Data on social media use related to age, gender and trust constructs of integrity, competence, concern, benevolence and identification.
This article contains data collected from self-report surveys of respondents to measure 1) social media usage, 2) age, 3) gender and 4) trust, measured within five major trust constructs of a) Integrity, b) Competence, c) Concern, d) Benevolence and e) Identification. The data includes all instruments used, SPSS syntax, the raw survey data and descriptive statistics from the analyses. Raw data was entered into SPSS software and scrubbed using appropriate techniques in order to prepare the data for analysis. We believe that our dataset and instrument may give important insights related to computers in human behavior, and predicting trust antecedents in social media use such as age, gender, number of hour online and choice of content provider. We have also created a parsimonious five factor trust instrument developed from the extant literature for future research. Hence, this newly developed trust instrument can be used to measure trust not only in social media, but also in other areas such as healthcare, economics and investor relations, CSR, management and education. Moreover, the survey items developed to measure social media use are concise and may be applied to measure social media use in other contexts such as national cultural differences, marketing and tourism. For interpretation and discussion of the data and constructs, please see original article entitled "Who trusts social media" (Warner-Søderholm et al., 2018) [1].


Nanomapping of CD1d-glycolipid complexes on THP1 cells by using simultaneous topography and recognition imaging.
CD1d molecule, a monomorphic major histocompatibility complex class I-like molecule, presents different types of glycolipids to invariant natural killer T (iNKT) cells that play an important role in immunity to infection and tumors, as well as in regulating autoimmunity. Here, we present simultaneous topography and recognition imaging (TREC) analysis to detect density, distribution and localization of single CD1d molecules on THP1 cells that were loaded with different glycolipids. TREC was conducted using magnetically coated atomic force microscopy tips functionalized with a biotinylated iNKT cell receptor (TCR). The recognition map revealed binding sites visible as dark spots, resulting from oscillation amplitude reduction during specific binding between iNKT TCR and the CD1d-glycolipid complex. THP1 cells were pulsed with three different glycolipids (α-GalCer, C20 and OCH12) for 4 and 16 hr. Whereas CD1d-α-GalCer and CD1d-C20:2 complexes on cellular membrane formed smaller microdomains up to ~10 000 nm(2) (dimension area), OCH12 loaded CD1d complexes presented larger clusters with a dimension up to ~30 000 nm(2). Moreover, the smallest size of recognition spots was about 25 nm, corresponding to a single CD1d binding site. TREC successfully revealed the distribution and localization of CD1d-glycolipid complexes on THP1 cell with single molecule resolution under physiological conditions.


Brain responses to altered auditory feedback during musical keyboard production: an fMRI study.
Alterations of auditory feedback during piano performance can be profoundly disruptive. Furthermore, different alterations can yield different types of disruptive effects. Whereas alterations of feedback synchrony disrupt performed timing, alterations of feedback pitch contents can disrupt accuracy. The current research tested whether these behavioral dissociations correlate with differences in brain activity. Twenty pianists performed simple piano keyboard melodies while being scanned in a 3-T magnetic resonance imaging (MRI) scanner. In different conditions they experienced normal auditory feedback, altered auditory feedback (asynchronous delays or altered pitches), or control conditions that excluded movement or sound. Behavioral results replicated past findings. Neuroimaging data suggested that asynchronous delays led to increased activity in Broca's area and its right homologue, whereas disruptive alterations of pitch elevated activations in the cerebellum, area Spt, inferior parietal lobule, and the anterior cingulate cortex. Both disruptive conditions increased activations in the supplementary motor area. These results provide the first evidence of neural responses associated with perception/action mismatch during keyboard production.


Maier-Saupe theory in four dimensions.
Maier-Saupe theory is the canonical mean field description of thermotropic nematic liquid crystals. In this paper, we examine the predictions of the theory in four spatial dimensions. Representations of the order parameter tensor and the existence of new phases are discussed. The phase diagram, based on numerical solution of the self-consistent equations and Landau theory, is presented. Orientational order decreases as the number of spatial dimensions is increased.


Aposematism: what should our starting point be?
The evolution of aposematism is considered to be a major evolutionary problem because if new aposematic forms emerged in defended cryptic populations, they would face the dual problems of rarity and conspicuousness. We argue that this commonly assumed starting point might not have wide validity. We describe a novel evolutionary computer model in which prey evolve secondary defences and become conspicuous by moving widely over a visually heterogeneous habitat. Unless crypsis imposes high opportunity costs (for instance, preventing prey from efficient foraging, thermoregulation and communication), costly secondary defences are not predicted to evolve at all. However, when crypsis imposes opportunity costs, prey evolve secondary defences that facilitate raised behavioural conspicuousness as prey exploit opportunities within their environment. Optimal levels of secondary defence and of behavioural conspicuousness increase with population sizes and the costs imposed by crypsis. When prey are already conspicuous by virtue of their behaviours, the evolution of aposematic appearances (bright coloration, etc.) is much easier to explain because aposematic traits add little further costs of conspicuousness, but can bring large benefits.


Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide: biomarkers for mortality in a large community-based cohort free of heart failure.
Recent studies report that, in the absence of heart failure and renal failure, plasma B-type natriuretic peptide (BNP) has prognostic value for mortality. We sought to confirm and extend these previous studies to assess BNP, measured by 3 distinct assays, as a biomarker for mortality in a strategy to enhance efforts at primary prevention and to better understand the clinical phenotype of such subjects at risk. We used a community-based cohort of 2042 subjects from Olmsted County, Minn, and individuals with heart or renal failure were excluded. BNP was assessed using 3 assays including Biosite and Shionogi for mature, biologically active BNP and the Roche assay for apparently nonbiologically active amino-terminal pro-BNP (NT-proBNP). Thorough echocardiographic and clinical data were recorded for all of the participants. Median follow-up for mortality was 5.6 years. BNP by all 3 of the assays was predictive of mortality. NT-proBNP and Biosite assays remained significant even after adjustment for traditional clinical risk factors and echocardiographic abnormalities including left ventricular hypertrophy and diastolic dysfunction. Echocardiography documented widespread structural changes in those with increasing BNP levels yet below levels observed in heart failure. We report in a large, well-characterized community-based cohort, free of heart failure, the first study to compare 3 distinct BNP assays as biomarkers for mortality in the same cohort. Our findings confirm the potential use of NT-proBNP and BNP biomarkers for future events and underscore that these peptides may also serve as biomarkers for underlying cardiac remodeling secondary to diverse cardiovascular disease entities.


Visual neglect as a predictor of functional outcome one year after stroke.
The aim was to study the role of visual neglect in acute right hemisphere brain infarct as a predictor of poor functional outcome during the first year after stroke. In particular, we were interested in the additional value of neglect measures besides hemiparesis, hemianopia, cognitive deficits and age. A consecutive series of 57 patients with a neuroradiologically verified right hemisphere infarct was examined within 10 days of the stroke. Fifty patients were followed up for 1 year. Neglect was measured with the Conventional and the Behavioural subtests of the Behavioural Inattention Test (BITC and BITB, respectively). The predictors were determined at the 10-day examination. Functional outcome was assessed 3, 6 and 12 months after the onset with the Frenchay Activities Index. Neglect in BITB was the best single predictor, which together with high age formed the best combination of predictors for poor functional outcome at each follow-up. Hemiparesis was also included in this prediction model at the 3-month follow-up, but hemianopia, BITC, or visuoconstructional and memory deficits showed no additional predictive value. However, neglect usually recovered soon. When neurological and cognitive deficits were assessed at the same time as the outcome, hemiparesis rather than neglect was the strongest correlate of poor outcome. Neglect in acute stroke is an important predictor of poor functional recovery. Residual neglect, which could be compensated in the follow-up tests, may nevertheless restrict patients' real-life activities and hobbies.


Inpatient rehabilitation outcomes of patients with apraxia after stroke.
Stroke-induced paresis commands much attention during rehabilitation; other stroke-related consequences receive less consideration. Apraxia is a stroke disorder that may have important implications for rehabilitation and recovery. To investigate association of apraxia with stroke rehabilitation outcomes during inpatient rehabilitation. This cohort study compared patients with and without apraxia after a first left hemispheric stroke. All study patients received standard of care. Clinical measures were the Functional Independence Measure (FIM) and the upper extremity section of the Fugl-Meyer Assessment (FMA) administered upon admission and at discharge. Length of stay was also documented. Florida Apraxia Battery subtests were used to classify patients with apraxia. Fifteen patients were included in this study, 10 of whom had apraxia. Data analysis revealed that patients with apraxia exhibited improvement from admission to discharge in clinical measures; however, admission FIM score was significantly lower compared to patients without apraxia. There was no statistically significant difference between groups on FMA score, length of stay, or amount of change on clinical measures. This study of acute patients found those with apraxia to be significantly less independent upon admission to inpatient rehabilitation compared to patients without apraxia. Although both groups improved a similar amount during rehabilitation, patients with apraxia discharged at a level of independence comparable to patients without apraxia upon admission. Such disparity in independence is of concern, and apraxia as a factor in stroke rehabilitation and recovery deserves further attention.


Does regular walnut consumption lead to weight gain?
Studies consistently show the beneficial effects of eating nuts, but as high-energy foods, their regular consumption may lead to weight gain. We tested if daily consumption of walnuts (approximately 12 % energy intake) for 6 months would modify body weight and body composition in free-living subjects. Ninety participants in a 12-month randomized cross-over trial were instructed to eat an allotted amount of walnuts (28-56 g) during the walnut-supplemented diet and not to eat them during the control diet, with no further instruction. Subjects were unaware that body weight was the main outcome. Dietary compliance was about 95 % and mean daily walnut consumption was 35 g during the walnut-supplemented diet. The walnut-supplemented diet resulted in greater daily energy intake (557 kJ (133 kcal)), which should theoretically have led to a weight gain of 3.1 kg over the 6-month period. For all participants, walnut supplementation increased weight (0.4 (se 0.1) kg), BMI (0.2 (se 0.1) kg/m(2)), fat mass (0.2 (se 0.1) kg) and lean mass (0.2 (se 0.1) kg). But, after adjusting for energy differences between the control and walnut-supplemented diets, no significant differences were observed in body weight or body composition parameters, except for BMI (0.1 (se 0.1) kg/m(2)). The weight gain from incorporating walnuts into the diet (control-->walnut sequence) was less than the weight loss from withdrawing walnuts from the diet (walnut-->control sequence). Our findings show that regular walnut intake resulted in weight gain much lower than expected and which became non-significant after controlling for differences in energy intake.


