Theoretical Insights into Heterogeneous (Photo)electrochemical CO2 Reduction.
Electrochemical and photoelectrochemical CO2 reduction technologies offer the promise of zero-carbon-emission renewable fuels needed for heavy-duty transportation. However, the inert nature of the CO2 molecule poses a fundamental challenge that must be overcome before efficient (photo)electrochemical CO2 reduction at scale will be achieved. Optimal catalysts exhibit enduring stability, fast kinetics, high selectivity, and low manufacturing cost. Identifying catalytic mechanisms of CO2 reduction in (photo)electrochemical systems could accelerate design of efficient catalysts. In recent decades, numerous theoretical studies have contributed to our understanding of CO2 reduction pathways and identifying rate-limiting steps. Although a significant body of work exists regarding homogeneous electrocatalysis for CO2 reduction, this review focuses specifically on the theory of heterogeneous (photo)electrochemical reduction. We first give an overview of the relevant thermodynamics and semiconductor physics. We then introduce important, widely used theoretical techniques and modeling approaches to catalysis. Recent progress in elucidating mechanisms of heterogeneous (photo)electrochemical CO2 reduction is discussed through the lens of two experimental systems: pyridine (Py)-catalyzed CO2 (photo)electrochemical reduction at p-GaP photoelectrodes and electrochemical CO2 reduction at Cu electrodes. We close by proposing strategies and principles for the future design of (photo)electrochemical catalysts to improve the selectivity and reaction kinetics of CO2 reduction.


Increased corticosterone in peripubertal rats leads to long-lasting alterations in social exploration and aggression.
Stress during childhood and adolescence enhances the risk of psychopathology later in life. We have previously shown that subjecting male rats to stress during the peripubertal period induces long-lasting effects on emotion and social behaviors. As corticosterone is increased by stress and known to exert important programming effects, we reasoned that increasing corticosterone might mimic the effects of peripubertal stress. To this end, we injected corticosterone (5 mg/kg) on 7 scattered days during the peripuberty period (P28-P30, P34, P36, P40, and P42), following the same experimental schedule as for stress administration in our peripubertal paradigm. We measured play behavior in the homecage and, at adulthood, the corticosterone response to novelty and behavioral responses in tests for anxiety- and depression-like behaviors, aggression, and social exploration. As compared to vehicle, corticosterone-treated animals exhibit more aggressive play behavior during adolescence, increased aggressive behavior in a resident-intruder (RI) test while reduced juvenile exploration and corticosterone reactivity at adulthood. Whereas the corticosterone treatment mimicked alterations induced by the peripuberty stress protocol in the social domain, it did not reproduce previously observed effects of peripuberty stress on increasing anxiety-like and depression-like behaviors, respectively evaluated in the elevated plus maze (EPM) and the forced swim tests. Our findings indicate that increasing corticosterone levels during peripuberty might be instrumental to program alterations in the social domain observed following stress, whereas other factors might need to be recruited for the programming of long-term changes in emotionality. Our study opens the possibility that individual differences on the degree of glucocorticoid activation during peripuberty might be central to defining differences in vulnerability to develop psychopathological disorders coursing with alterations in the social realm.


Differential impairment of triazolam and zolpidem clearance by ritonavir.
The viral protease inhibitor ritonavir has the capacity to inhibit and induce the activity of cytochrome P450-3A (CYP3A) isoforms, leading to drug interactions that may influence the efficacy and toxicity of other antiretroviral therapies, as well as pharmacologic treatments of coincident or complicating diseases. The inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam and zolpidem was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg zolpidem concurrent with low-dose ritonavir (four doses of 200 mg), or with placebo. Ritonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to < 4% of control values (p < .005), prolonged elimination half-life (41 versus 3 hours; p < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. In contrast, ritonavir reduced zolpidem clearance to 78% of control values (p < .08), and slightly prolonged elimination half-life (2.4 versus 2.0 hours; NS). Benzodiazepine agonist effects of zolpidem were not altered by ritonavir. Short-term low-dose administration of ritonavir produces a large and significant impairment of triazolam clearance and enhancement of clinical effects. In contrast, ritonavir produced small and clinically unimportant reductions in zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of zolpidem clearance on CYP3A.


A reservoir of time constants for memory traces in cortical neurons.
According to reinforcement learning theory of decision making, reward expectation is computed by integrating past rewards with a fixed timescale. In contrast, we found that a wide range of time constants is available across cortical neurons recorded from monkeys performing a competitive game task. By recognizing that reward modulates neural activity multiplicatively, we found that one or two time constants of reward memory can be extracted for each neuron in prefrontal, cingulate and parietal cortex. These timescales ranged from hundreds of milliseconds to tens of seconds, according to a power law distribution, which is consistent across areas and reproduced by a 'reservoir' neural network model. These neuronal memory timescales were weakly, but significantly, correlated with those of monkey's decisions. Our findings suggest a flexible memory system in which neural subpopulations with distinct sets of long or short memory timescales may be selectively deployed according to the task demands.


Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients.
Although various studies reported that pulse pressure, an indirect index of arterial stiffening, was an independent risk factor for mortality, a direct relationship between arterial stiffness and all-cause and cardiovascular mortality remained to be established in patients with essential hypertension. A cohort of 1980 essential hypertensive patients who attended the outpatient hypertension clinic of Broussais Hospital between 1980 and 1996 and who had a measurement of arterial stiffness was studied. At entry, aortic stiffness was assessed from the measurement of carotid-femoral pulse-wave velocity (PWV). A logistic regression model was used to estimate the relative risk of all-cause and cardiovascular deaths. Selection of classic risk factors for adjustment of PWV was based on their influence on mortality in this cohort in univariate analysis. Mean age at entry was 50+/-13 years (mean+/-SD). During an average follow-up of 112+/-53 months, 107 fatal events occurred. Among them, 46 were of cardiovascular origin. PWV was significantly associated with all-cause and cardiovascular mortality in a univariate model of logistic regression analysis (odds ratio for 5 m/s PWV was 2.14 [95% confidence interval, 1.71 to 2.67, P<0.0001] and 2.35 [95% confidence interval, 1.76 to 3.14, P<0.0001], respectively). In multivariate models of logistic regression analysis, PWV was significantly associated with all-cause and cardiovascular mortality, independent of previous cardiovascular diseases, age, and diabetes. By contrast, pulse pressure was not significantly and independently associated to mortality. This study provides the first direct evidence that aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with essential hypertension.


In vitro cytogenetic assessment of trichloroacetic acid in human peripheral blood lymphocytes.
Trichloroacetic acid (TCA), a common water disinfection byproduct and a persistent metabolite of trichloroethylene (TCE), has been examined for its genotoxic potential in human lymphocytes. Chromosomal aberration (CA) and cytokinesis-block micronucleus (CBMN) assay were employed to assess the toxicity of TCA. Lymphocytes obtained from three healthy donors were exposed to 25, 50, and 100 μg/ml concentration of TCA separately. TCA exposure resulted in chromosomal anomalies and the formation of micronuclei in lymphocytes. Chromosome analysis revealed the dose-dependent and significant induction of CA. Chromatid break/chromosome break, fragments, and chromatid exchanges were commonly observed. Exposure of higher concentration (50 and 100 μg/ml) significantly inhibited mitotic index. Data obtained with CBMN assay indicated that the induction of micronucleus (MN) formation was greater than that of CA. At 25 μg/ml, TCA induced significant frequencies of MN as compared to control cells. Significant induction of MN at the lowest concentration indicates TCA may also interact with mitotic spindles. Lower percentage of CA and MN at 100 μg/ml as compared to 50 μg/ml indicates occurrence of severe cytotoxicity on exposure of 100 μg/ml TCA in lymphocytes. Collectively, results of both cytogenetic assays indicate that exposure of TCA can induce significant genotoxic and cytotoxic effects.


Euthanasia in the Netherlands: a claims data cross-sectional study of geographical variation.
The annual incidence of euthanasia in the Netherlands as a percentage of all deaths rose from 1.9% in 1990 to 4.4% in 2017. Scarce literature on regional patterns calls for more detailed insight into the geographical variation in euthanasia and its possible explanations. This paper (1) shows the geographical variation in the incidence of euthanasia over time (2013-2017); (2) identifies the associations with demographic, socioeconomic, preferential and health-related factors; and (3) shows the remaining variation after adjustment and discusses its meaning. This cross-sectional study used national claims data, covering all healthcare claims during 12 months preceding the death of Dutch insured inhabitants who died between 2013 and 2017. From these claims all euthanasia procedures by general practitioners were selected (85% of all euthanasia cases). Rates were calculated and compared at three levels: 90 regions, 388 municipalities and 196 districts in the three largest Dutch cities. Data on possibly associated variables were retrieved from national data sets. Negative binomial regression analysis was performed to identify factors associated with geographical variation in euthanasia. There is considerable variation in euthanasia ratio. Throughout the years (2013-2017) the ratio in the three municipalities with the highest incidence was 25 times higher than in the three municipalities with the lowest incidence. Associated factors are age, church attendance, political orientation, income, self-experienced health and availability of voluntary workers. After adjustment for these characteristics a considerable amount of geographical variation remains (factor score of 7), which calls for further exploration. The Netherlands, with 28 years of legal euthanasia, experiences large-scale unexplained geographical variation in the incidence of euthanasia. Other countries that have legalised physician-assisted dying or are in the process of doing so may encounter similar patterns. The unexplained part of the variation may include the possibility that part of the euthanasia practice may have to be understood in terms of underuse, overuse or misuse.


