association with Bid cleavage, cytochrome c release, caspase-3 activation, and DNA fragmentation factor 45 cleavage. Z-IETD-fmk, a caspase-8 inhibitor, completely blocked caspase-8 activation and resulted in inhibition of caspase-3 (a caspase-3-like protease) activation and apoptotic cell death. Overexpression of a caspase-8 dominant negative mutant inhibited apoptosis induced by TRAIL. Caspase-8-deficient Jurkat cells were resistant to both TRAIL and Fas-induced apoptosis, whereas wild-type Jurkat cells were susceptible to both TRAIL- and Fas-induced apoptosis. The caspase-8-reintro duced caspase-8-deficient Jurkat cells acquired normal susceptibility to both TRAIL and agonistic Fas antibody. Reverse transcription-PCR and sequence analyses have revealed that these caspase-8-deficient Jurkat cell express wild-type caspase-10. Therefore, our data indicate that caspase-8 is required for TRAIL-induced apoptosis and suggest that caspase-10 may play a minor role, if any, in TRAIL-induced apoptosis.


[Glucagonoma without glucagonoma syndrome].
Glucagonomas are rare, frequently malignant tumours, arising from the Langerhans' islets of the pancreas. They usually secrete large amounts of glucagon that can cause a characteristic "glucagonoma syndrome", which includes necrolytic migratory erythema, glucose intolerance or diabetes, weight loss and sometimes, normochromic normocytic anaemia, stomatitis or cheilitis, diarrhoea or other digestive symptoms, thoromboembolism, hepatosplenomegaly, depression or other psychiatric and paraneoplastic symptoms. In certain cases, some or all glucagonoma symptoms may appear late, or even may be completely absent. The authors present a 43-year-old woman in whom an investigation for abdominal pain revealed a tumour of the body of the pancreas. During operation, the tumour of the body of the pancreas extending to the mesentery measuring 85 x 55 x 55 mm was excised. Histology and immunohistochemistry showed malignant glucagonoma, with co-expression of somatostatin in about 5% and pancreatic polypeptide in a few tumour cells. The recovery was uneventful. The patient stayed symptom-free with no signs of local recurrence or distant diseases 15 years after surgery. Glucagonoma syndrome may be absent in glucagonoma tumour patients so that in unclear pancreatic tumours the clinician should frequently request the serum hormone level (including glucagon) measurement by radioimmunoassay and the pathologist should perform immunohistochemistry investigation. Those two would probably result in discovery of more glucagonomas and other neuroendocrine tumours without characteristic clinical syndromes.


Molecularly proven mosaicism in phenotypically normal parent of a girl with Freeman-Sheldon Syndrome caused by a pathogenic MYH3 mutation.
We report a case of a female child who has classical Freeman-Sheldon syndrome (FSS) associated with a previously reported recurrent pathogenic heterozygous missense mutation, c.2015G > A, p. (Arg672His), in MYH3 where the phenotypically normal mother is a molecularly confirmed mosaic. To the best of our knowledge, this is the first report in the medical literature of molecularly confirmed parental mosaicism for a MYH3 mutation causing FSS. Since proven somatic mosaicism after having an affected child is consistent with gonadal mosaicism, a significantly increased recurrence risk is advised. Parental testing is thus essential for accurate risk assessment for future pregnancies and the use of new technologies with next generation sequencing (NGS) may improve the detection rate of mosaicism. © 2016 Wiley Periodicals, Inc.


Sex differences in preferences for humor: a replication, modification, and extension.
Evolutionary-minded scientists have proposed that humor is a sexually selected trait in men that signals mate quality. Indeed, women tend to prefer men who make them laugh and men tend to prefer women who laugh at their jokes. However, it is unclear how robust this pattern is. Here we report a replication of one of the first studies (Bressler, Martin, and Balshine, 2006) to examine the sex differences in preferences for humor receptivity versus humor production. We replicate Bressler et al.'s (2006) findings that men prefer women who are receptive to their humor whereas women prefer men who produce humor. These findings held even after we modified Bressler et al.'s questionnaire for better conceptual validity. Furthermore, using a separate measure designed to assess trade-offs, we found that men viewed humor receptivity as a necessity and humor production as a luxury when they were asked to create an ideal long-term partner. For women, it was just the opposite. These results bolster the claim that sexual selection has shaped sex differences regarding preferences for a prospective mate's sense of humor and that what one means by "sense of humor" can vary.


Non-uniform lithium-ion migration on micrometre scale for garnet- and NASICON-type solid electrolytes studied by 7Li PGSE-NMR diffusion spectroscopy.
The migration behaviours of Li+ in three garnet- and one NASICON-type solid oxide electrolytes were studied on the micrometre scale by pulsed-gradient spin-echo (PGSE) 7Li NMR diffusion spectroscopy to clarify common and specific characteristics of each electrolyte. In these solid electrolytes, clear evidences of grain boundary effects in the diffusion of Li+ were not observed. The Li+ diffusion constants were dependent on parameters such as observation time (Δ) and pulsed field gradient (PFG) strength (g) for all the studied inorganic solid electrolytes. For low Δ values, Li+ ions underwent collisions and diffractions with diffraction distance Rdiffraction [μm]. The apparent Li+ diffusion constants (Dapparent [m2 s-1]) exhibited distributions in a wide range. In this paper, we introduced the apparent diffusion radius, rradius [μm], and compared it with Rdiffraction and mean square displacement (MSD) [μm]; the lengths of these distances were of the micrometre order (10-6 m). The relations between the values of rradius, Rdiffraction and MSD suggested that the migration behaviours of Li+ on the micrometre scale were complicated. Using high Δ and high g values, we obtained an equilibrated value of DLi. The temperature dependences of the number of carrier ions were estimated from the DLi values and ionic conductivities in the four solid oxide electrolytes. For simple comparison and reference, the data of DLi and ionic conductivity of LiPF6 in 1 M solution of propylene carbonate were added.