The Drosophila proteasome undergoes changes in its subunit pattern during development.
The two-dimensional electrophoretic protein subunit pattern of the proteasome, which is a mulifunctional non-lysosomal proteinase, was analyzed throughout the development of Drosophila melanogaster. The experiments show that the proteasome is already present in early embryos and its characteristic gross morphology as judged by the outer diameter of 12 nm and the inner depression of 3 nm remains unaltered. The electrophoretic analysis of the enzyme subunits demonstrates that the proteasome undergoes, dependent on development, alterations in its protein composition. The most simple subunit pattern is observed in Schneider's S-3 tissue culture cells and early embryos while with ongoing fly development the subunit pattern of the proteasome becomes increasingly complex. 32P-Labeling and immunoblotting experiments indicate that post-translational modification of the subunits must in part be responsible for the development-dependent diversification of the subunit pattern. Our data raise the possibility that the in vivo proteolytic activity and the in vivo substrate specificity of the proteasome may be regulated by modification of its subunit composition during fly development.


Randomised controlled trial of paper, online and SMS diaries for collecting sexual behaviour information from young people.
Diaries are used in sexual behaviour research to reduce recall bias. Diary collection via mobile phone text messaging (SMS) has not been trialled previously in sexual behaviour research. This randomised controlled trial compared SMS, paper and online diaries on response rate, timeliness, completeness of data and acceptability. The correlation between behaviour reported in all three types of diaries and data collected in a retrospective questionnaire was also determined. Participants were recruited by telephone and randomised into one of three groups. They completed weekly sexual behaviour diaries for 3 months by SMS, online or paper (by post). An online survey was conducted at the end of 3 months to compare retrospective reports to the diaries and assess opinions on the diary collection method. 72 participants were enrolled in the study, 24 in each group. Online diaries were more likely to be submitted late than SMS diaries (p<0.001). 3.9% of SMS diaries, 3.1% of paper diaries and 0.5% of online diaries were incomplete (p=0.001). Online data collection was the preferred mode for 51%. 65 participants completed the end point retrospective questionnaire. The correlation between the diary and questionnaire on sexual risk classification was substantial (kappa=0.74) regardless of diary mode. SMS is a convenient and timely method of collecting brief behavioural data, but online data collection was preferable to most participants and more likely to be complete. Data collected in retrospective sexual behaviour questionnaires were found to agree substantially with data collected through weekly self-reported diaries.


Rasch analysis of the Personal Wellbeing Index.
The Personal Wellbeing Index (PWI) is used internationally to measure subjective well-being. While numerous studies have reported on the psychometric properties of the PWI using classic test theory, the current paper provides additional psychometric evaluation using the Rasch measurement model. The responses to the PWI items of 593 healthy adults living in Australia or Canada were analysed using Rasch analysis. Assessed were overall model fit was assessed, individual person fit and item fit, reliability, differential item functioning (DIF), unidimensionality, targeting, and response format. Results indicate excellent psychometric properties of the PWI, provided the religion/spirituality item is excluded. The seven-item PWI showed good model fit (overall item-trait interaction χ (2) = 70.59, df = 63, p = 0.24), excellent person separation (PSI = .89), no item or person misfit, and no DIF for country or gender, and unidimensionality was supported. In addition, only very mild disordered thresholds were observed for the 'safety' item, indicating that overall, the 11-point response format was suitable for this population. It is recommended that the religion/spirituality item not be included in the aggregated or averaged total score in Western context and that caution should be used in comparison across different groups where the eight-item version has been used.


Anti-nucleosome antibodies as a disease marker in systemic lupus erythematosus and its correlation with disease activity and other autoantibodies.
Detection of anti-nucleosome antibodies (anti-nuc) in patients with systemic lupus erythematosus (SLE) has been well established and it is claimed that their presence is associated with disease activity. The aim of this study is to evaluate the incidence of anti-nuc antibodies and to correlate them with disease activity and its association with other autoantibodies like anti-nuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), anti-histone antibodies (AHA), as well as autoantibodies to histone subfractions like H1, (H2A-H4) complex, H2B, and H3. This cross-sectional study included 100 SLE patients referred from the Rheumatology, Dermatology, and Nephrology Departments. SLE disease activity was evaluated by using SLE-Disease Activity Index (SLEDAI) score. A patient was defined as having active SLE when the SLEDAI score was more than 5.0. Fifty normal controls were also tested as a healthy control group. Anti-nuc antibodies, anti-dsDNA, and AHA were tested by Enzyme-Linked Immunosorbent Assay (ELISA) and ANA was detected by an indirect immunofluorescence test. All patients studied were in an active stage of disease and were untreated, of which 44 patients had renal biopsy-proven kidney involvement, which was categorized as lupus nephritis (LN) and 56 patients did not show any renal manifestations (SLE without LN). Anti-nuc antibodies were positive in 88%, anti-dsDNA in 80%, and AHA in 38% of the cases. ANA was positive in all SLE patients studied. None of the normal controls was found to be positive for these antibodies. Although a slightly higher incidence of autoantibodies were noted in LN, there was no statistical difference noted between LN and SLE without LN groups for anti-nuc and anti-dsDNA antibodies (p > 0.05). A higher incidence of autoantibodies to ANA specificities were noted in anti-nuc positive cases, but there was no statistical difference between anti-nuc positive and anti-nuc negative cases for ANA specificities among LN and SLE without nephritis groups (p > 0.05). Anti-nuc antibody detection could be a better tool for the diagnosis of SLE. Although there was no significant difference in LN and SLE without LN groups, this study suggests that anti-nuc detection can be useful as an additional disease activity marker to other laboratory tests.


Mutational analysis of the modulation of tyrosinase by tyrosinase-related proteins 1 and 2 in vitro.
The albino (tyrosinase, Tyrc), brown (tyrosinase-related protein 1, Tyrp1b) and slaty (tyrosinase-related protein 2, tyrp2slt) loci are all involved in the regulation of melanogenesis. Phenotypes of inbred mice mutant at two or more of these loci are not always explicable by simple summation of the established or suspected catalytic functions of the gene products. These phenotypes suggest that relationships among the proteins extend beyond the obvious fact that they catalyze different steps in the same melanogenic pathway, and that they may also interact intimately in such a way that a mutation in one impacts the function of the other(s). Previous studies have attributed catalytic activities to each member of this trio; however, it has been difficult to study the proteins individually, either in vivo or in tissues or cells. Therefore, we undertook to transfect the genes, in revealing combinations, into COS-7 cells (which have no melanogenic apparatus of their own) to clarify the interacting functions of their encoded proteins. Specifically, we attempted to evaluate the effects of Tyrp1 and Tyrp2 proteins on tyrosinase protein. We report evidence that Tyrp1 stabilizes tyrosinase, confirming previous observations, and, in addition, demonstrate that Tyrp1 decreases tyrosinase activity. By contrast, Tyrp2 increases tyrosinase activity by stabilizing the protein. We conclude that both Tyrp1 and Tyrp2, in addition to other catalytic functions they may possess, act together to modulate tyrosinase activity.


Variant origin of the superior thyroid artery in a Kenyan population.
Variant anatomy of the superior thyroid artery is important during surgical procedures, interpretation of angiograms, and interventional radiography in the neck. Pattern of the variations shows population differences but there is no data from the Kenyan population. This study therefore investigated the variations in origin of the superior thyroid artery in a Kenyan population. Forty six necks (36 males and 10 females) from 46 cadavers of black Kenyans in Department of Human Anatomy University of Nairobi, Kenya were bilaterally dissected to expose the origin of the superior thyroid artery. Pattern of origin of the vessel was determined on both sides in males and females. It originated from the external carotid artery common carotid artery and linguo-facial trunk in 80%, 13%, and 6.5% of the cadavers respectively on the right side. All but one of the superior thyroid arteries were ventral branches. There was asymmetric origin in 6.5% of cases. Origin from the common carotid artery was associated with high carotid bifurcation. Nearly 20% of superior thyroid arteries showed variant origin. Of these, 6.5% arose from the linguo-facial trunk, much higher than in the Caucasian and Oriental populations. Origin from common carotid artery is substantially lower than prevailing figures from other populations. These findings support ethnic variations. Preoperative angiographic evaluation is recommended.


Pharmacokinetics of morphine infusion in premature neonates.
Morphine pharmacokinetics were studied in 17 premature neonates (26-34 weeks' gestation) after intravenous infusion during the first 24 hours of life. Infants received either standard dose morphine that comprised of a 100 micrograms/kg/hour loading infusion for 2 hours followed by a maintenance infusion of 12.5 micrograms/kg/hour, or a high dose of 200 micrograms/kg/hour for 2 hours followed by 50 micrograms/kg/hour. Mean plasma concentrations of morphine (SD) after 2 and 24 hours were 99 (12.9) and 96.4 (3.2) ng/ml, and 184.2 (37.7) and 319 (71.2) ng/ml for the standard and high dose regimens, respectively. Morphine-3-glucuronide plasma concentrations achieved about 20% and 80% of morphine values at 2 and 24 hours respectively. Morphine-6-glucuronide could not be detected at 2 hours, but attained 20-25% of morphine plasma concentrations by 24 hours. The population mean morphine clearance was 2.4 ml/min/kg, the elimination half life was 8.75 hours and the volume of distribution was 1.82 1/kg. High plasma concentrations of morphine appeared to be well tolerated. Although mean arterial blood pressure decreased during the first six hours of treatment, this was not statistically significant; two infants experienced transient muscle rigidity, but no evidence of seizures was noted. There appears to be no clinical advantage in using the high dose regimen.