2,2'-Bipyrimidine as efficient sensitizer of the solid-state luminescence of lanthanide and uranyl ions from visible to near-infrared.
Treatment of Ln(NO(3))(3)nH(2)O with 1 or 2 equiv 2,2'-bipyrimidine (BPM) in dry THF readily afforded the monometallic complexes [Ln(NO(3))(3)(bpm)(2)] (Ln=Eu, Gd, Dy, Tm) or [Ln(NO(3))(3)(bpm)(2)]THF (Ln=Eu, Tb, Er, Yb) after recrystallization from MeOH or THF, respectively. Reactions with nitrate salts of the larger lanthanide ions (Ln=Ce, Nd, Sm) yielded one of two distinct monometallic complexes, depending on the recrystallization solvent: [Ln(NO(3))(3)(bpm)(2)]THF (Ln=Nd, Sm) from THF, or [Ln(NO(3))(3)(bpm)(MeOH)(2)]MeOH (Ln=Ce, Nd, Sm) from MeOH. Treatment of UO(2)(NO(3))(2)6H(2)O with 1 equiv BPM in THF afforded the monoadduct [UO(2)(NO(3))(2)(bpm)] after recrystallization from MeOH. The complexes were characterized by their crystal structure. Solid-state luminescence measurements on these monometallic complexes showed that BPM is an efficient sensitizer of the luminescence of both the lanthanide and the uranyl ions emitting visible light, as well as of the Yb(III) ion emitting in the near-IR. For Tb, Dy, Eu, and Yb complexes, energy transfer was quite efficient, resulting in quantum yields of 80.0, 5.1, 70.0, and 0.8 %, respectively. All these complexes in the solid state were stable in air.


Optimal surface segmentation using flow lines to quantify airway abnormalities in chronic obstructive pulmonary disease.
This paper introduces a graph construction method for multi-dimensional and multi-surface segmentation problems. Such problems can be solved by searching for the optimal separating surfaces given the space of graph columns defined by an initial coarse surface. Conventional straight graph columns are not well suited for surfaces with high curvature, we therefore propose to derive columns from properly generated, non-intersecting flow lines. This guarantees solutions that do not self-intersect. The method is applied to segment human airway walls in computed tomography images in three-dimensions. Phantom measurements show that the inner and outer radii are estimated with sub-voxel accuracy. Two-dimensional manually annotated cross-sectional images were used to compare the results with those of another recently published graph based method. The proposed approach had an average overlap of 89.3±5.8%, and was on average within 0.096±0.097mm of the manually annotated surfaces, which is significantly better than what the previously published approach achieved. A medical expert visually evaluated 499 randomly extracted cross-sectional images from 499 scans and preferred the proposed approach in 68.5%, the alternative approach in 11.2%, and in 20.3% no method was favoured. Airway abnormality measurements obtained with the method on 490 scan pairs from a lung cancer screening trial correlate significantly with lung function and are reproducible; repeat scan R(2) of measures of the airway lumen diameter and wall area percentage in the airways from generation 0 (trachea) to 5 range from 0.96 to 0.73.


Global gene expression differences associated with changes in glycolytic flux and growth rate in Escherichia coli during the fermentation of glucose and xylose.
The simplicity of the fermentation process (anaerobic with pH, temperature, and agitation control) in ethanologenic Escherichia coli KO11 and LY01 makes this an attractive system to investigate the utility of gene arrays for biotechnology applications. By using this system, gene expression, glycolytic flux, and growth rate have been compared in glucose-grown and xylose-grown cells. Although the initial metabolic steps differ, ethanol yields from both sugars were essentially identical on a weight basis, and little carbon was diverted to biosynthesis. Expression of only 27 genes changed by more than 2-fold in both strains. These included induction of xylose-specific operons (xylE, xylFGHR, and xylAB) regulated by XylR and the cyclic AMP-CRP system and repression of Mlc-regulated genes encoding glucose uptake (ptsHIcrr, ptsG) and mannose uptake (manXYZ) during growth on xylose. However, expression of genes encoding central carbon metabolism and biosynthesis differed by less than 2-fold. Simple statistical methods were used to investigate these more subtle changes. The reproducibility (coefficient of variation of 12%) of expression measurements (mRNA as cDNA) was found to be similar to that typically observed for in vitro measurements of enzyme activities. Using Student's t test, many smaller but significant sugar-dependent changes were identified (p < 0.05 in both strains). A total of 276 genes were more highly expressed during growth on xylose; 307 genes were more highly expressed with glucose. Slower growth (lower ATP yield) on xylose was accompanied by decreased expression of 62 genes concerned with the biosynthesis of small molecules (amino acids, nucleotides, cofactors, and lipids), transcription, and translation; 5 such genes were expressed at a higher level. In xylose-grown cells, 90 genes associated with the transport, catabolism, and regulation of pathways for alternative carbon sources were expressed at higher levels than in glucose-grown cells, consistent with a relaxation of control by the cyclic AMP-CRP regulatory system. Changes in expression of genes encoding the Embden-Meyerhof-Parnas (EMP) pathway were in excellent agreement with calculated changes in flux for individual metabolites. Flux through all but one step, pyruvate kinase, was predicted to be higher during glucose fermentation. Expression levels (glucose/xylose) were higher in glucose-grown cells for all EMP genes except the isoenzymes encoding pyruvate kinase (pykA and pykF). Expression of both isoenzymes was generally higher during xylose fermentation but statistically higher in both strains only for pykF encoding the isoenzyme activated by fructose-6-phosphate, a key metabolite connecting pentose metabolism to the EMP pathway. The coordinated changes in expression of genes encoding the EMP pathway suggest the presence of a common regulatory system and that flux control within the EMP pathway may be broadly distributed. In contrast, expression levels for genes encoding the Pentose-Phosphate pathway did not differ significantly between glucose-grown and xylose-grown cells.


Immunoglobulin heavy chain and binding protein complexes are dissociated in vivo by light chain addition.
Immunoglobulin heavy chain binding protein (BiP, GRP78) associates stably with the free, nonsecreted Ig heavy chains synthesized by Abelson virus transformed pre-B cell lines. In cells synthesizing both Ig heavy and light chains, the Ig subunits assemble rapidly and are secreted. Only incompletely assembled Ig molecules can be found bound to BiP in these cells. In addition to Ig heavy chains, a number of mutant and incompletely glycosylated transport-defective proteins are stably complexed with BiP. When normal proteins are examined for combination with BiP, only a small fraction of the intracellular pool of nascent, unfolded, or unassembled proteins can be found associated. It has been difficult to determine whether these BiP-associated molecules represent assembly intermediates which will be displaced from BiP and transported from the cell, or whether these are aberrant proteins that are ultimately degraded. In order for BiP to monitor and aid in normal protein transport, its association with these proteins must be reversible and the released proteins should be transport competent. In the studies described here, transient heterokaryons were formed between a myeloma line producing BiP-associated heavy chains and a myeloma line synthesizing the complementary light chain. Introduction of light chain synthesis resulted in assembly of prelabeled heavy chains with light chains, displacement of BiP from heavy chains, and secretion of Ig into the culture supernatant. These data demonstrate that BiP association can be reversible, with concordant release of transportable proteins. Thus, BiP can be considered a component of the exocytic secretory pathway, regulating the transport of both normal and abnormal proteins.


Scaffold-mediated delivery for non-viral mRNA vaccines.
mRNA is increasingly being recognized as a promising alternative to pDNA in gene vaccinations. Only recently, owing to the needs of cancer immunotherapies, has the biomaterials/gene delivery community begun to develop new biomaterial strategies for immunomodulation. Here, we report a novel way to use implantable porous scaffolds as a local gene delivery depot to enhance mRNA vaccine immunization in vitro, and in vivo when compared with conventional bolus injections. We first evaluated transfection efficiencies of single-stranded mRNA condensed and charge neutralized with two lipids (Lipofectamine Messenger MAXTM LM-MM and StemfectTM SF) and two cationic polymers (in vivo-jetPEI™, Poly (β-amino ester)) as gene carriers. As SF demonstrated highest in vitro transfection and cell viability, it was selected for subsequent porous polymer scaffold-loading trials. Enhanced in vitro transfection of SF:mRNA nanoparticle-loaded poly (2-hydroxyethyl methacrylate) (pHEMA) scaffolds was also observed with a DC2.4 cell line. Improved sustained local release and local transgene expression were also demonstrated with SF:mRNA nanoparticle-loaded pHEMA scaffolds in vivo compared with bolus injections. Our results suggest that mRNA polyplex-loaded scaffolds may be a superior alternative to either repeated bolus immunizations or ex vivo transfection cell immunotherapies.


Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link.
Papulopustular rosacea (PPR) is a common facial skin disease, characterized by erythema, telangiectasia, papules and pustules. Its physiopathology is still being discussed, but recently several molecular features of its inflammatory process have been identified: an overproduction of Toll-Like receptors 2, of a serine protease, and of abnormal forms of cathelicidin. The two factors which stimulate the Toll-like receptors to induce cathelicidin expression are skin infection and cutaneous barrier disruption: these two conditions are, at least theoretically, fulfilled by Demodex, which is present in high density in PPR and creates epithelial breaches by eating cells. So, the major pathogenic mechanisms of Demodex and its role in PPR are reviewed here in the context of these recent discoveries. In this review, the inflammatory process of PPR appears to be a consequence of the proliferation of Demodex, and strongly supports the hypothesis that: (1) in the first stage a specific (innate or acquired) immune defect against Demodex allows the proliferation of the mite; (2) in the second stage, probably when some mites penetrate into the dermis, the immune system is suddenly stimulated and gives rise to an exaggerated immune response against the Demodex, resulting in the papules and the pustules of the rosacea. In this context, it would be very interesting to study the immune molecular features of this first stage, named "pityriasis folliculorum", where the Demodex proliferate profusely with no, or a low immune reaction from the host: this entity appears to be a missing link in the understanding of rosacea.


Prognosis of myocardial infarctions involving more than 40% of the left ventricle after acute reperfusion therapy.
Prior studies based on autopsy data suggest that infarction of more than 40% of the left ventricle necessitates cardiogenic shock and death. Technetium-99m Sestamibi tomography was used prospectively to measure infarct size at discharge in 166 patients with acute myocardial infarction. Patients with previous myocardial infarction or revascularization were excluded from the trial. Sixteen patients were identified with final infarct sizes > 40% of the left ventricle despite acute reperfusion therapy. These 16 patients (13 men) had a mean age of 63 +/- 10 years; 44% had a previous history of angina. Ten patients had emergent coronary angioplasty only (mean time to percutaneous transluminal coronary angioplasty [PTCA], 6.0 +/- 3.0 hours); 6 had thrombolysis (mean time to tissue plasminogen activator, 4.0 +/- 1.5 hours), of which 2 had rescue PTCA (5 and 3 hours from onset of pain). Of 15 patients who had angiograms after therapy, 15 had open infarct-related arteries. The left anterior descending artery was the infarct-related artery in 14 (9 proximal and 5 distal lesions). Half the patients had only single-vessel disease. Infarct size measured 50 +/- 7% of the left ventricle (range, 42% to 68%). Ejection fraction by radionuclide angiogram was 0.33 +/- 0.09 and 0.38 +/- 0.07 at discharge and 6 weeks, respectively. Hospital complications included shock (1 patient), pulmonary edema (2), angina (3), symptomatic nonsustained ventricular tachycardia (1), transient complete heart block (2), and transient bifascicular block (1). At follow-up (13 +/- 9 months), the patient with shock had died, but the remaining 15 patients were asymptomatic (1 had late PTCA for angina). In the interventional and thrombolytic era, patients with large residual myocardial infarctions can survive without heart failure.


The synthesis of new weakly coordinating diborate anions: anion stability as a function of linker structure and steric bulk.
The successive addition of KCN and Ph3CCl to B(C6F4-C6F5-2)3 (PBB) affords triphenylmethyl salts of the [NC-PBB]- anion. By contrast, the analogous reaction with sodium dicyanamide followed by treatment with Ph(3)CCl leads to the zwitterionic aminoborane H2NB(C12F9)2C12F8, via nucleophilic attack on an o-F atom, together with CPh3[F-PBB]. Whereas treatment of [NC-PBB]- with either PBB or B(C6F5)3 fails to give isolable cyano-bridged diborates, the reaction of Me3SiNC-B(C6F5)3 with PBB in the presence of Ph3CCl affords [Ph3C][PBB-NC-B(C6F5)3]. Due to steric hindrance this anion is prone to borane dissociation. The longer linking group N(CN)2- gives the very voluminous anions [N[CNB(C6F5)3]2]- and [N(CN-PBB)2]-. A comparison of propylene polymerisations with rac-Me2Si(Ind)2ZrMe2 activated with the various boranes or trityl borates gives an anion-dependent activity sequence, in the order [NC-PBB]- < [MeB(C6F5)3]- < [MePBB]- approximately [PBB-NCB(C6F5)3]- approximately [N[CNB(C6F5)3]2]- < [F-PBB]-<< [B(C6F5)4]- < [N(CN-PBB)2]-. The anion [N(CN-PBB)2]- gives a catalyst productivity about 2500 times higher than that of [NC-PBB]- and exceeds that of [B(C6F5)4]- based catalysts. The van der Waals volumes and surface areas of the anions have been calculated and provide a rationale for the observed reactivity trends in polymerisation reactions.


Cloning and characterization of a novel apolipoprotein A-I binding protein, AI-BP, secreted by cells of the kidney proximal tubules in response to HDL or ApoA-I.
Apolipoprotein A-I (apoA-I) is the major apolipoprotein of high-density lipoproteins (HDL) and has an important role in the regulation of the stability, lipid transport, and metabolism of HDL particles. To identify novel proteins that are involved in HDL metabolism, we used mature apoA-I (amino acids 25-267) as a bait for the screening of a human liver two-hybrid cDNA library. Among the identified genes, several encoded known proteins, including serum amyloid A(2a) (SAA(2a)), apoC-I, and phosphodiesterase HCAM1 (PDE1A), found to interact with apoA-I. In addition, we have cloned a novel 29 kDa apoA-I interacting protein, which we named AI-BP (apoA-I binding protein). The AI-BP encoding gene, APOA1BP, which is located on chromosome 1q21, is composed of six exons and five introns and spans 2.5 kb. Northern blot analysis demonstrated ubiquitous expression of the APOA1BP mRNA with the highest expression in kidney, heart, liver, thyroid gland, adrenal gland, and testis. AI-BP protein is not detectable in serum of healthy probands, but serum samples of patients with septic syndromes may contain elevated levels of AI-BP. Significant amounts of AI-BP protein are found in cerebrospinal fluid and urine of healthy probands. The stimulation of cells derived from the kidney proximal tubules with apoA-I or HDL induces a concentration-dependent secretion of AI-BP indicating an important role for AI-BP, in the renal tubular degradation or resorption of apoA-I.


Age-related differences in the neural bases of phonological and semantic processes in the context of task-irrelevant information.
As we age we have increasing difficulty with phonological aspects of language production. Yet semantic processes are largely stable across the life span. This suggests a fundamental difference in the cognitive and potentially neural architecture supporting these systems. Moreover, language processes such as these interact with other cognitive processes that also show age-related decline, such as executive function and inhibition. The present study examined phonological and semantic processes in the presence of task-irrelevant information to examine the influence of such material on language production. Older and younger adults made phonological and semantic decisions about pictures in the presence of either phonologically or semantically related words, which were unrelated to the task. FMRI activation during the semantic condition showed that all adults engaged typical left-hemisphere language regions, and that this activation was positively correlated with efficiency across all adults. In contrast, the phonological condition elicited activation in bilateral precuneus and cingulate, with no clear brain-behavior relationship. Similarly, older adults exhibited greater activation than younger adults in several regions that were unrelated to behavioral performance. Our results suggest that as we age, brain-behavior relations decline, and there is an increased reliance on both language-specific and domain-general brain regions that are seen most prominently during phonological processing. In contrast, the core semantic system continues to be engaged throughout the life span, even in the presence of task-irrelevant information.