Comparison of capillary blood ketone measurement by electrochemical method and urinary ketone in treatment of diabetic ketosis and ketoacidosis in children.
We aimed to compare the recent practical method of capillary beta-hydroxy butyrate (betaOHB) measurement with the widely used urinary ketone measurement in monitoring metabolic status of the patient during treatment of diabetic ketoacidosis (DKA) and diabetic ketosis (DK). Patients with DKA and DK admitted to the hospital were followed with simultaneous measurements of capillary betaOHB by electrochemical method (Medisense Optium, Abbott), and urinary ketone by semi-quantitative method. Blood gases were measured in 2-4 h intervals. Fourteen patients with DKA/DK (7 males and 7 females, age: 9.2 +/- 4.2 years) were included with 50 simultaneous measurements of capillary and urinary ketone. No correlation was detected between urinary ketone and blood pH (P = 0.06) and HCO3 (P = 0.79), whereas a significant negative correlation was found between capillary betaOHB and blood pH (r = -0.41, P < 0.05) and HCO3 (r = -0.35, P < 0.05). Capillary betaOHB and urinary ketone levels did not correlate at the beginning and 3.3 +/- 1.4 h after treatment, but did correlate in the third samples taken 7.8 +/- 2.0 h after treatment (r = 0.8, P < 0.05). Capillary betaOHB levels show good correlation with the degree of acidosis (pH and HCO3). Capillary betaOHB measurement is more sensitive than urinary ketone measurement in reflecting the patient's metabolic status and improvement during treatment.


Tissue Doppler evaluation of systolic and diastolic cardiac functions in long-term survivors of Hodgkin lymphoma.
Monitoring for late adverse events is crucial in long-term management of childhood cancer survivors. A case-control study to evaluate long-term cardiovascular status of childhood Hodgkin lymphoma (HL) using tissue Doppler imaging (TDI) was performed. Patients diagnosed with HL before age of 18 that completed therapy and were in remission and a control group of healthy children were evaluated by echocardiography and TDI. Total of 72 HL survivors were included in the study. Median age at diagnosis, remission time, and age at time of echocardiography were 7 (2-16), 9 (2-20), and 17.5 (7-27) years, respectively. TDI revealed decreased S' velocity, reflecting systolic dysfunction in HL survivors, at medial and lateral mitral annuli and at middle segment of interventricular septum (IVS; P < 0.01) for all. Moreover, TDI showed decreased peak E' velocity at medial mitral annulus [12.4 cm/s (5.5-16.3) vs. 13.3 cm/s (10.2-18.9), P = 0.03] and at middle segment of IVS [10 cm/s (5.3-16.3) vs. 11.6 cm/s (6.7-16.7), P < 0.01] and prolongation of isovolemic relaxation time at medial and lateral annuli of the mitral valve (P < 0.01) and at middle segment of IVS (P = 0.03) suggesting diastolic dysfunction in HL survivors. Cardiac dysfunction after childhood cancer therapy may develop after many years. Since systolic and diastolic dysfunction can be seen in these patients periodic echocardiographic screening of both systolic and diastolic function in the survivors of HL might be useful in the follow-up of these patients.


Frigoribacterium mesophilum sp. nov., a mesophilic actinobacterium isolated from Bigeum Island, Korea.
A taxonomic study was performed on strain MSL-08T, which was isolated from a soil sample collected from Bigeum Island. The novel isolate was aerobic and Gram-positive. Cells were short and motile rods. Growth temperature ranged from 20 to 28 degrees C and the pH for growth ranged from 6.5 to 12.0. The optimum growth temperature and pH were 28 degrees C and 7.3, respectively. The predominant menaquinone was MK-9. Cell wall analysis showed B-type peptidoglycan containing 2,4-diaminobutyric acid, alanine, glycine, glutamate and lysine. The diagnostic phospholipids were diphosphatidylglycerol and phosphatidylglycerol. The major fatty acids were ai-C15:0, i-C16:0, C18:1omega7c and ai-C17:0. The DNA G+C content was 67.5 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain MSL-08(T) had less than 97 % similarity to any recognized species of the genus Frigoribacterium. Frigoribacterium faeni DSM 10309T was found to be the closest neighbour (96.95 %) to the novel strain. Based on the 16S rRNA gene sequence analysis and phenotypic characteristics, it is proposed that strain MSL-08T represents a novel member of the genus Frigoribacterium for which the name Frigoribacterium mesophilum sp. nov. is proposed. The type strain is MSL-08T (=DSM 19442T=KCTC 19311T).


A low-dose electron diffraction assay for protection of protein structure against damage from drying.
A new assay using low-dose electron diffraction to measure the protection of protein structure against damage from drying is described. When thin single crystals of catalase are dried within water alone, low-dose electron diffraction yields no Bragg spots. Drying within an experimental aqueous solution that permits detection of diffraction spots thereby indicates a positive result, and the extent of these Bragg reflections into the high angle range gives a quantitative measure of the degree of protection. Bragg spots out to 3.73.9 are recorded for drying within 100 mM solutions of the known structure-preserving sugars, sucrose, tannin, and trehalose. The ability of trehalose to maintain native protein structure during drying starts between 10 and 25 mM, and changes only slightly at concentrations above this threshold; with drying in 150-mM trehalose, catalase crystals yield diffraction spots out to 3.7. Drying within the organic nonsugar polymer polyvinylpyrrolidone gives Bragg spots to 4.0. This new assay should be useful to measure the unexamined structure-preserving capabilities of modified sugars, other nonsugars, and mixtures to identify which protective matrix maintains native protein structure to the greatest extent during drying; electron crystallography using that optimal matrix should yield protein structure at improved levels of high resolution.