Cloning, characterization, and expression of Bartonella henselae p26.
In order to identify immunoreactive Bartonella henselae proteins, B. henselae antiserum from an experimentally infected cat was used to screen a B. henselae genomic DNA expression library. One immunoreactive phage clone contained a gene (p26) with significant nucleotide identity with orthologs in brucellae, bartonellae, and several plant-associated bacteria. p26 gene sequences from four B. henselae strains, one B. koehlerae strain, and one B. clarridgeiae strain were cloned. Comparative nucleotide sequence analysis showed that p26 is a potential marker for molecular diagnosis of infection, as well as for identification to species level and genotyping of Bartonella sp. isolates. Alignment of the predicted amino acid sequences illustrated conserved putative protein features including a hydrophobic transmembrane region, a peptide cleavage site, and four dominant antigenic sites. Expression of p26 in Escherichia coli produced two proteins (26 and 27.5 kDa), both of which were reactive with feline anti-B. henselae antisera. Furthermore, murine hyperimmune serum raised against either recombinant protein reacted with both proteins. No reactivity to either recombinant protein was detected in nonimmune serum, and reactivity persisted as long as 20 weeks for one cat. The p26 protein product is an immunodominant antigen that is expressed during infection in cats as a preprotein and is subsequently cleaved to form mature P26.


Anger inhibition, cardiovascular recovery, and vagal function: a model of the link between hostility and cardiovascular disease.
A model of the association between hostility and cardiovascular disease (CVD) is proposed based upon anger inhibition, slow cardiovascular recovery, and low parasympathetic activity (vagal tone). This model is opposed to the more conventional model that emphasizes anger expression, cardiovascular reactivity, and high sympathetic tone. We argue that in social reality, incidences of anger inhibition outnumber incidences of anger expression to a great extent, irrespective of preferred expression style. Moreover, slow cardiovascular recovery, rather than high reactivity, may be the mechanism underlying the CVD risk associated with anger inhibition. Both anger inhibition and slow cardiovascular recovery are associated with a persistently low vagal tone. Thus, the anger inhibition/vagal inhibition model seems more consistent with the actual nature of anger in daily life and with the known cardiovascular control mechanisms. The model may better account for the chronic pathophysiological state that is believed to lead to CVD. Importantly, an experimental inhibition/recovery paradigm might also allow to test potential behavioral and cognitive accelerators of cardiovascular recovery. As an example of an important socially-mediated health risk that may be elucidated using the anger inhibition/vagal inhibition model, we discuss Black-White differences that have been found in CVD.


Artificial neural network and tissue genotyping of hepatocellular carcinoma in liver-transplant recipients: prediction of recurrence.
Liver transplantation (LT) is the treatment of choice for early stage hepatocellular carcinoma (HCC) with excellent 5-year survival, with a recurrence rate after LT of 3.4%. An artificial neural network (ANN), combined with genotyping for microsatellite mutations/deletions (TM-GTP), was designed at the University of Pittsburgh to predict tumor recurrence with a discriminatory power of 85%. This study aims to validate the ANN/TM-GTP model on patients receiving transplants in a single center. Nineteen patients with HCC underwent LT at our center between 1999 and 2002 (mean follow-up of 49.3 months). The ANN/TM-GTP analysis was performed blindly to prognosticate the risk of HCC recurrence, which was then validated against the actual clinical outcomes. Nineteen patients received transplants. The primary diagnosis was hepatitis C (n=16), cryptogenic cirrhosis (n=2), and autoimmune hepatitis (n=1). ANN/TM-GTP was applied to all patients. The combination of ANN/TM-GTP predicted three patients to suffer recurrence of HCC. All three had HCC recurrence within 39 months (11, 23, and 39 months) postLT and died. Fourteen patients were predicted not to have HCC recurrence, and none did. Two patients could not be classified and were termed indeterminate for recurrence. ANN/TM-GTP had a high discriminatory power (17/19, 89.5%) in our cohort, accurately predicting HCC recurrence.


A study of complement functions in a family with hereditary angioneurotic edema.
A study of some complement functions was performed in two patients affected with hereditary angioneurotic edema (HAE) - mother and daughter - from a Southern Italy family (Apulia) and in three of their relatives. A decreased level of the C1 esterase plasma inhibitor was found in both the patients, who were treated with tranexamic acid with a slight, but definite improvement. However, the disease could not be traced beyond two generations in the pedigree and a couple of ascendants was found who were free from HAE both from the clinical standpoint and from that of the laboratory evaluation of complement functions. The possibility that HAE arose in the family through a mutational event is discussed.


Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn's disease and regulate Th1/Th17 cell responses.
Increased T helper (Th)1/Th17 immune responses are a hallmark of Crohn's disease (CD) immunopathogenesis. CD90+ (myo-)fibroblasts (MFs) are abundant cells in the normal (N) intestinal mucosa contributing to mucosal tolerance via suppression of Th1 cell activity through cell surface membrane-bound PD-L1 (mPD-L1). CD-MFs have a decreased level of mPD-L1. Consequently, mPD-L1-mediated suppression of Th1 cells by CD-MFs is decreased, yet the mechanism responsible for the reduction in mPDL-1 is unknown. Increased expression of matrix metalloproteinases (MMPs) has been reported in CD. Herein we observed that when compared to N- and ulcerative colitis (UC)-MFs, CD-MFs increase in LPS-inducible levels of MMP-7 and -9 with a significant increase in both basal and inducible MMP-10. A similar pattern of MMP expression was observed in the CD-inflamed mucosa. Treatment of N-MFs with a combination of recombinant human MMP-7, -9 and -10 significantly decreased mPD-L1. In contrast, inhibition of MMP activity with MMP inhibitors or anti-MMP-10 neutralizing antibodies restores mPD-L1 on CD-MFs. CD-MFs demonstrated reduced capacity to suppress Th1 and Th17 responses from activated CD4+ T cells. By contrast, supplementation of the CD-MF:T-cell co-cultures with MMP inhibitors or anti-MMP neutralizing antibodies restored the CD-MF-mediated suppression. Our data suggest that (i) increased MMP-10 expression by CD-MFs and concomitant cleavage of PD-L1 from the surface of CD-MFs are likely to be one of the factors contributing to the decrease of mPD-L1-mediated suppression of Th1/Th17 cells in CD; and (ii) MMPs are likely to have a significant role in the intestinal mucosal immune responses.


Phase-object detection by use of double-exposure fringe-modulated speckle patterns.
We study the properties of a double-exposure image specklegram of a diffuse object obtained by use of a double-aperture pupil. A phase object is placed in front of one aperture during the first or the second exposure. Also, it is assumed that a uniform displacement of the diffuser between exposures is produced. The recorded specklegram is coherently illuminated and analyzed by Fourier transform operations. The average intensity distribution and the interference fringe visibility in the Fourier plane are investigated. On this basis, an alternative interference technique to detect phase objects is proposed.


The secretion of acute phase proteins and inflammatory cytokines during Trypanosoma congolense infection is not affected by the absence of the TNF-alpha gene.
Tumor necrosis factor-alpha (TNF-alpha) plays a role in the host's defence against infections with African trypanosomes. It helps to control the blood stream form of the parasite and in Trypanosoma congolense infections, it also prolongs survival. The mechanisms by which this cytokine can influence parasitemia and survival are unknown. Therefore, the levels of acute phase proteins and other inflammatory cytokines were monitored in trypano-tolerant wild-type and TNF-alpha-deficient mice during a T. congolense infection. The titres of ceruloplasmin (CP), alpha1-acid glycoprotein (AGP) and serum amyloid P (SAP) increased and reached their peaks at 11 days post-infection, when the first peak of parasitemia was observed. No significant differences were observed in the acute phase protein profiles between the two mouse strains. Also the profiles of serum titres of IFN-gamma, IL-1alpha, IL-6 and IL-10 were not significantly different. Our present results indicate that acute phase protein and cytokine responses can be induced in the absence of TNF-alpha during a T. congolense infection in mice, and that the susceptibility of the TNF-alpha-deficient mice is not due to modulation of expression of these molecules.


Cardiovascular diseases and the work environment. A critical review of the epidemiologic literature on chemical factors.
This is the second of two articles reviewing the epidemiologic research on cardiovascular diseases (CVD) and the work environment. It deals with chemical factors, i.e., lead, cadmium, cobalt, arsenic, carbon monoxide, passive smoking, organic solvents, carbon disulfide, nitroglycerin, nitroglycol, and others. The epidemiologic literature relating to each is assessed on the basis of a number of methodological criteria, and the need for future research, the methodology of literature reviews, and preventive implications and perspectives are discussed. It is concluded that the causal relationship between two of the chemicals, carbon disulfide and nitroglycerin/nitroglycol, and CVD is very well documented. For lead and passive smoking a causal relation to CVD is likely. More research is needed concerning cobalt, arsenic, antimony, and other chemical compounds. Exposure to carbon monoxide increases the acute risk of CVD but has probably no lasting atherosclerotic effect. Cadmium and organic solvents are probably not causally related to CVD.


FRET studies of various conformational states adopted by transthyretin.
Transthyretin (TTR) is an extracellular protein able to deposit into well-defined protein aggregates called amyloid, in pathological conditions known as senile systemic amyloidosis, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and leptomeningeal amyloidosis. At least three distinct partially folded states have been described for TTR, including the widely studied amyloidogenic state at mildly acidic pH. Here, we have used fluorescence resonance energy transfer (FRET) experiments in a monomeric variant of TTR (M-TTR) and in its W41F and W79F mutants, taking advantage of the presence of a unique, solvent-exposed, cysteine residue at position 10, that we have labelled with a coumarin derivative (DACM, acceptor), and of the two natural tryptophan residues at positions 41 and 79 (donors). Trp41 is located in an ideal position as it is one of the residues of β-strand C, whose degree of unfolding is debated. We found that the amyloidogenic state at low pH has the same FRET efficiency as the folded state at neutral pH in both M-TTR and W79F-M-TTR, indicating an unmodified Cys10-Trp41 distance. The partially folded state populated at low denaturant concentrations also has a similar FRET efficiency, but other spectroscopic probes indicate that it is distinct from the amyloidogenic state at acidic pH. By contrast, the off-pathway state accumulating transiently during refolding has a higher FRET efficiency, indicating non-native interactions that reduce the Cys10-Trp41 spatial distance, revealing a third distinct conformational state. Overall, our results clarify a negligible degree of unfolding of β-strand C in the formation of the amyloidogenic state and establish the concept that TTR is a highly plastic protein able to populate at least three distinct conformational states.