The effect of short-term calcium hydroxide treatment on dentin bond strengths to composite resin.
The purpose of this study was to evaluate the influence of calcium hydroxide (Ca(OH)2) treatment on the bond strengths to dentin of a resin-based composite material. Two distinct dental adhesives, Prime & Bond (P&B) NT and Single Bond (SB) were used. One hundred and twenty-seven bovine incisors were mounted in acrylic, ground flat to expose middle dentin, polished to 600-grit, and randomly assigned to 10 groups: (i) 0 days, no Ca(OH)2, P&B NT; (ii) 7 days, no Ca(OH)2, P&B NT; (iii) 7 days, Ca(OH)2, P&B NT; (iv) 30 days, no Ca(OH)2, P&B NT; (v) 30 days, Ca(OH)2, P&B NT; (vi) 0 days, no Ca(OH)2, SB; (vii) 7 days, no Ca(OH)2, SB; (viii) 7 days, Ca(OH)2, SB; (ix) 30 days, no Ca(OH)2, SB; (x) 30 days, Ca(OH)2, SB. All specimens were stored in an incubator at 37 degrees C. Specimens were then retrieved and the dentin surface was rinsed with air/water spray from a triple syringe. Dentin was etched with 37% phosphoric acid (PA) for 15 s, rinsed, blot dried, and coated with adhesive according to manufacturer's instructions. The adhesive was light cured for 10 s, and Filtek Z250 was applied to the surface with a #5 gelatin capsule and light cured for 160 s. Shear bond strengths were measured for each specimen in an Instron unit at a cross-head speed of 0.5 mm min(-1). The data were subjected to anova and Duncan post-hoc tests. Mean shear bond strengths for P&B NT ranged from 8.02 to 11.79 MPa. There was no significant difference between P&B NT groups treated with or without Ca(OH)2 at any time interval. Mean shear bond strengths for SB ranged from 14.70 to 19.54 MPa. No significant difference was found between SB groups treated with or without Ca(OH)2 at 7 days. At 30 days, SB with Ca(OH)2 was significantly higher than SB without Ca(OH)2. Short-term Ca(OH)2 treatment had no detrimental effect on dentin bond strengths to the ethanol or acetone-based adhesive resin systems tested.


Neuronal activity-related coupling in cortical arterioles: involvement of astrocyte-derived factors.
Neuronal activity-evoked dilatation was investigated in cortical arterioles in brain slices from mature rats maintained in vitro at 31-33 degrees C. In the presence of the thromboxane A2 agonist U46619 (75 nM) to preconstrict vessels, internal diameter decreased by 14.2% and rhythmic contractile activity (vasomotion) developed. Addition of the epoxygenase inhibitor miconazole (20 microm) produced a further decrease in diameter and increase in the frequency of vasomotion, suggesting that tonic release of epoxygenase products maintains a level of cerebrovascular dilator tone. Addition of 1 mum AMPA for 5 min evoked a 15.4 +/- 3.7% increase in diameter and the frequency of vasomotion decreased by -6.7 +/- 1.4 contractions min(-1). The response persisted in the presence of 1 mum TTX, indicating that it was independent of neuronal activity and thus likely to have been evoked by activation of AMPA receptors on astrocytes rather than neurones. The response to the brief (5 min) application of AMPA remained unchanged in the presence of miconazole (20 microm). Prolonged (30 min) application of AMPA produced a +12.1 +/- 1.5% increase in internal diameter and reduction in vasomotion (-8.4 +/- 1.7 contractions min(-1)) that were sustained throughout the stimulation period. However, when AMPA was applied in the presence of miconazole (20 microm) it evoked only a transient increase in diameter (+9.8 +/- 3.1%) and decrease in vasomotion (-6.6 +/- 1.5 contractions min(-1)) that lasted for less than 10 min despite continued application of AMPA. The results suggest that products of epoxygenase activity, probably epoxyeicosatrienoic acids (EETs) are involved in activity-related dilatation in cortical arterioles. Whilst epoxygenase activity is not required to initiate dilatation, it appears to be involved in sustaining the response. Thus EETs released from membrane stores could contribute to the initial stages, but once these have been depleted de novo synthesis of EETs is required to maintain the effect.


Making it work: the evolution of a medical educational fellowship program.
Longitudinal programs to enhance the educational skills of medical school faculty are present in many medical schools and academic health centers. Multiinstitutional programs are less common. Three health professions schools, Baylor College of Medicine, The University of Texas Medical School at Houston, and The University of Texas Dental Branch have jointly sponsored the Educational Scholars Fellowship Program (ESFP) since 2003. The evolution of this program, from one that addressed the faculty educator development needs of one medical school in the mid-1990s to a more flexible model that includes faculty and fellows from three institutions, reflects the changing needs of faculty as well as those of other health professions schools. The ESFP's strengths lie in the effective use of resources across three schools; the opportunity for an interinstitutional and interdisciplinary collaborative network; the flexibility of the curriculum offerings; and the positive impact on fellows' knowledge, skills and leadership in medical and dental education. The evolution of this program represents a cost-effective and educationally sound response to the changing needs of faculty educators.


Fast, transient cardiac accelerations and decelerations during fear conditioning in rats.
The current study reports on a number of heart rate responses observed in rats subjected to a discriminatory Pavlovian fear conditioning procedure. Rats learned that a series of six auditory pips was followed by a footshock when presented alone, but not when the pip series was preceded by a visual safety signal. Each auditory pip in the series evoked a fast transient (<1s) cardiac deceleration. This was the case on both trials followed by shock and on trials not followed by shock. The onset of the safety light evoked a similar fast deceleration. We propose that these transient decelerations are similar to the human Evoked Cardiac Response 1 (ECR1), a brief modest deceleration evoked by simple sensory stimuli that is thought to reflect an early process of stimulus registration. Immediately following these pip-evoked decelerations, modest fast accelerations were observed. These accelerations were larger when the pip series was followed by shock than when it was not followed by shock. We propose a potential linkage between these accelerations and the human acceleratory ECR2 component, which is associated with more elaborate processing following stimulus registration; something likely to take place when the pip series predicts an aversive event. Both the ECR1- and ECR2-like responses were embedded within a slow, gradual heart rate increase across the entire pip series. This tonic increase was significantly larger on trials with footshock and is therefore probably associated with anticipatory fear of the upcoming shock. An additional special type of cardiac response was found to the first pip in the series not preceded by the safety signal; here, a much larger and more sustained deceleration was apparent. This response appears relatable to the prolonged deceleration reported in humans in response to aversive picture content. We discuss the cardiac responses found in rats in the current study in the context of heart rate responses known in the human literature.


Treatment pattern and overall survival in esophageal cancer during a 13-year period: A nationwide cohort study of 6,354 Korean patients.
Using data from the real world to solve clinical questions that cannot be answered using data from clinical trials is attracting more attention. Clinical outcomes for patients with esophageal cancer in a real-world setting might be different from data in randomized controlled trials. This study aimed to provide real world data on treatment and prognosis in Korean patients with esophageal cancer. This retrospective cancer cohort included newly diagnosed cases of esophageal cancer at 19 tertiary hospitals between January 1, 2005 and December 31, 2017. Cancer staging was defined according to the 7th edition of the American Joint Committee on Cancer criteria. We identified 6,354 patients with newly diagnosed esophageal cancer (mean age: 64.9 ± 9.0 years, 96.9% squamous cell carcinoma). The proportion of early esophageal cancer increased from 24.7% in 2005 to 37.2% in 2015 (p<0.001). Among all cases, surgery alone was 31.3%, followed by definitive concurrent chemoradiotherapy (CCRT) (27.0%), neoadjuvant therapy (12.4%), adjuvant therapy (11.1%), and endoscopic resection (5.8%). The 5-year overall survival rate was 45.7 ± 0.7%. Endoscopic resection provided similar median survival relative to surgery for stage Ia cases. Among stage II-III cases, definitive CCRT was associated with poorer survival than neoadjuvant or adjuvant therapy, although there was no survival difference between neo-adjuvant and adjuvant therapy. Early esophageal cancer is gradually becoming more common and endoscopic resection provided similar long-term survival relative to surgery. Surgery with combined therapy provided better survival in locally advanced esophageal cancer, relative to definitive CCRT.


Gene and MicroRNA Expression Responses to Exercise; Relationship with Insulin Sensitivity.
Healthy individuals on the lower end of the insulin sensitivity spectrum also have a reduced gene expression response to exercise for specific genes. The goal of this study was to determine the relationship between insulin sensitivity and exercise-induced gene expression in an unbiased, global manner. Euglycemic clamps were used to measure insulin sensitivity and muscle biopsies were done at rest and 30 minutes after a single acute exercise bout in 14 healthy participants. Changes in mRNA expression were assessed using microarrays, and miRNA analysis was performed in a subset of 6 of the participants using sequencing techniques. Following exercise, 215 mRNAs were changed at the probe level (Bonferroni-corrected P<0.00000115). Pathway and Gene Ontology analysis showed enrichment in MAP kinase signaling, transcriptional regulation and DNA binding. Changes in several transcription factor mRNAs were correlated with insulin sensitivity, including MYC, r=0.71; SNF1LK, r=0.69; and ATF3, r= 0.61 (5 corrected for false discovery rate). Enrichment in the 5'-UTRs of exercise-responsive genes suggested regulation by common transcription factors, especially EGR1. miRNA species of interest that changed after exercise included miR-378, which is located in an intron of the PPARGC1B gene. These results indicate that transcription factor gene expression responses to exercise depend highly on insulin sensitivity in healthy people. The overall pattern suggests a coordinated cycle by which exercise and insulin sensitivity regulate gene expression in muscle.