Influence of oleic acid on serum lipoprotein-X in vitro.
Lipoprotein-X is no longer detectable in serum by either the agar gel-electrophoresis/polyanion precipitation technique or immunoelectrophoresis with specific antiserum after in vitro addition of oleic acid. Evidence is presented which indicates that this ostensible loss is due not to its destruction, but rather to altered electrophoretic mobility. The findings suggest an explanation for the well known post-heparin "disappearance" of lipoprotein-X, and indicate that caution may be needed in the interpretation of such lipoprotein-X testing of sera from subjects with increased concentrations of lysolipids in their blood.


Prolongation of the QT interval and the sudden infant death syndrome.
The sudden infant death syndrome (SIDS) is multifactorial in origin, but its causes remain unknown. We previously proposed that prolongation of the QT interval on the electrocardiogram, possibly resulting from a developmental abnormality in cardiac sympathetic innervation, may increase the risk of life-threatening ventricular arrhythmias and contribute to this devastating disorder. We prospectively tested this hypothesis. Between 1976 and 1994, we recorded electrocardiograms on the third or fourth day of life in 34,442 newborns and followed them prospectively for one year. The QT interval was analyzed with and without correction for the heart rate. One-year follow-up data were available for 33,034 of the infants. There were 34 deaths, of which 24 were due to SIDS. The infants who died of SIDS had a longer corrected QT interval (QTc) than did the survivors (mean [+/-SD], 435+/-45 vs. 400+/-20 msec, P<0.01) and the infants who died from causes other than SIDS (393+/-24 msec, P<0.05). Moreover, 12 of the 24 SIDS victims but none of the other infants had a prolonged QTc (defined as a QTc greater than 440 msec). When the absolute QT interval was determined for similar cardiac-cycle lengths, it was found that 12 of the 24 infants who died of SIDS had a QT value exceeding the 97.5th percentile for the study group as a whole. The odds ratio for SIDS in infants with a prolonged QTc was 41.3 (95 percent confidence interval, 17.3 to 98.4). Prolongation of the QT interval in the first week of life is strongly associated with SIDS. Neonatal electrocardiographic screening may permit the early identification of a substantial percentage of infants at risk for SIDS, and the institution of preventive measures may therefore be possible.


SUMO is a pervasive regulator of meiosis.
Protein modification by SUMO helps orchestrate the elaborate events of meiosis to faithfully produce haploid gametes. To date, only a handful of meiotic SUMO targets have been identified. Here, we delineate a multidimensional SUMO-modified meiotic proteome in budding yeast, identifying 2747 conjugation sites in 775 targets, and defining their relative levels and dynamics. Modified sites cluster in disordered regions and only a minority match consensus motifs. Target identities and modification dynamics imply that SUMOylation regulates all levels of chromosome organization and each step of meiotic prophase I. Execution-point analysis confirms these inferences, revealing functions for SUMO in S-phase, the initiation of recombination, chromosome synapsis and crossing over. K15-linked SUMO chains become prominent as chromosomes synapse and recombine, consistent with roles in these processes. SUMO also modifies ubiquitin, forming hybrid oligomers with potential to modulate ubiquitin signaling. We conclude that SUMO plays diverse and unanticipated roles in regulating meiotic chromosome metabolism.


Pharmacokinetics and pharmacodynamics of oleylphosphocholine in a hamster model of visceral leishmaniasis.
This study evaluated the pharmacokinetic properties of oleylphosphocholine (OlPC) in hamsters following a single oral dose. Its prophylactic activity was tested to establish exposure-activity relationships, while a 5 + 5 day oral regimen at 20 mg/kg with long post-treatment follow-up was performed to assess its curative potential. Single oral doses of 20, 50 and 100 mg/kg were administered for pharmacokinetic analysis while a 100 mg/kg single oral dose was given on day 7, 4 or 1, or 4 h prior to infection in the prophylactic efficacy study. The animals were infected on day 0 with Leishmania infantum and the resulting parasite burdens were measured in target organs on day 21. In the curative model, treatment started on day 21 post-infection at 20 mg/kg for 5 + 5 days and amastigote burdens were determined in target organs either on day 42 [10 days after the end of treatment (dpt)] or day 72 (40 dpt). OlPC showed elimination t1/2 of ∼50 h and dose-proportional exposure. The prophylactic action of OlPC was in agreement with model-simulated drug exposures, showing dose-dependent residual activity. Interestingly, the 100 mg/kg single dose administered 4 days before infection (day -4) still reduced the overall parasite burden by ∼50%. In the curative model, >99% clearance of infection was observed at 10 dpt in all OlPC-treated animals and remained so at 40 dpt. This study reveals that total plasma exposure (AUCt-∞) correlates well with the prophylactic and curative efficacy of OlPC in the L. infantum hamster model.