Monitoring the Opening and Recovery of the Blood-Brain Barrier with Noninvasive Molecular Imaging by Biodegradable Ultrasmall Cu2- xSe Nanoparticles.
The reversible and controllable opening and recovery of the blood-brain barrier (BBB) is crucial for the treatment of brain diseases, and it is a big challenge to noninvasively monitor these processes. In this article, dual-modal photoacoustic imaging and single-photon-emission computed tomography imaging based on ultrasmall Cu2- xSe nanoparticles (3.0 nm) were used to noninvasively monitor the opening and recovery of the BBB induced by focused ultrasound in living mice. The ultrasmall Cu2- xSe nanoparticles were modified with poly(ethylene glycol) to exhibit a long blood circulation time. Both small size and long blood circulation time enable them to efficiently penetrate into the brain with the assistance of ultrasound, which resulted in a strong signal at the sonicated site and allowed for photoacoustic and single-photon emission computed tomography imaging monitoring the recovery of the opened BBB. The results of biodistribution, blood routine examination, and histological staining indicate that the accumulated Cu2- xSe nanoparticles could be excreted from the brain and other major organs after 15 days without causing side effects. By the combination of the advantages of noninvasive molecular imaging and focused ultrasound, the ultrasmall biocompatible Cu2- xSe nanoparticles holds great potential for the diagnosis and therapeutic treatment of brain diseases.


Human hypervirulent Clostridium difficile strains exhibit increased sporulation as well as robust toxin production.
Toxigenic Clostridium difficile strains produce two toxins (TcdA and TcdB) during the stationary phase of growth and are the leading cause of antibiotic-associated diarrhea. C. difficile isolates of the molecular type NAP1/027/BI have been associated with severe disease and hospital outbreaks worldwide. It has been suggested that these "hypervirulent" strains produce larger amounts of toxin and that a mutation in a putative negative regulator (TcdC) allows toxin production at all growth phases. To rigorously explore this possibility, we conducted a quantitative examination of the toxin production of multiple hypervirulent and nonhypervirulent C. difficile strains. Toxin gene (tcdA and tcdB) and toxin gene regulator (tcdR and tcdC) expression was also monitored. To obtain additional correlates for the hypervirulence phenotype, sporulation kinetics and efficiency were measured. In the exponential phase, low basal levels of tcdA, tcdB, and tcdR expression were evident in both hypervirulent and nonhypervirulent strains, but contrary to previous assumptions, toxin levels were below the detectable thresholds. While hypervirulent strains displayed robust toxin production during the stationary phase of growth, the amounts were not significantly different from those of the nonhypervirulent strains tested; further, total toxin amounts were directly proportional to tcdA, tcdB, and tcdR gene expression. Interestingly, tcdC expression did not diminish in stationary phase, suggesting that TcdC may have a modulatory rather than a strictly repressive role. Comparative genomic analyses of the closely related nonhypervirulent strains VPI 10463 (the highest toxin producer) and 630 (the lowest toxin producer) revealed polymorphisms in the tcdR ribosome binding site and the tcdR-tcdB intergenic region, suggesting that a mechanistic basis for increased toxin production in VPI 10463 could be increased TcdR translation and read-through transcription of the tcdA and tcdB genes. Hypervirulent isolates produced significantly more spores, and did so earlier, than all other isolates. Increased sporulation, potentially in synergy with robust toxin production, may therefore contribute to the widespread disease now associated with hypervirulent C. difficile strains.


Progressively restricted expression of a new homeobox-containing gene during Xenopus laevis embryogenesis.
We have isolated cDNAs encoding a novel Xenopus homeodomain-containing protein homologous to the mouse Hox-7.1 and the Drosophila muscle segment homebox (msh). Northern blot and RNAase protection experiments established that transcripts of the frog gene, termed Xhox-7.1, first appear at about the beginning of gastrulation. After a rapid increase, mRNA levels plateau between the neurula and middle-tailbud stages, and decrease steadily thereafter. In situ hybridization localized the Xhox-7.1 message to the dorsal mesodermal mantle of gastrula stage embryos. Comparison of the hybridization patterns of progressively more anterior cross-section of tailbud stage embryos localized the signal to the dorsal neural tube and neural crest, to specific regions of the lateral plate mesoderm, and to the cardiogenic region. By the tadpole stage, the Xhox-7.1 message appears only at specific sites in the central nervous system, such as in the dorsal hindbrain. Thus, during embryonic development levels of Xhox-7.1 expression decrease as the transcript becomes more progressively localized. Finally, evidence is presented of a distinct msh-like transcript (provisionally termed Xhox-7.1') which begins to accumulate at early-gastrula stage, as well.


Mutations in transhydrogenase change the fluorescence emission state of TRP72 from 1La to 1Lb.
The dI component of Rhodospirillum rubrum transhydrogenase has a single Trp residue (Trp(72)), which has distinctive optical properties, including short-wavelength fluorescence emission with clear vibrational fine structure, and long-lived, well-resolved phosphorescence emission. We have made a set of mutant dI proteins in which residues contacting Trp(72) are conservatively substituted. The room-temperature fluorescence-emission spectra of our three Met(97) mutants are blue shifted by approximately 4 nm, giving them a shorter-wavelength emission than any other protein described in the literature, including azurin from Pseudomonas aeruginosa. Fluorescence spectra in low-temperature glasses show equivalent well-resolved vibrational bands in wild-type and the mutant dI proteins, and in azurin. Substitution of Met(97) in dI changes the relative intensities of some of these vibrational bands. The analysis supports the view that fluorescence from the Met(97) mutants arises predominantly from the (1)L(b) excited singlet state of Trp(72), whereas (1)L(a) is the predominant emitting state in wild-type dI. It is suggested that the sulfur atom of Met(97) promotes greater stabilization of (1)L(a) than either (1)L(b) or the ground state. The phosphorescence spectra of Met(97) mutants are also blue-shifted, indicating that the sulfur atom decreases the transition energy between the (3)L(a) state of the Trp and the ground state.


Drug design and identification of potent leads against mycobacterium tuberculosis thymidine monophosphate kinase.
Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases impeding DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), which is essential to DNA replication, was selected as a promising target for the design of new inhibitors. This review describes stepwise modifications of the TMPKmt substrate, guided by the feedback of enzyme assays and crystallographic analysis to afford potent enzyme inhibitors some of which also exhibited antitubercular activity. More importantly, several of the reported thymidine analogues provided a deeper understanding of the structure and catalytic mechanism of this intriguing enzyme.


Mobile phones and head tumours. The discrepancies in cause-effect relationships in the epidemiological studies - how do they arise?
Whether or not there is a relationship between use of mobile phones (analogue and digital cellulars, and cordless) and head tumour risk (brain tumours, acoustic neuromas, and salivary gland tumours) is still a matter of debate; progress requires a critical analysis of the methodological elements necessary for an impartial evaluation of contradictory studies. A close examination of the protocols and results from all case-control and cohort studies, pooled- and meta-analyses on head tumour risk for mobile phone users was carried out, and for each study the elements necessary for evaluating its reliability were identified. In addition, new meta-analyses of the literature data were undertaken. These were limited to subjects with mobile phone latency time compatible with the progression of the examined tumours, and with analysis of the laterality of head tumour localisation corresponding to the habitual laterality of mobile phone use. Blind protocols, free from errors, bias, and financial conditioning factors, give positive results that reveal a cause-effect relationship between long-term mobile phone use or latency and statistically significant increase of ipsilateral head tumour risk, with biological plausibility. Non-blind protocols, which instead are affected by errors, bias, and financial conditioning factors, give negative results with systematic underestimate of such risk. However, also in these studies a statistically significant increase in risk of ipsilateral head tumours is quite common after more than 10 years of mobile phone use or latency. The meta-analyses, our included, examining only data on ipsilateral tumours in subjects using mobile phones since or for at least 10 years, show large and statistically significant increases in risk of ipsilateral brain gliomas and acoustic neuromas. Our analysis of the literature studies and of the results from meta-analyses of the significant data alone shows an almost doubling of the risk of head tumours induced by long-term mobile phone use or latency.


White matter lesion progression, brain atrophy, and cognitive decline: the Austrian stroke prevention study.
White matter lesions progress over time, but the clinical consequences are widely unknown. Three-hundred twenty-nine elderly community-dwelling volunteers underwent serial magnetic resonance imaging scanning and cognitive testing at baseline and at 3- and 6-year follow-up. We measured the changes in white matter lesion and brain parenchymal volumes. After 6 years, the median increase in white matter lesion load was 0.2 cm3 (interquartile range [IQR], 0.0-0.80 cm3) with a maximum of 31.4 cm3. The median loss of brain volume was 2.3% (IQR, 1.13-3.58%). Increasing white matter lesion volume was correlated with loss of brain volume (p < 0.0001) and performance decline in tests of memory (p = 0.022), conceptualization (p = 0.046), and visuopractical skills (p = 0.005). Associations between changes in white matter lesion load and cognitive functioning were no longer significant when adding change in brain volume to the models, suggesting that cognitive decline related directly to loss of brain substance with progression of lesion burden.