Chinese hamster ovary K2 cell lipid droplets appear to be metabolic organelles involved in membrane traffic.
The principal lipids in animal cell lipid droplets are cholesterol, cholesterol ester, and triglyceride, but the protein composition of this compartment is largely unknown. Here we report on the proteomic analysis of lipid droplets. Using a combination of mass spectrometry and immunoblotting, we identify nearly 40 specifically associated proteins in droplets isolated from Chinese hamster ovary K2 cells grown in normal medium. The proteins fall in to five groups: structural molecules of the droplet-like adipose differentiation-related protein; multiple enzymes involved in the synthesis, storage, utilization, and degradation of cholesterol esters and triglycerides; multiple, different Rab GTPases known to be involved in regulating membrane traffic; signaling molecules such as p50RhoGAP; and a group of proteins that do not fit any classification but include proteins often found in caveolae/rafts such as caveolin-1 and 2 and flotillin-1. The proteome of droplets isolated from cells grown in the presence of oleate is largely the same except for an increase in the amount of adipose differentiation-related protein, caveolin-1, and a protein thought to be involved in phospholipid recycling called CGI-58. Based on the protein profile, the lipid droplet appears to be a complex, metabolically active organelle that is directly involved in membrane traffic and possibly phospholipid recycling. We propose the name adiposome for this organelle.


''It was the end of the world" - The lifeworld of elite male rugby union players living with injury. An interpretative phenomenological analysis.
Professional rugby is an aggressive sport. Consequently, injuries are an inevitable part of a rugby player's career. It is therefore crucial for sports medicine professionals to understand the subjective experience of injured athletes in order to optimize their care. The purpose of this study was to take a lifeworld perspective to explore how living with injury was meaningful to professional rugby players. A purposive sample of five participants were recruited and data collection undertaken via semi-structured interviews. Audio-recordings were transcribed verbatim and analyzed using interpretative phenomenological analysis methodology to develop the themes. Three master themes emerged from the analysis, each comprising of two subthemes; 1) Sense of Uncertainty (1a. Fear of the Unknown, 1b. Lack of Control), 2) Experienced Change in Relationships (2a. Lived Human Relations, 2b. Coping), 3) Sense of Self (3a. Isolation and Belonging, 3b. ''Being" an Athlete). Participants described the challenge to their sense of self and 'being' athletes', as the isolation from the team deprived them of their sense of belonging. Participants illustrated the experienced significance of their relationships, the uncertainty over their lives and the unique strategies to cope. Emotions of anxiety, grief, anger, and shock reverberate throughout their accounts.


Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria.
Dendritic cells (DC) are APCs essential for the development of primary immune responses. In pluristratified epithelia, Langerhans cells (LC) are a critical subset of DC which take up Ags and migrate toward lymph nodes upon inflammatory stimuli. TLR allow detection of pathogen-associated molecular patterns (PAMP) by different DC subsets. The repertoire of TLR expressed by human LC is uncharacterized and their ability to directly respond to PAMP has not been systematically investigated. In this study, we show for the first time that freshly purified LC from human skin express mRNA encoding TLR1, TLR2, TLR3, TLR5, TLR6 and TLR10. In addition, keratinocytes ex vivo display TLR1-5, TLR7, and TLR10. Accordingly, highly enriched immature LC efficiently respond to TLR2 agonists peptidoglycan and lipoteichoic acid from Gram-positive bacteria, and to dsRNA which engages TLR3. In contrast, LC do not directly sense TLR7/8 ligands and LPS from Gram-negative bacteria, which signals through TLR4. TLR engagement also results in cytokine production, with marked differences depending on the PAMP detected. TLR2 and TLR3 ligands increase IL-6 and IL-8 production, while dsRNA alone stimulates TNF-alpha release. Strikingly, only peptidoglycan triggers IL-10 secretion, thereby suggesting a specific function in tolerance to commensal Gram-positive bacteria. However, LC do not produce IL-12p70 or type I IFNs. In conclusion, human LC are equipped with TLR that enable direct detection of PAMP from viruses and Gram-positive bacteria, subsequent phenotypic maturation, and differential cytokine production. This implies a significant role for LC in the control of skin immune responses.


Army research needs for automated neuropsychological tests: monitoring soldier health and performance status.
Information on the mental status of soldiers operating at the limits of human tolerance will be vital to their management in future deployments; it may also allow earlier intervention for conditions such as undiagnosed Gulf War illnesses and Parkinson's Disease. The Army needs a parsimonious set of neuropsychological tests that reliably identify subtle changes for: (1) early detection of individual health and military performance impairments and (2) management of occupational and deployment health risks. Testing must characterize cognitive lapses in healthy individuals faced with relevant operational stressors (i.e., anxiety, information overload, thermal strain, hypoxia, fatigue, head impact, chemical or radiation exposures, metabolic challenges). This effort must also explore the neuropsychological methods in militarily relevant conditions to extend our understanding of relevant functional domains and how well they correspond to modes of testing. The ultimate objective is unobtrusive real-time mental status monitoring.


Evaluation of four proposed bleeding criteria for the onset of late menopausal transition.
The current criterion for onset of late menopausal transition is amenorrhea of 90 d or more. The Stages of Reproductive Aging Workshop proposed alternative criteria based on a shorter period of amenorrhea. Empirical data comparing proposed criteria are not available. This paper evaluates the several bleeding criteria that served as the basis of these recommendations. The goal was to provide empirically based guidance regarding which bleeding criterion may be optimal for widespread application in clinical and research settings. The study used prospective menstrual calendar data from four community and population-based cohort studies: TREMIN, Melbourne Women's Midlife Health Project, Seattle Midlife Women's Health Study, and Study of Women's Health Across the Nation. The study included 735 TREMIN, 279 Seattle Midlife Women's Health Study, 216 Melbourne Women's Midlife Health Project, and 2270 Study of Women's Health Across the Nation women aged 35-57 yr at baseline who contributed 10 menstrual cycles or more. The main measures were the frequency of and median age at occurrence and time from occurrence to final menstrual period (FMP) for four criteria: skipped segment, 10-segment running range, 60- and 90-d amenorrhea. A skipped segment, 10-segment running range greater than 42 d and 60-d amenorrhea identify a similar time in women's reproductive lives. The latter two identify the exact same date in two thirds of women. All three criteria occur in a greater proportion of women than the 90-d criterion and are equally predictive of the FMP, although they occur 1-2 yr earlier. These findings support the recommendation of the Stages of Reproductive Aging Workshop that 60 d of amenorrhea be used to define onset of the late menopausal transition.


The evolution of early cellular systems viewed through the lens of biological interactions.
The minimal cell concept represents a pragmatic approach to the question of how few genes are required to run a cell. This is a helpful way to build a parts-list, and has been more successful than attempts to deduce a minimal gene set for life by inferring the gene repertoire of the last universal common ancestor, as few genes trace back to this hypothetical ancestral state. However, the study of minimal cellular systems is the study of biological outliers where, by practical necessity, coevolutionary interactions are minimized or ignored. In this paper, we consider the biological context from which minimal genomes have been removed. For instance, some of the most reduced genomes are from endosymbionts and are the result of coevolutionary interactions with a host; few such organisms are "free-living." As few, if any, biological systems exist in complete isolation, we expect that, as with modern life, early biological systems were part of an ecosystem, replete with organismal interactions. We favor refocusing discussions of the evolution of cellular systems on processes rather than gene counts. We therefore draw a distinction between a pragmatic minimal cell (an interesting engineering problem), a distributed genome (a system resulting from an evolutionary transition involving more than one cell) and the looser coevolutionary interactions that are ubiquitous in ecosystems. Finally, we consider the distributed genome and coevolutionary interactions between genomic entities in the context of early evolution.


Ventral lamina terminalis mediates enhanced cardiovascular responses of rostral ventrolateral medulla neurons during increased dietary salt.
Increased dietary salt enhances sympathoexcitatory and sympathoinhibitory responses evoked from the rostral ventrolateral medulla (RVLM). The purpose of the present study was to determine whether neurons of the forebrain lamina terminalis (LT) mediated these changes in the RVLM. Male Sprague-Dawley rats with and without LT lesions were fed normal chow and given access to water or 0.9% NaCl for 14 to 15 days. Unilateral injection of l-glutamate into the RVLM produced significantly larger increases in renal sympathetic nerve activity and arterial blood pressure of sham rats ingesting 0.9% NaCl versus water. However, these differences were not observed between ventral LT-lesioned rats drinking 0.9% NaCl versus water. Similar findings were observed when angiotensin II or gamma-aminobutyric acid was injected into the RVLM. Interestingly, a subset of animals drinking 0.9% but with damage restricted to the organum vasculosum of the lamina terminalis did not show enhanced responses to l-glutamate or gamma-aminobutyric acid. In marked contrast, RVLM injection of l-glutamate or gamma-aminobutyric acid produced exaggerated sympathetic nerve activity and arterial blood pressure responses in animals drinking 0.9% NaCl versus water after an acute ventral LT lesion or chronic lesion of the subfornical organ. Additional experiments demonstrated that plasma sodium concentration and osmolality were increased at night in rats ingesting 0.9% NaCl. These findings suggest that neurons of the ventral LT mediate the ability of increased dietary salt to enhance the responsiveness of RVLM sympathetic neurons.