Hormonal regulation of fibrinogen synthesis in cultured hepatocytes.
Most of what was originally known of the effects of hormones on fibrinogen synthesis was based, as noted above, on experiments involving surgical removal of endocrine glands. Some caution should be exercised when using such in vivo experiments to derive the hormonal requirements of fibrinogen synthesis, however, since multiple hormonal alterations often occur in these animals. The development of a variety of ex vivo systems has allowed investigators to more carefully control the hepatocellular environment. The work of several laboratories, including our own, has now made it clear that hormones and other agents directly stimulate hepatocellular synthesis of fibrinogen. From the studies summarized here, using chick embryo hepatocytes as a model, several generalizations emerge: Fibrinogen synthesis may be considered to be a "constitutive" liver function, since hepatocytes cultured without serum, hormones or other macromolecular supplements synthesize this protein at a basal rate for several days. Addition of certain hormones (e.g. T3, dexamethasone, insulin), individually and in physiological concentrations, elicits an increase in fibrinogen production, varying with each agent in onset, dose, minimum exposure required and accompanying effects on the synthesis of other plasma proteins. Glucocorticoids and thyroid hormones are similar in the selectivity of their stimulation (neither affects albumin or transferrin synthesis) but differ in that thyroid hormones need to be present for just a short "triggering" period. The stimulation of fibrinogen synthesis by insulin occurs only following prolonged exposure to concentrations 10-times higher than the very low doses to which albumin synthesis responds rapidly.


Risk and Blood Pressure Control Rates Across the Spectrum of Coronary Artery Disease in Hypertensive Women: An Analysis from The INternational VErapamil SR-Trandolapril STudy (INVEST).
Background: Hypertension is a major modifiable risk factor for coronary artery disease (CAD), the main cause of death in women. While association between the two is frequent, limited data exist regarding the feasibility of blood pressure (BP) management and outcomes in women across the spectrum of CAD. Accordingly, we analyzed patient characteristics, BP control rates, and outcomes among hypertensive women with CAD, enrolled in The INternational VErapamil SR-trandolapril STudy (INVEST). Methods: The 11,770 hypertensive women with CAD in INVEST were studied based on presence (n = 3,879) or absence (n = 7,891) of history of myocardial infarction (MI) or coronary revascularization, to evaluate outcomes across risk groups based on severity of CAD. Results: Women with prior MI or revascularization were older (4 years, p < 0.0001), were predominantly white (62% vs. 29%), and had more associated comorbidities than women without these events. At 24 months, JNC VI (sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) BP control rates were lower in women with prior MI or revascularization (57% vs. 64%, p < 0.0001), despite more intensive antihypertensive therapy. The primary outcome (first occurrence of all-cause death, nonfatal MI, or nonfatal stroke) was also more frequent in women with prior MI or revascularization (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.34-1.74), who were 42% more likely to die (adjusted HR 1.42; 95% CI 1.22-1.64), twice as likely to have a nonfatal MI (adjusted HR 2.4, 95% CI 1.64-3.51), and 56% more likely to have a nonfatal stroke (adjusted HR 1.56, 95% CI 1.1-2.21). Conclusions: In a prospective, multinational cohort of hypertensive women with CAD, those with prior MI or revascularization comprised a group at higher risk for death, nonfatal MI, and nonfatal stroke, and were less likely to have their BP controlled, despite more aggressive therapy. The feasibility and benefit of reducing BP to <130/80 mmHg in women, particularly with more severe CAD, warrant further investigation.


Effect of digoxin on ST-segment changes detected by ambulatory electrocardiographic monitoring in healthy subjects.
Digoxin causes false-positive ST depression during exercise stress testing, but it is unknown if digoxin produces ST depression during ambulatory electrocardiographic monitoring. Fifty healthy volunteers underwent both exercise stress testing and ambulatory electrocardiographic monitoring before and after 14 days of digoxin (0.25 mg/day) administration. Significant ST depression was defined as greater than or equal to 1 mm of horizontal or downsloping ST depression 80 ms after the J point lasting for greater than or equal to 60 seconds. During therapy, 13 subjects (26%) had at least 1 episode of ST depression and 5 subjects (10%) had multiple episodes of ST depression detected by ambulatory monitoring. Ten subjects (20%) had ST depression that occurred during exercise that was detected by both stress test and ambulatory monitoring. Three subjects (6%) had ST depression that was detected on the ambulatory recording only at times other than during the stress test. Stratification of demographic and clinical variables did not predict digoxin-induced ST depression. Thus, digoxin causes false-positive ST depression detected by ambulatory monitoring. The incidence is similar to that observed during stress testing, but also occurs at heart rates lower than that achieved during stress tests. Ambulatory electrocardiographic monitoring will be less useful in the noninvasive assessment of coronary artery disease in patients receiving digoxin.


Socioeconomic reorganization of communication and mobility networks in response to external shocks.
Socioeconomic segregation patterns in networks usually evolve gradually, yet they can change abruptly in response to external shocks. The recent COVID-19 pandemic and the subsequent government policies induced several interruptions in societies, potentially disadvantaging the socioeconomically most vulnerable groups. Using large-scale digital behavioral observations as a natural laboratory, here we analyze how lockdown interventions lead to the reorganization of socioeconomic segregation patterns simultaneously in communication and mobility networks in Sierra Leone. We find that while segregation in mobility clearly increased during lockdown, the social communication network reorganized into a less segregated configuration as compared to reference periods. Moreover, due to differences in adaption capacities, the effects of lockdown policies varied across socioeconomic groups, leading to different or even opposite segregation patterns between the lower and higher socioeconomic classes. Such secondary effects of interventions need to be considered for better and more equitable policies.