Mutants of pertussis toxin suitable for vaccine development.
Immunization with chemically detoxified pertussis toxin can prevent severe whooping cough with an efficacy similar to that of the cellular pertussis vaccine, which normally gives unwanted side effects. To avoid the reversion to toxicity and the loss of immunogenicity that may follow chemical treatment of pertussis toxin, inactive toxins were constructed by genetic manipulation. A number of genetically engineered alleles of the pertussis toxin genes, constructed by replacing either one or two key amino acids within the enzymatically active S1 subunit, were introduced into the chromosome of strains of Bordetella pertussis, B. parapertussis, and B. bronchiseptica. These strains produce mutant pertussis toxin molecules that are nontoxic and immunogenic and that protect mice from the intracerebral challenge with virulent Bordetella pertussis. Such molecules are ideal for the development of new and safer vaccines against whooping cough.


Space Radiation Alters Genotype-Phenotype Correlations in Fear Learning and Memory Tests.
Behavioral and cognitive traits have a genetic component even though contributions from individual genes and genomic loci are in many cases modest. Changes in the environment can alter genotype-phenotype relationships. Space travel, which includes exposure to ionizing radiation, constitutes environmental challenges and is expected to induce not only dramatic behavioral and cognitive changes but also has the potential to induce physical DNA damage. In this study, we utilized a genetically heterogeneous mouse model, dense genotype data, and shifting environmental challenges, including ionizing radiation exposure, to explore and quantify the size and stability of the genetic component of fear learning and memory-related measures. Exposure to ionizing radiation and other external stressors altered the genotype-phenotype correlations, although different behavioral and cognitive measures were affected to different extents. Utilizing an integrative genomic approach, we identified pathways and functional ontology categories associated with these behavioral and cognitive measures.


Analysis of gene expression data from non-small cell lung carcinoma cell lines reveals distinct sub-classes from those identified at the phenotype level.
Microarray data from cell lines of Non-Small Cell Lung Carcinoma (NSCLC) can be used to look for differences in gene expression between the cell lines derived from different tumour samples, and to investigate if these differences can be used to cluster the cell lines into distinct groups. Dividing the cell lines into classes can help to improve diagnosis and the development of screens for new drug candidates. The micro-array data is first subjected to quality control analysis and then subsequently normalised using three alternate methods to reduce the chances of differences being artefacts resulting from the normalisation process. The final clustering into sub-classes was carried out in a conservative manner such that sub-classes were consistent across all three normalisation methods. If there is structure in the cell line population it was expected that this would agree with histological classifications, but this was not found to be the case. To check the biological consistency of the sub-classes the set of most strongly differentially expressed genes was be identified for each pair of clusters to check if the genes that most strongly define sub-classes have biological functions consistent with NSCLC.


Oral alterations in Steinert's myotonic dystrophy: a presentation of two cases.
Two patients with Steinert's myotonic dystrophy are presented. The disease was suspected because of alterations in orofacial musculature clinically manifest as difficulties in swallowing, mastication, and speech, and as occlusal anomalies and maxillary bone deformities. The presumed diagnosis was reached as a result of the presence of percussion myotonia of the tongue; confirmation was based on family antecedents, electromyographic alterations, and muscle histopathologic findings.


Accounting for misalignments and thermal fluctuations in fluorescence correlation spectroscopy experiments on membranes.
Several authors have exploited the ability of the fluorescence correlation spectroscopy to probe motion at the molecular level. In a couple of decades, all their efforts have allowed the application of this technique even to the diffusion measurement of cellular components. Nowadays, the fluorescence correlation spectroscopy is considered a standard tool to measure diffusion in cells both in vivo and in vitro. Unfortunately, while the interpretation and the set-up have been consolidated for 3D diffusion measurements (i.e. diffusion in an aqueous solution), the experiments carried out on flat elements, such as membranes, show unusually high relative errors. Furthermore, long tail correlations are generally detected and ascribed to diffusion anomalies. The 2D fluorescence correlation measurements have been interpreted under certain hypotheses, whereby the membrane is assumed to be perfectly flat, motionless and aligned with the optical axes. Here, we investigated the robustness of these hypotheses, trying to understand, in an elementary but not trivial way, how misalignments and thermal fluctuations affect the temporal correlation of the intensity fluctuation collected during measurements on membranes.


Remarkable enhancement of charge carrier mobility of conjugated polymer field-effect transistors upon incorporating an ionic additive.
Organic semiconductors with high charge carrier mobilities are crucial for flexible electronic applications. Apart from designing new conjugated frameworks, different strategies have been explored to increase charge carrier mobilities. We report a new and simple approach to enhancing the charge carrier mobility of DPP-thieno[3,2-b]thiophene-conjugated polymer by incorporating an ionic additive, tetramethylammonium iodide, without extra treatments into the polymer. The resulting thin films exhibit a very high hole mobility, which is higher by a factor of 24 than that of thin films without the ionic additive under the same conditions. On the basis of spectroscopic grazing incidence wide-angle x-ray scattering and atomic force microscopy studies as well as theoretical calculations, the remarkable enhancement of charge mobility upon addition of tetramethylammonium iodide is attributed primarily to an inhibition of the torsion of the alkyl side chains by the presence of the ionic species, facilitating a more ordered lamellar packing of the alkyl side chains and interchain π-π interactions.


Membrane filter technique for enumeration of enterococci in marine waters.
A membrane filter procedure is described for the enumeration of enterococci in marine waters. The procedure utilizes a highly selective and somewhat differential primary isolation medium followed by an in situ substrate test for identifying colonies of those organisms capable of hydrolyzing esculin. The procedure (mE) was evaluated with known streptococci strains and field samples with regard to its accuracy, sensitivity, selectivity, precision, and comparability to existing methods. Essentially quantitative recovery was obtained with seawater-stressed cells of Streptococcus faecalis and S. faecium. Neither S. bovis, S. equinus, S. mitis, nor S. salivarius grew on the medium. The selectivity of the medium was such that a 10,000-fold reduction in background organisms was obtained relative to a medium which contained no inhibitors and was incubated at 35 C. About 90% of those typical colonies designated as enterococci confirmed as such and about 12% of the colonies not so designated were, in fact, identified as enterococci. Plate to plate variability across samples approximated that expected by chance alone. Verified recoveries of enterococci from natural samples by the mE procedure, on the average, exceeded those by the KF method by one order of magnitude.


Genetic diversity of the fish pathogen Aeromonas salmonicida demonstrated by random amplified polymorphic DNA and pulsed-field gel electrophoresis analyses.
The current taxonomy of Aeromonas salmonicida includes 4 subspecies. A. salmonicida subsp. salmonicida is associated with salmonid furunculosis, and A. salmonicida subsp. achromogenes, A. salmonicida subsp. masoucida, and A. salmonicida subsp. smithia are strains that show variation in some biochemical properties. This classification does not readily encompass isolates from a wide range of fish hosts currently described as atypical A. salmonicida. This study examined 17 typical strains, 39 atypical strains and 3 type A. salmonicida subspecies strains for genetic similarity using the random amplified polymophic DNA (RAPD) and pulsed-field gel electrophoresis (PFGE) techniques. On the basis of RAPD- and PFGE-derived profiles, similarity matrices and dendrograms were constructed. The results showed that species A. salmonicida constituted a genetically heterogeneous group of strains, encompassing within an homogeneous or clonal lineage comprised solely of typical strains and the A. salmonicida subsp. salmonicida type strain.


Epidemiological features of Guillain-Barré syndrome in Sweden, 1978-93.
To describe the incidence of Guillain-Barré syndrome in Sweden during the period 1978-93 and its temporal and geographical variations. Stratified and Poisson regression analyses and tests for detection of small epidemics were applied to population based hospital discharge data from 2257 incident cases of Guillain-Barré syndrome in Sweden during the study period. The incidence of Guillain-Barré syndrome was (1) 1.77 per 100000 person-years when age adjusted to the European population; (2) higher in males; and (3) stable across time, although occasional increases of annual incidence rates were found-namely, in 1978 (relative risk (RR) 1.30 (95% CI 1.10-1.54)), and in 1983 (RR 1.24 (95% CI 1.06-1.40)). The incidence increased with age and was bimodal, with peaks at 20-24 and 70-74 years. There was a moderate but significant seasonality with a peak in August, particularly among the young age groups. The age adjusted incidence by county varied from 1.11 to 2.57 per 100000 person-years. Neither temporal nor spatial clustering was significant, except during the period July-September in 1983 at ages below 40 years. The incidence of Guillain-Barré syndrome in Sweden during the period 1978-93 had a magnitude similar to those described in other surveys, a bimodal distribution by age, and modest geographical and temporal variations with significantly high rates in 1978 and 1983 and in autumn. Minor outbreaks might have passed unnoticed up to the present. Whereas reported drug induced cases of Guillain-Barré syndrome may in part explain the high incidence in 1983, the cause of the aberrant incidence in 1978 remains unknown. Epidemiological surveillance of Guillain-Barré syndrome in Sweden might have been useful.


Does Psychosocial Stress Impact Cognitive Reappraisal? Behavioral and Neural Evidence.
Cognitive reappraisal (CR) is regarded as an effective emotion regulation strategy. Acute stress, however, is believed to impair the functioning of prefrontal-based neural systems, which could result in lessened effectiveness of CR under stress. This study tested the behavioral and neurobiological impact of acute stress on CR. While undergoing fMRI, adult participants ( n = 54) passively viewed or used CR to regulate their response to negative and neutral pictures and provided ratings of their negative affect in response to each picture. Half of the participants experienced an fMRI-adapted acute psychosocial stress manipulation similar to the Trier Social Stress Test, and a control group received parallel manipulations without the stressful components. Relative to the control group, the stress group exhibited heightened stress as indexed by self-report, heart rate, and salivary cortisol throughout the scan. Contrary to our hypothesis, we found that reappraisal success was equivalent in the control and stress groups, as was electrodermal response to the pictures. Heart rate deceleration, a physiological response typically evoked by aversive pictures, was blunted in response to negative pictures and heightened in response to neutral pictures in the stress group. In the brain, we found weak evidence of stress-induced increases of reappraisal-related activity in parts of the PFC and left amygdala, but these relationships were statistically fragile. Together, these findings suggest that both the self-reported and neural effects of CR may be robust to at least moderate levels of stress, informing theoretical models of stress effects on cognition and emotion.