Community-Based Services to Improve Testing and Linkage to Care Among Non-U.S.-Born Persons with Chronic Hepatitis B Virus Infection - Three U.S. Programs, October 2014-September 2017.
Among an estimated 850,000 to 2.2 million persons with chronic hepatitis B virus (HBV) infection in the United States, 70% are non-U.S.-born (1,2). All patients require linkage to care, and approximately 20%-40% require antiviral treatment (3). Without treatment, one in four persons chronically infected with HBV will die prematurely from liver failure, liver cirrhosis, or hepatocellular carcinoma (4). To mitigate morbidity and mortality, CDC funded a cooperative agreement to develop hepatitis B testing and linkage-to-care programs serving non-U.S.-born persons during October 2014-September 2017. This report describes each program's operational services and partnerships with primary care centers, community-based organizations, and public health departments to recruit non-U.S.-born persons for HBV testing using the hepatitis B surface antigen (HBsAg) and link those whose test results were positive to HBV-directed care (medical visit attendance with monitoring of HBV DNA and liver enzyme tests). Among 10,152 program participants, 757 (7.5%) were HBsAg-positive, indicative of chronic HBV infection; among these, 643 (85%) attended ≥1 medical visit, 587 (78%) received HBV-directed care, and 137 (18%) were prescribed antiviral treatment. Among 273 household contacts of HBsAg-positive persons, 39 (14%) had positive test results for HBsAg. Prevalence of current HBV infection was high in this non-U.S.-born population and among household and sexual contacts of HBV-infected persons. HBV testing and linkage to care can be achieved through partnerships with community organizations, health centers, and public health departments.


Insights into the functional architecture of the catalytic center of a maize beta-glucosidase Zm-p60.1.
The maize (Zea mays) beta-glucosidase Zm-p60.1 has been implicated in regulation of plant development by the targeted release of free cytokinins from cytokinin-O-glucosides, their inactive storage forms. The crystal structure of the wild-type enzyme was solved at 2.05-A resolution, allowing molecular docking analysis to be conducted. This indicated that the enzyme specificity toward substrates with aryl aglycones is determined by aglycone aromatic system stacking with W373, and interactions with edges of F193, F200, and F461 located opposite W373 in a slot-like aglycone-binding site. These aglycone-active site interactions recently were hypothesized to determine substrate specificity in inactive enzyme substrate complexes of ZM-Glu1, an allozyme of Zm-p60.1. Here, we test this hypothesis by kinetic analysis of F193I/Y/W mutants. The decreased K(m) of all mutants confirmed the involvement of F193 in determining enzyme affinity toward substrates with an aromatic aglycone. It was unexpected that a 30-fold decrease in k(cat) was found in F193I mutant compared with the wild type. Kinetic analysis and computer modeling demonstrated that the F193-aglycone-W373 interaction not only contributes to aglycone recognition as hypothesized previously but also codetermines catalytic rate by fixing the glucosidic bond in an orientation favorable for attack by the catalytic pair, E186 and E401. The catalytic pair, assigned initially by their location in the structure, was confirmed by kinetic analysis of E186D/Q and E401D/Q mutants. It was unexpected that the E401D as well as C205S and C211S mutations dramatically impaired the assembly of a catalysis-competent homodimer, suggesting novel links between the active site structure and dimer formation.


Poverty and human immunodeficiency virus in children: a view from the Western Cape, South Africa.
Sub-Saharan Africa is the region affected worst by human immunodeficiency virus (HIV), with the most southern countries, including Botswana, Zimbabwe, Swaziland, and South Africa, carrying the highest disease burden. This geographic distribution represents a complex interaction among virological, political, social, cultural, and economic forces. In South Africa the HIV epidemic is seemingly unchecked, with 18% of the adult population infected. Although South Africa is a mid-developed country, there is a large chasm between the wealthy and the poor, with many living in moderate to extreme poverty. Poverty creates conditions that fuel the HIV epidemic while HIV exacerbates the multiple interlinking causes of poverty. Children are the most vulnerable members of society, severely affected by all components of the poverty cycle. Although improved health education and access to care will alleviate many problems, sustainable poverty alleviation should form an essential component of the response to AIDS. The formulation of the United Nations Millennium Developmental Goals is an important step in the right direction, but global and local political commitment is essential for success.


Sequential Metastatic Breast Cancer Chemotherapy: Should the Median be the Message?
Counseling and anticipatory guidance of the expected course of treatment for women newly diagnosed with metastatic breast cancer (MBC) are difficult due to multiple factors influencing survival following MBC therapy. In order to better tailor counseling at the onset and through the duration of MBC we used non-clinical trial data to better characterize real life experience of sequential MBC treatment. We examined the following aims: (1) What demographic and tumor characteristics are predictive of survival in MBC? (2) What is the median duration of each sequential chemotherapy regimen and subsequent survival of women following each sequence of chemotherapy regimen in MBC? Retrospective study included 792 women diagnosed from January 1999 through December 2009 at the University of Pittsburgh Cancer Institute Breast Cancer Program. Median duration of sequential chemotherapy regimen and median survival from completion of sequence of chemotherapy regimens were relatively short with a wide range of treatment duration and survival. Characteristics for poor survival included hormone status, human epidermal growth factor receptor-2 (HER 2/neu) status, and increased number and type of metastatic sites. Women who took more than the second sequential chemotherapy regimens had no more than median 3 months of treatment duration and 6 months survival from treatment termination. Median clinical response and survival shorten with sequential chemotherapy regimen but with wide ranges. The rare clinical response of the minority should not set the standard for treatment expectations. All cancer clinicians, including oncology nurses, must ensure that patients are receiving tailored counseling regarding their specific risks and benefits for sequential MBC chemotherapy.


Absence of a moderating effect of parent health literacy on Early Head Start enrollment and dental use.
To examine the moderating effect of parents' health literacy (HL) on the effectiveness of North Carolina Early Head Start (EHS) in improving children's dental use. Parents of 479 children enrolled in EHS and 699 Medicaid-matched parent-child dyads were interviewed at baseline when children were approximately 10 months old and 24 months later. We used in-person computer-assisted, structured interviews to collect information on sociodemographic characteristics, dental use, and administer the Short Assessment of Health Literacy - Spanish and English (SAHL-S&E). This quasi-experimental study tested whether the interaction effect between EHS and parents' HL was associated with dental use. Logit (any use) and marginalized zero-inflated negative binomial count models (number of dental visits) included random effects to account for clustering and controlled for baseline dental use, dental need, survey language, and a propensity score covariate. Nineteen percent of parents in EHS had low literacy compared to 12 percent of parents in the non-EHS group (P < 0.01). The interaction term between EHS and parent's HL was not significant in the adjusted logit model (ratio of aORs 0.98, 95 percent CI: 0.43-2.20) or the adjusted count model (ratio of aRRs 0.88, 95 percent CI: 0.72-1.09). Parents in EHS had a higher prevalence of low HL compared to non-EHS parents. Parents' HL did not moderate the relationship between EHS and child dental use, suggesting that EHS results in similar improvements in dental use regardless of parent's HL levels.


Animal Health and Welfare Issues Facing Organic Production Systems.
The demand for organically-grown produce is increasing worldwide, with one of the drivers being an expectation among consumers that animals have been farmed to a high standard of animal welfare. This review evaluates whether this expectation is in fact being met, by describing the current level of science-based knowledge of animal health and welfare in organic systems. The primary welfare risk in organic production systems appears to be related to animal health. Organic farms use a combination of management practices, alternative and complementary remedies and convenional medicines to manage the health of their animals and in many cases these are at least as effective as management practices employed by non-organic producers. However, in contrast to non-organic systems, there is still a lack of scientifically evaluated, organically acceptable therapeutic treatments that organic animal producers can use when current management practices are not sufficient to maintain the health of their animals. The development of such treatments are necessary to assure consumers that organic animal-based food and fibre has not only been produced with minimal or no chemical input, but under high standards of animal welfare.


Core principles for fracture prevention: North American Consensus from the National Osteoporosis Foundation, Osteoporosis Canada, and Academia Nacional de Medicina de Mexico.
Core principles for fracture prevention address fundamental concepts for the evaluation and management of patients at risk for fracture. These are intended to form the foundation of clinical practice guidelines and represent a first step toward guideline harmonization. The large number of clinical practice guidelines for osteoporosis and discordance of recommendations has led to confusion among clinicians and patients, and likely contributes to the large osteoporosis treatment gap. We propose that stakeholder organizations reach agreement on fundamental principles in the management of osteoporosis and prevention of fracture as a first step toward a goal of guideline harmonization. The best available evidence, as interpreted by an ad hoc working group of expert representatives from major osteoporosis societies in North America, was considered in the development of core principles for skeletal healthcare. These principles were subsequently endorsed by the USA National Osteoporosis Foundation, Osteoporosis Canada, and Academia Nacional de Medicina de Mexico (National Academy of Medicine of Mexico). Core principles are summarized here in bullet format. Categories include evaluation, lifestyle and nutrition, pharmacological therapy, and monitoring. A pathway forward to achieve guideline harmonization, at least in part, is proposed. Greater concordance of recommendations for the care of patients at risk for fracture are expected to lead to improved patient care across jurisdictions, with a narrowing of the osteoporosis treatment gap and reduced burden of fractures.


Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients.
Effective systemic therapy is vital for successful breast cancer treatment, but early onset toxicities like neutropenia hinder systemic therapy administration, especially in the elderly. Primary prophylactic use of granulocyte-colony stimulating factors (G-CSF) helps prevent neutropenia, and according to some clinical trials, facilitates chemotherapy completion. Nevertheless, evidence supporting the effectiveness of primary prophylactic G-CSF in the elderly is limited. Thus, the ASCO recommendations for primary prophylactic G-CSF use in the elderly are not explicit. This retrospective observational study examined the association between primary prophylactic G-CSF administration at the start of first course chemotherapy with adequate first course chemotherapy and radiation therapy administration in elderly breast cancer patients. The study analyzes newly diagnosed breast cancer patients receiving chemotherapy present in the SEER-Medicare data from 1994 to 2003. To account for the non-random nature of the observational data, a non-parametric matching technique was used to pre-process the data before estimating the effect of primary prophylactic G-CSF on adequate chemotherapy and radiation therapy administration. Adequate chemotherapy was defined as administration of six or more cycles during the first course. Primary prophylactic G-CSF administered at the start of the first course chemotherapy was associated with a statistically significant increase in the probability of administration of six or more first course chemotherapy cycles by 29% [95% CI 7.7-50.6%] and any radiation therapy administration by 42% [95% CI 25.2-58.4%]. Primary prophylactic G-CSF use with the first course of chemotherapy is associated with improved chemotherapy completion rates and radiation therapy. These findings emphasize the clinical value of primary prophylactic G-CSF use for systemic therapy completion, and have implications for ASCO guidelines and medicare coverage policies.


NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis.
Liver fibrosis, which involves activation of hepatic stellate cells (HSC), is a major health problem and is the end outcome of all chronic liver diseases. The liver is populated with lymphocytes, among which are natural killer (NK) cells, whose activity is controlled by inhibitory and activating receptors. NKp46, one of the major NK activating receptors expressed by NK cells, is also a specific NK marker that discriminates NK cells from all other lymphocyte subsets. It recognises viral haemagglutinins and unknown cellular ligands. The anti-fibrotic activity of the NKp46 receptor was assessed in vivo and in vitro using NKp46-deficient mice (NCR1(gfp/gfp)), the carbon tetrachloride model and in vitro NK killing assays. Primary murine and human HSC were stained for the expression of the NKp46 ligand using fusion proteins composed of the extracellular portions of the murine and human NKp46 receptors fused to human IgG1. It was shown that murine HSC express a ligand for the murine orthologue of the NKp46 receptor, NCR1. NCR1 inhibited liver fibrosis in vivo; in vitro, murine HSC were killed in an NCR1-dependent manner. In humans it was shown that human HSC also express a ligand for the human NKp46 receptor and that the killing of human HSC is NKp46 dependent. In addition to NKG2D, NKp46/NCR1 play an important role in inhibition of liver fibrosis. This suggests that fibrosis can be better controlled through the manipulation of NKp46 activity.


Patellar resurfacing in total knee replacement: five-year clinical and economic results of a large randomized controlled trial.
There is conflicting evidence regarding the merits of patellar resurfacing during total knee arthroplasty, as many of the previous randomized controlled trials have not been adequately powered. A pragmatic, multicenter, randomized controlled trial was initiated in 1999 in the United Kingdom. Within a partial factorial design, 1715 patients were randomly allocated to receive or not receive patellar resurfacing during total knee arthroplasty. The primary outcome measure was the Oxford Knee Score; secondary measures included the Short Form-12, the EuroQoL 5D, cost, cost-effectiveness, and the need for subsequent knee surgery. The mean Oxford Knee Score was 35 points at five years postoperatively in both groups. There was no significant difference between the groups with respect to the mean Oxford Knee Score (difference, 0.59 point; 95% confidence interval, -0.58 to 1.76 points) or any other outcome measure at five years postoperatively. The outcome was not affected by whether the patella was domed or anatomic. There was no significant difference between the two groups with respect to the prevalence of knee-related readmission, of minor or intermediate reoperation, or of subsequent patella-related surgery. The total health care cost for the primary arthroplasty, subsequent monitoring, and any revision surgery did not differ significantly between the two groups. In the largest randomized controlled trial of patellar resurfacing reported to date, the functional outcome, reoperation rate, and total health care cost five years after primary total knee arthroplasty were not significantly affected by the addition of patellar resurfacing to the surgical procedure.


Load-insensitive temperature sensor based on azobenzene-chloroform-solution-filled microstructured optical fiber.
A solid-core microstructured optical fiber is infiltrated with the Dispersed Yellow 7 and chloroform mixture solution, resulting in the appearance of several transmission dips with different temperature and axial load responses. The temperature- and load-dependent spectral characteristics of these dips have been investigated and the experimental results indicate that they are pretty temperature-sensitive, but insensitive to the variation of applied axial load. Such a compact fiber-optic device with electric perturbation immunity could be employed for load-insensitive temperature sensing with high sensitivity.


AUX1 promotes lateral root formation by facilitating indole-3-acetic acid distribution between sink and source tissues in the Arabidopsis seedling.
Arabidopsis root architecture is regulated by shoot-derived signals such as nitrate and auxin. We report that mutations in the putative auxin influx carrier AUX1 modify root architecture as a result of the disruption in hormone transport between indole-3-acetic acid (IAA) source and sink tissues. Gas chromatography-selected reaction monitoring-mass spectrometry measurements revealed that the aux1 mutant exhibited altered IAA distribution in young leaf and root tissues, the major IAA source and sink organs, respectively, in the developing seedling. Expression studies using the auxin-inducible reporter IAA2::uidA revealed that AUX1 facilitates IAA loading into the leaf vascular transport system. AUX1 also facilitates IAA unloading in the primary root apex and developing lateral root primordium. Exogenous application of the synthetic auxin 1-naphthylacetic acid is able to rescue the aux1 lateral root phenotype, implying that root auxin levels are suboptimal for lateral root primordium initiation in the mutant.


The UK Myotonic Dystrophy Patient Registry: facilitating and accelerating clinical research.
Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy worldwide with complex, multi-systemic, and progressively worsening symptoms. There is currently no treatment for this inherited disorder and research can be challenging due to the rarity and variability of the disease. The UK Myotonic Dystrophy Patient Registry is a patient self-enrolling online database collecting clinical and genetic information. For this cross-sectional "snapshot" analysis, 556 patients with a confirmed diagnosis of DM1 registered between May 2012 and July 2016 were included. An almost even distribution was seen between genders and a broad range of ages was present from 8 months to 78 years, with the largest proportion between 30 and 59 years. The two most frequent symptoms were fatigue and myotonia, reported by 79 and 78% of patients, respectively. The severity of myotonia correlated with the severity of fatigue as well as mobility impairment, and dysphagia occurred mostly in patients also reporting myotonia. Men reported significantly more frequent severe myotonia, whereas severe fatigue was more frequently reported by women. Cardiac abnormalities were diagnosed in 48% of patients and more than one-third of them needed a cardiac implant. Fifteen percent of patients used a non-invasive ventilation and cataracts were removed in 26% of patients, 65% of which before the age of 50 years. The registry's primary aim was to facilitate and accelerate clinical research. However, these data also allow us to formulate questions for hypothesis-driven research that may lead to improvements in care and treatment.


Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions.
Glycogen synthase kinase-3 (GSK3) has recently been linked to mood disorders and schizophrenia, and the neurotransmitter systems and therapeutic treatments associated with these diseases. GSK3 is a widely influential enzyme that is capable of phosphorylating, and thereby regulating, over forty known substrates. Four mechanisms regulating GSK3 (phosphorylation, protein complexes, localization, and substrate phosphorylation) combine to provide substrate-specific regulation of the actions of GSK3. Several intracellular signaling cascades converge on GSK3 to modulate its activity, and several neurotransmitter systems also regulate GSK3, including serotonergic, dopaminergic, cholinergic, and glutamatergic systems. Because of changes in these neurotransmitter systems and the actions of therapeutic drugs, GSK3 has been linked to the mood disorders, bipolar disorder and depression, and to schizophrenia. Inhibition of GSK3 may be an important therapeutic target of mood stabilizers, and regulation of GSK3 may be involved in the therapeutic effects of other drugs used in psychiatry. Dysregulated GSK3 in bipolar disorder, depression, and schizophrenia could have multiple effects that could impair neural plasticity, such as modulation of neuronal architecture, neurogenesis, gene expression, and the ability of neurons to respond to stressful, potentially lethal, conditions. In part because of these key actions of GSK3 and its associations with mood disorders and schizophrenia, much research is currently being devoted to identifying new selective inhibitors of GSK3.