Predictors of Maternal Depression Management among Primary Care Physicians.
Purpose. The present surveillance study examined predictors of the management of maternal depression in primary care settings. Methods. A total of 217 physicians completed a 60-item survey assessing demographics, physicians' attitudes, beliefs, efficacy, current practices, and perceived barriers regarding the management of maternal depression. Structural equation modeling was used to estimate a model that examined the relationships among physicians' knowledge, beliefs, self-efficacy, perceived barriers, past training toward and current management practices for maternal depression. Results. In a model predicting physician depression management practices, a good overall fit was observed (χ(2) = 136.63, CFI = .97, TLI = .95, RMSEA = .05), with physician comfort with, confidence in, and perceived responsibility for managing maternal depression all having prominent positive associations. Conclusions. These findings will guide the development of future multifaceted intervention strategies to enhance physician skills in managing maternal depression in primary care settings.


Using Unlabeled Data to Discover Bivariate Causality with Deep Restricted Boltzmann Machines.
An important question in microbiology is whether treatment causes changes in gut flora, and whether it also affects metabolism. The reconstruction of causal relations purely from non-temporal observational data is challenging. We address the problem of causal inference in a bivariate case, where the joint distribution of two variables is observed. We consider, in particular, data on discrete domains. The state-of-the-art causal inference methods for continuous data suffer from high computational complexity. Some modern approaches are not suitable for categorical data, and others need to estimate and fix multiple hyper-parameters. In this contribution, we introduce a novel method of causal inference which is based on the widely used assumption that if X causes Y, then P(X) and P(Y|X) are independent. We propose to explore a semi-supervised approach where P(Y|X) and P(X) are estimated from labeled and unlabeled data respectively, whereas the marginal probability is estimated potentially from much more (cheap unlabeled) data than the conditional distribution. We validate the proposed method on the standard cause-effect pairs. We illustrate by experiments on several benchmarks of biological network reconstruction that the proposed approach is very competitive in terms of computational time and accuracy compared to the state-of-the-art methods. Finally, we apply the proposed method to an original medical task where we study whether drugs confound human metagenome.


Organofluorine Mass Balance Analysis of Whole Blood Samples in Relation to Gender and Age.
Studies have highlighted the increasing fraction of unidentified organofluorine (UOF) compounds in human blood, whose health effects are not known. In this study, 130 whole blood samples from the Swedish general population were analyzed for extractable organofluorine (EOF) and selected per- and polyfluoroalkyl substances (PFAS). Organofluorine mass balance analysis revealed that 60% (0-99%) of the EOF in female samples could not be explained by the 63 monitored PFAS; in males, 41% (0-93%) of the EOF was of unidentified origin. Significant differences between both age groups and gender were seen, with the highest fraction of UOF in young females (70% UOF, aged 18-44), which is contrary to what has been reported in the literature for commonly monitored compounds (e.g., perfluorooctane sulfonic acid, PFOS). Increasing the number of monitored PFAS did not lead to a large decrease of the UOF fraction; the seven highest PFAS (C8-C11 PFCAs, C6-C8 PFSAs) accounted for 98% of sum 63 PFAS. The high fraction of UOF in human samples is of concern, as the chemical species of these organofluorine compounds remain unknown and thus their potential health risks cannot be assessed.


Previous emergency department use among homicide victims and offenders: a case-control study.
We differentiate risk factors for future homicide victimization and offending, and we measure emergency department (ED) use among homicide victims, offenders, and controls. The design was a matched case-control study conducted in Bernalillo County, NM, and its university-affiliated health sciences center and hospital. All Bernalillo County homicide victims (N=124) and offenders (N=138) identified between January 1996 and December 2001 who were linked to university physician billing records and who had health care use during the 3 years before the homicide incident were included as cases. Randomly selected age-matched (+/-1 year) and sex-matched subjects with health care use within 3 years of their matched pair's homicide were included as controls. Main outcome measures were the number and type of ED visits by cases and controls. Among the 124 victims and 138 offenders who used health care, most were men (80%) and averaged 27.7 years of age. Victims and offenders had similar health care use and were grouped for final analyses. Cases (victims and offenders) were more likely to have had an ED visit within 3 years of the homicide (85%) compared with controls (59%) (odds ratio [OR] 4.3; 95% confidence interval [CI] 3.0 to 6.2). Within previous ED visits, assault (OR 4.5; 95% CI 2.9 to 7.0), firearm injury (OR 13.6; 95% CI 4.9 to 37.7), and substance abuse (OR 3.7; 95% CI 2.2 to 6.0) were associated with future homicide. ED visits clustered closer to the homicide incident for cases (median days before the homicide -402 days; 95% CI -434 to -364) compared with controls (median -487 days; 95% CI -498 to -474). Patients with ED visits for assault, firearm injuries, and substance abuse are at increased risk for homicide and often have an escalating number of visits leading up to the homicide event. ED-based identification and referral programs similar to those used for intimate partner violence or other preventive strategies should be considered for this high-risk population.