The basic reproduction number as a predictor for epidemic outbreaks in temporal networks.
The basic reproduction number R0--the number of individuals directly infected by an infectious person in an otherwise susceptible population--is arguably the most widely used estimator of how severe an epidemic outbreak can be. This severity can be more directly measured as the fraction of people infected once the outbreak is over, Ω. In traditional mathematical epidemiology and common formulations of static network epidemiology, there is a deterministic relationship between R0 and Ω. However, if one considers disease spreading on a temporal contact network--where one knows when contacts happen, not only between whom--then larger R0 does not necessarily imply larger Ω. In this paper, we numerically investigate the relationship between R0 and Ω for a set of empirical temporal networks of human contacts. Among 31 explanatory descriptors of temporal network structure, we identify those that make R0 an imperfect predictor of Ω. We find that descriptors related to both temporal and topological aspects affect the relationship between R0 and Ω, but in different ways.


Longterm effects of endothelin receptor antagonism on microvascular damage evaluated by nailfold capillaroscopic analysis in systemic sclerosis.
Systemic sclerosis (SSc) is characterized by microvascular injury, fibrosis, and hypoxia of involved tissues. The vasoactive peptide endothelin-1 (ET-1) seems to be implicated in these events. Using nailfold videocapillaroscopy (NVC), we evaluated longterm effects of ET-1 antagonist treatment on nailfold microvascular damage in patients with SSc, over a 3-year followup period. Thirty patients with SSc (mean age 64 ± 5 yrs, mean disease duration 8 ± 1 yrs) were recruited during their programmed standard treatment protocols. At baseline (T0), 15 patients with SSc (mean age 63 ± 15 yrs, mean disease duration 7 ± 3 yrs), already receiving cyclic intravenous infusion of iloprost (5 continuous days, average 80 μg/day, every 3 mo), continued the treatment for a further 3 years (ILO group). The remaining 15 patients with SSc (mean age 68 ± 13 yrs, mean disease duration 8 ± 4 yrs), although they continued the same cyclic intravenous iloprost treatment as the previous group, also received bosentan 125 mg twice a day for 3 years (ILO+BOS group). Qualitative analysis (scleroderma patterns) and semiquantitative scoring of the microvascular damage were performed by validated routine NVC methods. During followup, a statistically significant increase of capillary number was observed in the ILO+BOS group (p < 0.02), with a significant and progressive increase of angiogenesis (p < 0.01). In contrast, the ILO group showed a statistically significant decrease of capillary number (p < 0.05). After 3 years the number of capillaries was significantly higher in the ILO+BOS group than in the ILO group (p < 0.05). The score for giant capillaries decreased significantly in both groups of patients with SSc (p < 0.05). In this open study, longterm treatment with ET-1 receptor antagonist in combination with iloprost was found to interfere with progression of nailfold microvascular damage in patients with SSc, as assessed by NVC over a 3-year followup period.


Improved Survival of Patients with ST-Segment Elevation Myocardial Infarction 3-6 Hours After Symptom Onset Is Associated with Inter-Hospital Transfer for Primary Percutaneous Coronary Intervention (PCI) at a Large Regional ST-Segment Elevation Myocardial Infarction (STEMI) Program vs. In-Hospital Thrombolysis in a Community Hospital.
BACKGROUND This study sought to compare the 30-day and 1-year survival of patients diagnosed with ST-segment elevation myocardial infarction (STEMI), whose symptom onset to in-hospital first medical contact (IHFMC) was 3-6 h, who received either in-hospital thrombolysis (IHT) in the nearest county hospital or direct transfer to a larger hospital in Henan province, China for primary percutaneous coronary intervention (PPCI). MATERIAL AND METHODS Patients were allocated into 2 groups: one group received IHT in the local county hospital, whereas the other group were transferred to the PCI centers to receive PPCI. Patient demographic data, baseline characteristics, and time between different stages of patient contact to the initiation of treatment for IHT or PPCI were recorded for analysis. RESULTS No significant difference was identified between the 2 groups with the baseline characteristics and demographic data. The all-cause mortality was not significantly different between the IHT and PPCI group at 30 days (13.0% vs. 9.9%, p=0.386). However, a significant difference in mortality between the IHT and PPCI group was observed at 1 year (23.4% vs. 14.1%, p=0.035). Inter-hospital transfer time for PPCI tended to be the independent predictor for survival (OR: 4.4 CI 95%: 1.9-14.5, p 0.001). Overall, the patients undergoing PPCI in inter-hospital transfer had a higher survival rates for 1 year compared with patients receiving IHT. CONCLUSIONS Despite the delay associated with inter-hospital transfer for PPCI, patients with STEMI 3-6 h after symptom onset have improved survival with PPCI over patients treated locally with IHT.


Factors associated with successful discontinuation of certolizumab pegol in early rheumatoid arthritis.
The Certolizumab-Optimal Prevention of joint damage for Early Rheumatoid Arthritis (C-OPERA) study demonstrated that in methotrexate (MTX)-naïve early RA patients with poor prognostic factors, 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year optimized MTX therapy brings radiographic and clinical benefits through 2 years even after stopping CZP. This exploratory analysis aimed to identify factors at baseline and at CZP discontinuation associated with successful CZP discontinuation. MTX-naïve early RA patients with poor prognostic factors entered C-OPERA (NCT01451203), a multicenter, randomized controlled trial. Patients were randomized to CZP + MTX (n = 159) or PBO + MTX (n = 157); those who completed the 1-year, double-blind period received MTX alone in Year 2 (CZP + MTX→MTX, n = 108; PBO + MTX→MTX, n = 71). Association between factors at baseline or at discontinuation of CZP and clinical/radiographic outcomes were evaluated by multiple logistic regression analysis. Predictive value cut-offs were calculated using receiver operating characteristic analysis. Sex (male) and low baseline Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR) were associated with simple disease activity index (SDAI) remission (≤3.3), whereas high baseline DAS28-ESR and modified total Sharp score (mTSS) were associated with clinically relevant radiographic progression (yearly progression mTSS > 3) at Week 104 (across both treatment arms). Low DAS28-ESR (<2.1) and rheumatoid factor (RF; <74 IU/mL) at discontinuation of CZP were associated with SDAI remission at Week 104. At Week 104, SDAI remission was achieved by 75.0% (42/56) of patients with low DAS28-ESR and RF at discontinuation, compared to 15.4% (2/13) of patients with high DAS28-ESR and RF. Patients with low RF and low disease activity after treatment with CZP + MTX may be able to discontinue CZP without risk of loss of response.


Incidence of acquired thrombotic thrombocytopenic purpura in Germany: a hospital level study.
Acquired thrombotic thrombocytopenic Purpura (aTTP) is a life-threatening ultra-orphan disease with a reported annual incidence between 1.5 and 6.0 cases per million in Europe and mainly affecting otherwise young and healthy adults aged 40 years on average. The goal of this study was to assess the incidence of aTTP in Germany. A systematic review was performed to determine the published evidence on the aTTP epidemiology in Germany. To obtain additional evidence on the proportion of aTTP cases within the national Thrombotic Microangiopathy (TMA) population a hospital-level study was performed, using a retrospective data collection approach. Diagnosis of aTTP was confirmed if ADAMTS13 level were < 10% and/or the medical records explicitly mentioned aTTP diagnosis. The aggregated hospital data were then projected to the national level using logistic regression techniques. The systematic literature search did not provide incidence estimates of aTTP in Germany. Eight centers (≈27% of the top 30 TMA hospitals) delivered data according to a predefined data collection form. On average (year 2014-2016) a total number of 172 aTTP episodes per year was projected (95% confidence interval [95%CI]: 132-212). The majority were newly diagnosed aTTP cases (n = 121; 95%CI: 105-129), and 51 were recurrent aTTP cases (95%CI: 27-84). The average annual projected incidence (year 2014-2016) of aTTP episodes was 2.10 per million inhabitants in Germany (95%CI: 1.60-2.58). The determined annual incidence of newly diagnosed aTTP cases and the overall annual incidence of aTTP episodes in Germany confirm the ultra-orphan character of aTTP. An external validation against international registries (France, UK and USA) shows that our findings are quite comparable with those international incidence rates.


Intestinal cell cycle regulations. Interactions of cyclin D1, Cdk4, and p21Cip1.
The p21Cip1 protein is a potent stoichiometric inhibitor of cyclin-dependent kinase activity, and p21Cip1 mRNA expression is localized to the nonproliferative compartment of the intestinal villus, suggesting an in vivo growth-inhibitory role in the gut. The authors determined whether nontransformed rat intestinal epithelial cells (IECs) underwent reversible cell cycle arrest by contact inhibition, and determined whether increases in the relative amount of p21 associated with cyclin D/Cdk4 protein complexes were associated with cell growth arrest. Density arrest was achieved by prolonged culture IEC-6 in confluent conditions (5 or more days). Release from density arrest was achieved by detaching the cells from the culture plate and reseeding them at a 1:4 ratio. The DNA synthesis was estimated by [3H]-thymidine incorporation and expressed as mean plus or minus standard error of the mean (n = 4). Cyclin D1, Cdk4, and p21 mRNA and protein levels were determined by standard Northern and Western blot analyses, respectively. Cyclin D1, Cdk4, and p21 protein complex formation was analyzed by immunoprecipitating the complexes from cell lysates with an antibody to one of the constituents, followed by SDS polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis of the precipitated complexes using antibodies to the other proteins. The kinase activity of the immunoprecipitated Cdk4 was determined using recombinant Rb as substrate. The IEC-6[3H]-thymidine incorporation was decreased 7.5-fold from day 1 confluence to day 7 of confluence. Twenty-four hours after release from density arrest, there was a 43-fold increase in [3H]-thymidine incorporation. Cyclin D1 and Cdk4 mRNA levels remained relatively constant during contact inhibition, whereas immunoblotting showed that the levels of cyclin D1 and Cdk4 proteins decreased by 70.9% and 68.7%, respectively, comparing day 3 with day 9 during density arrest. The levels of cyclin D1 increased 5.8-fold and Cdk4 increased by 4.4-fold by 24 hours after reseeding the day 9 density-arrested cultures, coincident with the increase in DNA synthesis. The amount of p21 associated with the cyclin D1 and Cdk4 complex in the density-arrested cells was 170% of that observed in the reseeded, proliferating cells. More important, the p21::Cdk4 ratio was 6.4-fold higher in the density-arrested (quiescent) cells as compared with rapidly proliferating cells by 24 hours after release from growth arrest. Recovery of Cdk4-dependent kinase activity occurred by 4 hours after release from growth arrest, coincident with decreased binding of p21 to the complex. Intestinal epithelial cells in culture can undergo density-dependent growth arrest. This process involves downregulation of cyclin D1 and Cdk4 at the level of protein expression, whereas the mRNA levels remain relatively unchanged. Further, during contact inhibition, there is more p21 associated with cyclin D1/Cdk4, which further contributes to the inhibition of the kinase complex. The authors also have shown that the process of contact inhibition is reversible, which may explain partly the ability of the intestinal epithelium to increase proliferative activity in response to injury.