Dietary L-glutamine supplementation improves pregnancy outcome in mice infected with type-2 porcine circovirus.
Porcine circovirus type 2 (PCV2) causes reproductive failure in swine. As glutamine can enhance immune function in animals, this study was conducted with mice to test the hypothesis that dietary glutamine supplementation will improve pregnancy outcome in PCV2-infected dams. Beginning on day 0 of gestation, mice were fed a standard diet supplemented with 1.0% L-glutamine or 1.22% L-alanine (isonitrogenous control). All mice were infected with PCV2 (2000 TCID50) on day 10 of gestation. On day 17 of gestation, six mice from each group were euthanized to obtain maternal tissues and fetuses for hematology and histopathology tests. The remaining mice continued to receive their respective diets supplemented with 1.0% L-glutamine or 1.22% L-alanine through lactation. The PCV2 virus was present in maternal samples (serum and lung) of most mice in the control group but was not detected in the glutamine-supplemented mice. Dietary glutamine supplementation reduced abortion, decreased fetal deaths, and enhanced neonatal survival. The glutamine treatment also reduced concentrations of interleukin-6, while increasing concentrations of tumor necrosis factor-α and C-reactive protein, in the maternal serum of mice. Furthermore, glutamine supplementation attenuated microscopic lesions in maternal tissues (lung, spleen, and liver). Collectively, these results indicate that dietary glutamine supplementation is beneficial for ameliorating reproductive failure in virus-infected mice. The findings support the notion that gestating dams require adequate amounts of dietary glutamine for the optimal survival and growth of embryos, fetuses, and neonates, and have important implications for nutritional support of mammals (including swine and humans) during gestation and lactation.


Ultrasound-guided liver resections for hepatocellular carcinoma.
Imaging-guided interventional procedures have modified the approach to hepatocellular carcinoma including the surgical one. In fact, liver resections can be carried out with no mortality even if cirrhosis is associated, combining the needs for oncological radicality and liver parenchyma sparing mainly because of the extensive use of intraoperative ultrasonography either for tumor staging or resection-guidance. The aid of intraoperative ultrasonography is therefore optimizing the balance between the oncological radicality and the sparing of the highest amount of functioning liver parenchyma. Intraoperative ultrasonography allows the accomplishment of anatomical resections otherwise not possible such as the systematic segmentectomy. This is of crucial importance if taking into account that anatomical resections seem able to provide better prognosis than the non-anatomical one. However, if non-anatomical resection is carried out intraoperative ultrasonography guidance allows a better tumor clearance. Precise definition of hepatic vein anatomy and association with color Doppler enables hepatectomies otherwise not possible, expanding the indication at surgical resection. In conclusion, we can affirm that liver resection is an imaging-guided procedure and as every interventional imaging-guided procedure, its features are the highest therapeutic efficacy combined with the minimal invasiveness. Then, with the intraoperative ultrasonography guidance liver resection remains the treatment of choice of hepatocellular carcinoma.


Disparities in HIV/AIDS Risk Behaviors After Youth Leave Detention: A 14-Year Longitudinal Study.
To examine changes in the prevalence of 15 HIV/AIDS sex and drug risk behaviors in delinquent youth during the 14 years after they leave detention, focusing on sex and racial/ethnic differences. The Northwestern Juvenile Project, a prospective longitudinal study of 1829 youth randomly sampled from detention in Chicago, Illinois, recruited between 1995 and 1998 and reinterviewed up to 11 times. Independent interviewers assessed HIV/AIDS risk behaviors using the National Institutes on Drug Abuse Risk Behavior Assessment. Fourteen years after detention (median age, 30 years), one-quarter of males and one-tenth of females had >1 sexual partner in the past 3 months. One-tenth of participants reported recent unprotected vaginal sex with a high-risk partner. There were many sex and racial/ethnic differences. For example, African American males had 4.67 times the odds of having >1 partner than African American females (95% confidence interval [CI], 3.22-6.76). Over time, compared with non-Hispanic white males, African American males had 2.56 times the odds (95% CI, 1.97-3.33) and Hispanic males had 1.63 times the odds (95% CI, 1.24-2.12) of having multiple partners, even after adjusting for incarceration and age. Non-Hispanic white females were more likely to have multiple partners than racial/ethnic minority females. Although rates decrease over time, prevalence of sex risk behaviors are much higher than the general population. Among males, racial/ethnic minorities were at particular risk. The challenge for pediatric health is to address how disproportionate confinement of racial/ethnic minority youth contributes to disparities in the HIV/AIDS epidemic.


MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition.
Selected subpopulations of hypothalamic neurons play important roles in the regulation of whole body energy homeostasis. Studies have shown that the saturated fats present in large amounts in western diets can activate an inflammatory response in the hypothalamus, affecting the capacity of such neurons to respond appropriately to satiety and adipostatic signals. In the first part of this review, we will explore the mechanisms behind saturated fatty acid-induced hypothalamic dysfunction. Next, we will present and discuss recent studies that have identified the mechanisms that mediate some of the anti-inflammatory actions of unsaturated fatty acids in the hypothalamus and the potential for exploring these mechanisms to prevent or treat obesity.


Muscleblind isoforms are functionally distinct and regulate alpha-actinin splicing.
Drosophila Muscleblind (Mbl) proteins control terminal muscle and neural differentiation, but their molecular function has not been experimentally addressed. Such an analysis is relevant as the human Muscleblind-like homologs (MBNL1-3) are implicated in the pathogenesis of the inherited muscular developmental and degenerative disease myotonic dystrophy. The Drosophila muscleblind gene expresses four protein coding splice forms (mblA to mblD) that are differentially expressed during the Drosophila life cycle, and which vary markedly in their ability to rescue the embryonic lethal phenotype of muscleblind mutant flies. Analysis of muscleblind mutant embryos reveals misregulated alternative splicing of the transcripts encoding Z-band component alpha-Actinin, which can be replicated in human cells expressing a Drosophilaalpha-actinin minigene and epitope-tagged Muscleblind isoforms. MblC appreciably altered alpha-actinin splicing in this assay, whereas other isoforms had only a marginal or no effect, demonstrating functional specialization among Muscleblind proteins. To further analyze the molecular basis of these differences, we studied the subcellular localization of Muscleblind isoforms. Consistent with the splicing assay results, MblB and MblC were enriched in the nucleus while MblA was predominantly cytoplasmic. In myotonic dystrophy, transcripts bearing expanded non-coding CUG or CCUG repeats interfere with the function of human MBNL proteins. Co-expression of CUG repeat RNA with the alpha-actinin minigene altered splicing compared with that seen in muscleblind mutant embryos, indicating that CUG repeat expansion RNA also interferes with Drosophila muscleblind function. Moreover MblA, B, and C co-localize with CUG repeat RNA in nuclear foci in cell culture. Our observations indicate that Muscleblind isoforms perform different functions in vivo, that MblC controls muscleblind-dependent alternative splicing events, and establish the functional conservation between Muscleblind and MBNL proteins both over a physiological target (alpha-actinin) and a pathogenic one (CUG repeats).