Rifampicin-resistant initiation of DNA synthesis on the isolated strands of ColE plasmid DNA.
The opposite strands of the ColE1 and ColE3 plasmids were isolated as circular single-stranded DNA molecules. These molecules were compared with M13 and phi X174 viral DNA with respect to their capacity to function as templates for in vitro DNA synthesis by a replication enzyme fraction from Escherichia coli. It was found for both ColE plasmids that the conversion of H as well as L strands to duplex DNA molecules closely resembles phi X174 complementary strand synthesis and occurs by a rifampicin-resistant priming mechanism involving the dnaB, dnaC, and dnaG gene products. Restriction analysis of partially double-stranded intermediates indicates that preferred start sites for DNA synthesis are present on both strands of the ColE1 HaeII-C fragment. Inspection of the nucleotide sequence of this region reveals structural similarities with the origin of phi X174 complementary strand synthesis. We propose that the rifampicin-resistant initiation site (rri) in the ColE1 L strand is required for the priming of discontinuous lagging strand synthesis during vegetative replication and that the rri site in the H strand is involved in the initiation of L strand synthesis during conjugative transfer.


Uptake and outcomes of intensity-modulated radiation therapy for uterine cancer.
While intensity-modulated radiation therapy (IMRT) allows more precise radiation planning, the technology is substantially more costly than conformal radiation and, to date, the benefits of IMRT for uterine cancer are not well defined. We examined the use of IMRT and its effect on late toxicity for uterine cancer. Women with uterine cancer treated from 2001 to 2007 and registered in the SEER-Medicare database were examined. We investigated the extent and predictors of IMRT administration. The incidence of acute and late-radiation toxicities was compared for IMRT and conformal radiation. We identified a total of 3555 patients including 328 (9.2%) who received IMRT. Use of IMRT increased rapidly and reached 23.2% by 2007. In a multivariable model, residence in the western U.S. and receipt of chemotherapy were associated with receipt of IMRT. Women who received IMRT had a higher rate of bowel obstruction (rate ratio=1.41; 95% CI, 1.03-1.93), but other late gastrointestinal and genitourinary toxicities as well as hip fracture rates were similar between the cohorts. After accounting for other characteristics, the cost of IMRT was $14,706 (95% CI, $12,073 to $17,339) greater than conformal radiation. The use of IMRT for uterine cancer is increasing rapidly. IMRT was not associated with a reduction in radiation toxicity, but was more costly.


Hip fracture in women without osteoporosis.
The proportion of fractures that occur in women without osteoporosis has not been fully described, and the characteristics of nonosteoporotic women who fracture are not well understood. We measured total hip bone mineral density (BMD) and baseline characteristics including physical activity, falls, and strength for 8065 women aged 65 yr or older participating in the Study of Osteoporotic Fractures and then followed these women for hip fracture for up to 5 yr after BMD measurement. Among all participants, 17% had osteoporosis (total hip BMD T-score < or = -2.5). Of the 243 women with incident hip fracture, 54% were not osteoporotic at start of follow-up. Nonosteoporotic women who fractured were less likely than osteoporotic women with fracture to have baseline characteristics associated with frailty. Nevertheless, among nonosteoporotic participants, several characteristics increased fracture risk, including advancing age, lack of exercise in the last year, reduced visual contrast sensitivity, falls in the last year, prevalent vertebral fracture, and lower total hip BMD. These findings call attention to the many older women who suffer hip fracture but do not have particularly low antecedent BMD measures and help begin to identify risk factors associated with higher bone density levels.


Fibrochondrogenesis in two embryonic stem cell lines: effects of differentiation timelines.
Human embryonic stem cells (hESCs) are an exciting cell source for fibrocartilage engineering. In this study, the effects of differentiation time and cell line, H9 versus BG01V, were examined. Embryoid bodies (EBs) were fibrochondrogenically differentiated for 1, 3, or 6 weeks and then used to engineer tissue constructs that were grown for an additional 4 weeks. Construct matrix was fibrocartilaginous, containing glycosaminoglycans (GAGs) and collagens I, II, and VI. A differentiation time of 3 or 6 weeks produced homogeneous constructs, with matrix composition varying greatly with cell line and differentiation time: from 2.6 to 17.4 microg of GAG per 10(6) cells and from 22.3 to 238.4 microg of collagen per 10(6) cells. Differentiation for 1 week resulted in small constructs with poor structural integrity that could not be mechanically tested. The compressive stiffness of the constructs obtained from EBs differentiated for 3 or 6 weeks did not vary significantly as a function of either differentiation time or cell line. In contrast, the tensile properties were markedly greater with the H9 cell line, 1,562-1,940 versus 32-80 kPa in the BG01V constructs. These results demonstrate the dramatic effects of hESC line and differentiation time on the biochemical and functional properties of tissue-engineered constructs and show progress in fibrocartilage tissue engineering with an exciting new cell source.


Revision of the aseptic and septic total ankle replacement.
Total ankle replacement has become a popular treatment of symptomatic end-stage ankle osteoarthritis. Contemporary total ankle replacement systems provide more anatomic and biomechanically sound function. However, longevity is still limited and long-term results of modern total ankle replacement designs are not available. In the case of failure, conversion into arthrodesis has remained the treatment of choice but at the cost of hindfoot function and potential degeneration of the adjacent joints. Thus, revision total ankle replacement by exchange of the prosthetic components represents an attractive solution. This article focuses on revision total ankle replacement and conversion to ankle arthrodesis.


Association between perfluoroalkyl substance exposure and asthma and allergic disease in children as modified by MMR vaccination.
Perfluoroalkyl substances (PFASs) are highly persistent chemicals that might be associated with asthma and allergy, but the associations remain unclear. Therefore, this study examined whether pre- and postnatal PFAS exposure was associated with childhood asthma and allergy. Measles, mumps, and rubella (MMR) vaccination in early life may have a protective effect against asthma and allergy, and MMR vaccination is therefore taken into account when evaluating these associations. In a cohort of Faroese children whose mothers were recruited during pregnancy, serum concentrations of five PFASs - Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) - were measured at three timepoints (maternal serum in pregnancy week 34-36 and child serum at ages 5 and 13 years) and their association with immunoglobulin E (IgE) (cord blood and at age 7 years) and asthma/allergic diseases (questionnaires at ages 5 and 13 years and skin prick test at age 13 years) was determined. A total of 559 children were included in the analyses. Interactions with MMR vaccination were evaluated. Among 22 MMR-unvaccinated children, higher levels of the five PFASs at age 5 years were associated with increased odds of asthma at ages 5 and 13. The associations were reversed among MMR-vaccinated children. Prenatal PFAS exposure was not associated with childhood asthma or allergic diseases regardless of MMR vaccination status. In conclusion, PFAS exposure at age 5 was associated with increased risk of asthma among a small subgroup of MMR-unvaccinated children but not among MMR-vaccinated children. While PFAS exposure may impact immune system functions, this study suggests that MMR vaccination might be a potential effect-modifier.


Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.


Variation and Temporal Trends in Delivery Room Management of Moderate and Late Preterm Infants.
Although delivery room (DR) intervention decreases with increasing gestational age (GA), little is known about DR management of moderate and late preterm (MLP) infants. Using the Vermont Oxford Network database of all NICU admissions, we examined the receipt of DR interventions including supplemental oxygen, positive pressure ventilation, continuous positive airway pressure, endotracheal tube ventilation, chest compressions, epinephrine, and surfactant among MLP infants (30 to 36 weeks') without congenital anomalies born from 2011 to 2020. Pneumothorax was examined as a potential resuscitation-associated complication. Intervention frequency was assessed at the infant- and hospital-level, stratified by GA and over time. Overall, 55.3% of 616 110 infants (median GA: 34 weeks) from 483 Vermont Oxford Network centers received any DR intervention. Any DR intervention frequency decreased from 89.7% at 30 weeks to 44.2% at 36 weeks. From 2011 to 2020, there was an increase in the provision of continuous positive airway pressure (17.9% to 47.8%, P ≤.001) and positive pressure ventilation (22.9% to 24.9%, P ≤.001) and a decrease in endotracheal tube ventilation (6.9% to 4.0% P ≤.001), surfactant administration (3.5% to 1.3%, P ≤.001), and pneumothorax (1.9% to 1.6%, P ≤.001). Hospital rates of any DR intervention varied (median 54%, interquartile range 47% to 62%), though the frequency was similar across hospitals with different NICU capabilities after adjustment. The DR management of MLP infants varies at the individual- and hospital-level and is changing over time. These findings illustrate the differing interpretation of resuscitation guidelines and emphasize the need to study MLP infants to improve evidence-based DR care.


DHA-paclitaxel (Taxoprexin) as first-line treatment in patients with stage IIIB or IV non-small cell lung cancer: report of a phase II open-label multicenter trial.
This prospective, open-label, non-randomized, multi-institutional phase II study was undertaken to assess the antitumor activity and safety of docosahexaenoic acid-paclitaxel (Taxoprexin) as first-line treatment of patients with advanced non-small cell lung cancer. Chemotherapy-naive patients were eligible if they had measurable stage IIIB or IV non-small cell lung cancer. Forty-four patients received docosahexaenoic acid-paclitaxel by intravenous infusion every 21 days. Two doses were evaluated: 1100 mg/m and 900 mg/m. Patients were monitored for toxicity and tumor response. Patients received between one and seven (median, two) cycles of treatment. Twenty-eight courses were administered in the cohort starting at 1100 mg/m and 109 courses at 900 mg/m. The starting dose was reduced to 900 mg/m because of toxicity in the first 13 patients. Subsequently, the most severe toxicity was neutropenia (grade III/IV in 68% of patients treated with 900 mg/m). Forty patients were eligible for assessment of tumor response. Two partial responses (4.5%) were documented, and a further 16 patients (36.4%) had stable disease based on an intent-to-treat analysis. The median duration of survival for all patients was 243 days (range, 154-359) and the 1-year survival rate was 35%. As a single-agent, docosahexaenoic acid-paclitaxel has little activity in patients with advanced non-small cell lung cancer, with 18 patients (40.1%) achieving either stable disease or a partial response after treatment. Despite the low objective response rate, treatment was associated with survival comparable to that seen with standard platinum-based combination chemotherapy. The dose-limiting toxicity was myelosuppression.


Control of ammonia formation during Bacillus subtilis fermentation of legumes.
The control of ammonia formation during the Bacillus subtilis fermentation of autoclaved, roasted soybean cotyledons (Glycine max) and of autoclaved African locust bean cotyledons (Parkia spp.) was investigated. Addition of NaCl, 1.5 mol (kg wet cotyledons)-1, part way through the fermentation inhibited ammonia formation and softening of the cotyledons. Addition of glycerol, 1.7 mol (kg wet cotyledons)-1 part way through the fermentation inhibited alkalinisation and ammonia formation while allowing enzymic activity and softening of the cotyledons to continue. Restriction of the oxygen supply by incubating the cotyledons in a sealed container also prevented excessive ammonia production and increase in pH value. Fermentations conducted in sealed containers with an air to cotyledons ratio of approximately 130-175 ml air (g wet cotyledons)-1 supported good microbial growth and proteolysis without the formation of detectable ammonia aroma.


Cross-Domain Metric and Multiple Kernel Learning Based on Information Theory.
Learning an appropriate distance metric plays a substantial role in the success of many learning machines. Conventional metric learning algorithms have limited utility when the training and test samples are drawn from related but different domains (i.e., source domain and target domain). In this letter, we propose two novel metric learning algorithms for domain adaptation in an information-theoretic setting, allowing for discriminating power transfer and standard learning machine propagation across two domains. In the first one, a cross-domain Mahalanobis distance is learned by combining three goals: reducing the distribution difference between different domains, preserving the geometry of target domain data, and aligning the geometry of source domain data with label information. Furthermore, we devote our efforts to solving complex domain adaptation problems and go beyond linear cross-domain metric learning by extending the first method to a multiple kernel learning framework. A convex combination of multiple kernels and a linear transformation are adaptively learned in a single optimization, which greatly benefits the exploration of prior knowledge and the description of data characteristics. Comprehensive experiments in three real-world applications (face recognition, text classification, and object categorization) verify that the proposed methods outperform state-of-the-art metric learning and domain adaptation methods.


MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14 468 individuals worldwide.
Deep learning has emerged as a powerful approach to constructing imaging signatures of normal brain ageing as well as of various neuropathological processes associated with brain diseases. In particular, MRI-derived brain age has been used as a comprehensive biomarker of brain health that can identify both advanced and resilient ageing individuals via deviations from typical brain ageing. Imaging signatures of various brain diseases, including schizophrenia and Alzheimer's disease, have also been identified using machine learning. Prior efforts to derive these indices have been hampered by the need for sophisticated and not easily reproducible processing steps, by insufficiently powered or diversified samples from which typical brain ageing trajectories were derived, and by limited reproducibility across populations and MRI scanners. Herein, we develop and test a sophisticated deep brain network (DeepBrainNet) using a large (n = 11 729) set of MRI scans from a highly diversified cohort spanning different studies, scanners, ages and geographic locations around the world. Tests using both cross-validation and a separate replication cohort of 2739 individuals indicate that DeepBrainNet obtains robust brain-age estimates from these diverse datasets without the need for specialized image data preparation and processing. Furthermore, we show evidence that moderately fit brain ageing models may provide brain age estimates that are most discriminant of individuals with pathologies. This is not unexpected as tightly-fitting brain age models naturally produce brain-age estimates that offer little information beyond age, and loosely fitting models may contain a lot of noise. Our results offer some experimental evidence against commonly pursued tightly-fitting models. We show that the moderately fitting brain age models obtain significantly higher differentiation compared to tightly-fitting models in two of the four disease groups tested. Critically, we demonstrate that leveraging DeepBrainNet, along with transfer learning, allows us to construct more accurate classifiers of several brain diseases, compared to directly training classifiers on patient versus healthy control datasets or using common imaging databases such as ImageNet. We, therefore, derive a domain-specific deep network likely to reduce the need for application-specific adaptation and tuning of generic deep learning networks. We made the DeepBrainNet model freely available to the community for MRI-based evaluation of brain health in the general population and over the lifespan.


Information content of visual scenes influences systematic search of desert ants.
Many animals - including insects - navigate visually through their environment. Solitary foraging desert ants are known to acquire visual information from the surrounding panorama and use it to navigate along habitual routes or to pinpoint a goal such as the nest. Returning foragers that fail to find the nest entrance engage in searching behaviour, during which they continue to use vision. The characteristics of searching behaviour have typically been investigated in unfamiliar environments. Here we investigated in detail the nest-searching behaviour of Melophorus bagoti foragers within the familiar visual environment of their nest. First, by relating search behaviour to the information content of panoramic (360 deg) images, we found that searches were more accurate in visually cluttered environments. Second, as observed in unfamiliar visual surrounds, searches were dynamic and gradually expanded with time, showing that nest pinpointing is not rigidly controlled by vision. Third, contrary to searches displayed in unfamiliar environments, searches observed here could be modelled as a single exponential search strategy, which is similar to a Brownian walk, and there was no evidence of a Lévy walk. Overall, our results revealed that searching behaviour is remarkably flexible and varies according to the relevance of information provided by the surrounding visual scenery.


Genetic diversity and population parameters of sea otters, Enhydra lutris, before fur trade extirpation from 1741-1911.
All existing sea otter, Enhydra lutris, populations have suffered at least one historic population bottleneck stemming from the fur trade extirpations of the eighteenth and nineteenth centuries. We examined genetic variation, gene flow, and population structure at five microsatellite loci in samples from five pre-fur trade populations throughout the sea otter's historical range: California, Oregon, Washington, Alaska, and Russia. We then compared those values to genetic diversity and population structure found within five modern sea otter populations throughout their current range: California, Prince William Sound, Amchitka Island, Southeast Alaska and Washington. We found twice the genetic diversity in the pre-fur trade populations when compared to modern sea otters, a level of diversity that was similar to levels that are found in other mammal populations that have not experienced population bottlenecks. Even with the significant loss in genetic diversity modern sea otters have retained historical structure. There was greater gene flow before extirpation than that found among modern sea otter populations but the difference was not statistically significant. The most dramatic effect of pre fur trade population extirpation was the loss of genetic diversity. For long term conservation of these populations increasing gene flow and the maintenance of remnant genetic diversity should be encouraged.


Retroposition of the AFC family of SINEs (short interspersed repetitive elements) before and during the adaptive radiation of cichlid fishes in Lake Malawi and related inferences about phylogeny.
Lake Malawi is home to more than 450 species of endemic cichlids, which provide a spectacular example of adaptive radiation. To clarify the phylogenetic relationships among these fish, we examined the presence and absence of SINEs (short interspersed repetitive elements) at orthologous loci. We identified six loci at which a SINE sequence had apparently been specifically inserted by retroposition in the common ancestor of all the investigated species of endemic cichlids in Lake Malawi. At another locus, unique sharing of a SINE sequence was evident among all the investigated species of endemic non-Mbuna cichlids with the exception of Rhamphochromis sp. The relationships were in good agreement with those deduced in previous studies with various different markers, demonstrating that the SINE method is useful for the elucidation of phylogenetic relationships among cichlids in Lake Malawi. We also characterized a locus that exhibited transspecies polymorphism with respect to the presence or absence of the SINE sequence among non-Mbuna species. This result suggests that incomplete lineage sorting and/or interspecific hybridization might have occurred or be occurring among the species in this group, which might potentially cause misinterpretation of phylogenetic data, in particular when a single-locus marker, such as a sequence in the mitochondrial DNA, is used for analysis.


Political ideology and vaccination willingness: implications for policy design.
The COVID-19 pandemic has forced governments to impose major restrictions on individual freedom in order to stop the spread of the virus. With the successful development of a vaccine, these restrictions are likely to become obsolete-on the condition that people get vaccinated. However, parts of the population have reservations against vaccination. While this is not a recent phenomenon, it might prove a critical one in the context of current attempts to manage the COVID-19 pandemic. Consequently, the task of designing policies suitable for attaining high levels of vaccination deserves enhanced attention. In this study, we use data from the Eurobarometer survey fielded in March 2019. They show that 39% of Europeans consider vaccines to cause the diseases which they should protect against, that 50% believe vaccines have serious side effects, that 32% think that vaccines weaken the immune system, and that 10% do not believe vaccines are tested rigorously before authorization. We find that-even when controlling for important individual-level factors-ideological extremism on both ends of the spectrum explains skepticism of vaccination. We conclude that policymakers must either politicize the issue or form broad alliances among parties and societal groups in order to increase trust in and public support for the vaccines in general and for vaccines against COVID-19 in particular, since the latter were developed in a very short time period and resulted-in particular in case of the AstraZeneca vaccine-in reservations because of the effectiveness and side effects of the new vaccines. The online version contains supplementary material available at 10.1007/s11077-021-09428-0.