Comparative study of the anesthetic efficacy of 4% articaine versus 2% lidocaine in inferior alveolar nerve block during surgical extraction of impacted lower third molars.
A comparative study is made of the anesthetic efficacy of 4% articaine versus 2% lidocaine, both with epinephrine 1:100,000, in truncal block of the inferior alveolar nerve during the surgical extraction of impacted lower third molars. A randomized double-blind clinical trial was conducted of 30 patients programmed for the bilateral surgical extraction of symmetrical lower third molars in the context of the Master of Oral Surgery and Implantology (University of Barcelona, Barcelona, Spain). Following the obtainment of informed consent, two operators performed surgery on an extemporaneous basis, using as local anesthetic 4% articaine or 2% lidocaine with the same concentration of vasoconstrictor (epinephrine 1:100,000). The study variables for each anesthetic were: latency (time to action) and duration of anesthetic effect, the amount of anesthetic solution used, and the need of re-anesthetize the surgical zone. A visual analog scale was used to assess pain during surgery, and thus subjectively evaluate the anesthetic efficacy of the two solutions. Statistically significant differences (p = 0.003) were observed in the mean duration of anesthetic effect (220.86 min. for 4% articaine vs. 168.20 min. for 2% lidocaine). Latency, the amount of anesthetic solution and the need to re-anesthetize the surgical field showed clinical differences in favor of articaine, though statistical significance was not reached. The pain scores indicated similar anesthetic efficacy with both solutions. The results obtained suggest that 4% articaine offers better clinical performance than 2% lidocaine, particularly in terms of latency and duration of the anesthetic effect. However, no statistically significant differences in anesthetic efficacy were recorded between the two solutions.


A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma.
Molecular methods for predicting prognosis in patients with oral cavity squamous cell carcinoma (OSCC) are urgently needed, considering its high recurrence rate and tendency for metastasis. The present study investigated the genetic basis of variations in gene expression associated with poor prognosis in OSCC using Affymetrix SNP 6.0 and Affymetrix GeneChip Human Gene 1.0 ST arrays. We identified recurrent DNA amplifications scattered from 8q22.2 to 8q24.3 in 112 OSCC specimens. These amplicons demonstrated significant associations with increased incidence of extracapsular spread, development of second primary malignancies, and poor survival. Fluorescence in situ hybridization, in a validation panel consisting of 295 cases, confirmed these associations. Assessment of the effects of copy number variations (CNVs) on genome-wide variations in gene expression identified a total of 85 CNV-associated transcripts enriched in the MYC-centered regulatory network. Twenty-four transcripts associated with increased risk of second primary malignancies, tumor relapse, and poor survival. Besides MYC itself, a novel dysregulated MYC module plays a key role in OSCC carcinogenesis. This study identified a candidate molecular signature associated with poor prognosis in OSCC patients, which may ultimately facilitate patient-tailored selection of therapeutic strategies.


Characterization of the low molecular weight human serum proteome.
Serum potentially carries an archive of important histological information whose determination could serve to improve early disease detection. The analysis of serum, however, is analytically challenging due to the high dynamic concentration range of constituent protein/peptide species, necessitating extensive fractionation prior to mass spectrometric analyses. The low molecular weight (LMW) serum proteome is that protein/peptide fraction from which high molecular weight proteins, such as albumin, immunoglobulins, transferrin, and lipoproteins, have been removed. This LMW fraction is made up of several classes of physiologically important proteins such as cytokines, chemokines, peptide hormones, as well as proteolytic fragments of larger proteins. Centrifugal ultrafiltration of serum was used to remove the large constituent proteins resulting in the enrichment of the LMW proteins/peptides. Because albumin is known to bind and transport small molecules and peptides within the circulatory system, the centrifugal ultrafiltration was conducted under solvent conditions effecting the disruption of protein-protein interactions. The LMW serum proteome sample was digested with trypsin, fractionated by strong cation exchange chromatography, and analyzed by microcapillary reversed-phase liquid chromatography coupled on-line with electrospray ionization tandem mass spectrometry. Analysis of the tandem mass spectra resulted in the identification of over 340 human serum proteins; however, not a single peptide from serum albumin was observed. The large number of proteins identified demonstrates the efficacy of this method for the removal of large abundant proteins and the enrichment of the LMW serum proteome.


CXCR4/CXCL12 Signaling and Protumor Macrophages in Primary Tumors and Sentinel Lymph Nodes Are Involved in Luminal B Breast Cancer Progression.
Luminal B breast cancers (BC) have a more aggressive behavior associated with a higher rate of tumor relapse and worse prognosis compared to luminal A tumors. In this study, we evaluated the involvement of specific epithelial-to-mesenchymal transition- (EMT-) and immune-related pathways in the dissemination of luminal B BC cells. The expression of 42 EMT- and immune-related genes was evaluated in matched sentinel lymph nodes (SLNs) analyzed by the one-step nucleic acid amplification assay (OSNA) and primary tumors of 40 luminal B BC patients by gene array and immunohistochemistry. The results were validated in an independent group of 150 luminal B tumors by immunohistochemistry and immunofluorescence and using gene expression data from 315 luminal B BC patients included in the Metabric dataset. We found that the expression of CXCR4 (p = 3.28E - 02) and CD163 (p = 6.92E - 03) was significantly upregulated in SLNs of recurrent luminal B BC patients. Luminal B primary tumors overexpressing CXCR4 were characterized by an increased expression of vimentin and a high content of CD163-positive macrophages. Bioinformatics analysis confirmed the correlation of CXCR4 with CXCL12, VIM, and CD163 expression and LN involvement. Our results suggest that the upregulation of the CXCR4/CXCL12 pathway and the presence of protumor macrophages in the primary tumor and SLNs sustain the aggressiveness of an important subgroup of luminal B BC.


The universal ancestor and the ancestors of Archaea and Bacteria were anaerobes whereas the ancestor of the Eukarya domain was an aerobe.
The use of an oxyphobic index (OI) based on the propensity of amino acids to enter more frequently the proteins of anaerobes makes it possible to make inferences on the environment in which the last universal common ancestor (LUCA) lived. The reconstruction of the ancestral sequences of proteins using a method based on maximum likelihood and their attribution by means of the OI to the set of aerobe or anaerobe sequences has led to the following conclusions: the LUCA was an anaerobic 'organism', as were the ancestors of Archaea and Bacteria, whereas the ancestor of Eukarya was an aerobe. These observations seem to falsify the hypothesis that the LUCA was an aerobe and help to identify better the environment in which the first organisms lived.


Identifying factors behind the general practice use of the term 'decline' for the childhood immunisation programme in New Zealand.
INTRODUCTION The role of healthcare providers and their use of systems is one of the most important factors in vaccination uptake. AIM To identify reasons and find patterns behind why immunisation providers code the word 'decline' in their system for childhood immunisation events. METHODS A qualitative study involving face-to-face semi-structured interviews with staff members involved in immunisation delivery. General practices were purposively selected for having either high or low rates of registered children coded on the electronic practice management system as having declined immunisation events. Thematic analysis was undertaken using an inductive approach to link themes to the data. RESULTS A total of 35 interviews were conducted with practice nurses; 21 were from practices with high rates of registered children recorded as having declining immunisation events, and 14 practices with low rates of declining. Common themes were: effective use of systems, early and ongoing engagement, adequate health care practitioner time and practitioner experience. Practices with low rates of coded decliners had stronger approaches for early and ongoing engagement, and were less likely to use formalised decline forms. As practice immunisation coverage rates improved over time, there was perceived to be less expressed vaccine hesitancy from families. CONCLUSIONS The reasons for coding individuals as 'decliners' are a complex mixture of individual, community, practitioner and practice systems. Front-line providers need adequate tools, time and resourcing to support effective and ongoing engagement with families. Community factors have influence but can change over time.


Stochasticity in transcriptional expression of a negative regulator of Arabidopsis ABA network.
Stably heritable spatiotemporal co/over-expression of distinct transcriptional regulators across generations is a desired target as they signal traffic in the cell. Here, the stability and expression pattern of AtHB7 (Arabidopsis homeodomain-leucine zipper class I) cDNA was characterized in 220 random population of transformed tomato clones where no AtHB7 orthologous has been identified in to date. Integration of p35S::AtHB7 casette was tested by the amplification of the stretches (700/425 bp) in the target by NPT II/AtHB7 oligos. Transcriptional expression pattern for the amplicons of the specific transcripts in the leaf tissues of transformants were determined by qRT-PCR. Transgene copy number was negatively correlated with transgene expression level, yet a majority of transformants (78%) carried single-copy of transgene. About 1:3 of the lines containing two-copy inserts showed less transcript expression. Heterologous CaMV 35S promoter drove AtHB7, illuminated no penalty on transgene expression levels, stability or plant phenotype under drought stress. Integration and expression analysis of transcription factors is of great significance for reliable prediction of gene dosing/functions in plant genomes so as to sustain breeding under abiotic stress to guarantee food security.


Evaluation of an oviposition-stimulating kairomone for the yellow fever mosquito, Aedes aegypti, in Recife, Brazil.
A synthetic mixture of an oviposition-stimulating kairomone for the yellow fever mosquito, Aedes aegypti, comprising of 83% tetradecanoic acid, 16% nonanoic acid and 1% tetradecanoic acid methyl ester (NTT, in short) was tested in a dengue endemic area in Recife, Brazil. Gravid female mosquitoes confined to a cage under semi-field conditions deposited significantly higher numbers of eggs in traps baited with NTT at doses ranging from 0.6 to 600 ng/microl than in control (water) traps. When tested in homes, egg-laying in traps baited with 60 ng NTT/microl (final concentration in trap, approximately 3.33 ng/ml) and in control traps was not significantly different, but egg deposited in traps with lower dosage (6 ng NTT/microl; final concentration in trap, approximately 0.33 ng/ml) was significantly higher than in control traps. In subsequent trials, the numbers of eggs laid in traps baited with 0.6 ng NTT/microl (final concentration in trap, approximately 0.033 ng/ml) were not significantly different from the numbers deposited in trap loaded with 6 ng NTT/microl. Egg-laying was significantly higher in these treatments than in control traps.