The phosphatase inhibitor okadaic acid induces AQP2 translocation independently from AQP2 phosphorylation in renal collecting duct cells.
Phosphorylation by kinases and dephosphorylation by phosphatase markedly affect the biological activity of proteins involved in intracellular signaling. In this study we investigated the effect of the serine/threonine phosphatase inhibitor okadaic acid on water permeability properties and on aquaporin2 (AQP2) translocation in AQP2-transfected renal CD8 cells. In CD8 cells both forskolin alone and okadaic acid alone increased the osmotic water permeability coefficient P(f) by about 4- to 5-fold. In intact cells, in vivo phosphorylation studies revealed that forskolin stimulation resulted in a threefold increase in AQP2 phosphorylation. In contrast, okadaic acid treatment promoted only a 60% increase in AQP2 phosphorylation which was abolished when this treatment was performed in the presence of 1 microM H89, a specific protein kinase A (PKA) inhibitor. Nevertheless, in this latter condition, confocal microscopy analysis revealed that AQP2 translocated and fused to the apical membrane. Okadaic acid-induced AQP2 translocation was dose dependent having its maximal effect at a concentration of 1 microM. In conclusion, our results clearly indicate that okadaic acid exerts a full forskolin-like effect independent from AQP2 phosphorylation. Thus AQP2 phosphorylation is not essential for water channel translocation in renal cells, indicating that different pathways might exist leading to AQP2 apical insertion and increase in P(f).


Attribute dimensions that distinguish master and novice physical therapy clinicians in orthopedic settings.
The purpose of this qualitative case study was to further investigate the work of master and novice clinicians within the practice setting. The sample consisted of three master clinicians and three novice clinicians practicing in orthopedic outpatient physical therapy settings in three different regions of the United States. Data collection by three researchers included observation of each clinician treating at least three patients, audiotaping of all treatment sessions, interviews with clinicians and patients, and a review of patient records. Analysis of the data within and across cases revealed five attribute dimensions that distinguished the master clinician from the novice clinician. One attribute dimension (ie, confidence in predicting patient outcomes) related to knowledge, and four attribute dimensions (ie, ability to control the environment, evaluation and use of patient illness and disease data, focus of verbal and nonverbal communication with patients, and importance of teaching to hands-on care) related to improvisational performance. Further investigations are needed to confirm these findings and add to the body of knowledge concerning the parameters of physical therapy that may affect the efficacy and quality of patient care.


The role of crude human saliva and purified salivary MUC5B and MUC7 mucins in the inhibition of Human Immunodeficiency Virus type 1 in an inhibition assay.
Despite the continuous shedding of HIV infected blood into the oral cavity and the detectable presence of the AIDS virus at a high frequency, human saliva is reported to inhibit oral transmission of HIV through kissing, dental treatment, biting, and aerosolization. The purpose of this study was to purify salivary MUC5B and MUC7 mucins from crude saliva and determine their anti-HIV-1 activities. Following Sepharose CL-4B column chromatography and caesium chloride isopycnic density-gradient ultra-centrifugation, the purity and identity of the mucins was determined by SDS-PAGE and Western blotting analysis respectively. Subsequently an HIV-1 inhibition assay was carried out to determine the anti-HIV-1 activity of the crude saliva and purified salivary mucins by incubating them with subtype D HIV-1 prior to infection of the CD4+ CEM SS cells. Western blotting analysis confirmed that the mucin in the void volume is MUC5B and the mucin in the included volume is MUC7. The HIV inhibition assay revealed that both the crude saliva and salivary MUC5B and MUC7 mucins inhibited HIV-1 activity by 100%. Although the mechanism of action is not clear the carbohydrate moieties of the salivary mucins may trap or aggregate the virus and prevent host cell entry.


Understanding what wellbeing means to medical and nursing staff working in paediatric intensive care: an exploratory qualitative study using appreciative inquiry.
To explore what wellbeing means to medical and nursing staff working in a large paediatric intensive care (PIC). Exploratory qualitative design using an appreciative inquiry framework. PIC unit; primary, secondary and tertiary. 46 nurses and doctors working on PIC. A set of images were used together with open-ended questions to prompt staff to discuss what wellbeing means to them. Interviews were audiorecorded and transcribed. Data were analysed thematically. Images depicting nature, children and groups of adults were selected most. Meanings of wellbeing for PIC staff can be understood through three themes: (1) Being nurtured and supported at work, (2) Importance of nature and (3) Social support independent of work. The first theme considered the importance of being listened to at work as well as staff highlighting the value of being in control at work. Within the second theme, being active in nature and outdoors as well as the importance of being in the present moment was illustrated. Within the final theme, staff expressed the value of having support independent of work and highlighted the importance of spending time with family. This study provides a unique insight into how individuals working in PIC experience wellbeing and what wellbeing means to them. Understanding how healthcare professionals in PIC settings experience wellbeing and what wellbeing means to them will enable researchers to develop interventions designed to enhance staff wellbeing based on lived experience.


Inhibition of Miro1 disturbs mitophagy and pancreatic β-cell function interfering insulin release via IRS-Akt-Foxo1 in diabetes.
Mitochondrial function is essential to meet metabolic demand of pancreatic beta cells respond to high nutrient stress. Mitophagy is an essential component to normal pancreatic β-cell function and has been associated with β-cell failure in Type 2 diabetes (T2D). Our previous studies have indicated that mitochondrial Rho (Miro) GTPase-mediated mitochondrial dysfunction under high nutrient stress leads to NOD-like receptor 3 (NLRP3)-dependent proinflammatory responses and subsequent insulin resistance. However, the in vivo mechanism by which Miro1 underlies mitophagy has not been identified. Here we show firstly that the expression of Miro is reduced in human T2D and mouse db/db islets and in INS-1 cell line exposed to high glucose and palmitate. β-cell specific ablation of Miro1 (Miro1f/f: Rip-cre mice, or (IKO) under high nutrient stress promotes the development of hyperglycemia. β-cells from IKO mice display an inhibition of mitophagy under oxidative stress and induces mitochondrial dysfunction. Dysfunctional mitophagy in IKO mice is represented by damaged islet beta cell mitochondrial and secretory capacity, unbalanced downstream MKK-JNK signalling without affecting the levels of MEK, ERK or p38 activation and subsequently, impaired insulin secretion signaling via inhibition IRS-AKT-Foxo1 pathway, leading to worsening glucose tolerance in these mice. Thus, these data suggest that Miro1 may be responsible for mitophagy deficiency and β-cell dysfunction in T2D and that strategies target Miro1 in vivo may provide a therapeutic target to enhance β-cell mitochondrial quality and insulin secretion to ameliorate complications associated with T2D.


Standardizing Flow Cytometry Immunophenotyping Analysis from the Human ImmunoPhenotyping Consortium.
Standardization of immunophenotyping requires careful attention to reagents, sample handling, instrument setup, and data analysis, and is essential for successful cross-study and cross-center comparison of data. Experts developed five standardized, eight-color panels for identification of major immune cell subsets in peripheral blood. These were produced as pre-configured, lyophilized, reagents in 96-well plates. We present the results of a coordinated analysis of samples across nine laboratories using these panels with standardized operating procedures (SOPs). Manual gating was performed by each site and by a central site. Automated gating algorithms were developed and tested by the FlowCAP consortium. Centralized manual gating can reduce cross-center variability, and we sought to determine whether automated methods could streamline and standardize the analysis. Within-site variability was low in all experiments, but cross-site variability was lower when central analysis was performed in comparison with site-specific analysis. It was also lower for clearly defined cell subsets than those based on dim markers and for rare populations. Automated gating was able to match the performance of central manual analysis for all tested panels, exhibiting little to no bias and comparable variability. Standardized staining, data collection, and automated gating can increase power, reduce variability, and streamline analysis for immunophenotyping.


The growth cycle of Simkania negevensis.
Simkania negevensis, a bacterium formerly referred to as 'the micro-organism Z' or 'Simkania Z', belongs to the order Chlamydiales, assigned to the family Simkaniaceae: The purpose of this study was to investigate the production of Simkania negevensis progeny in infected cells in comparison with the well-documented Chlamydiaceae developmental cycle. It was found that replicating Simkania negevensis in Vero cells resembled the reticulate bodies of all known chlamydial species: in electron micrographs they were reticulated, homogeneously staining, and often caught in the process of binary division. These replicative forms were found in low abundance shortly after infection, but by 3 days post-infection they were the most prevalent particles in host cells. Electron-dense forms of Simkania negevensis began to appear on the third day post-infection, but quantitatively did not account for the high titre of infectivity in extracts from these host cells. These had both electron-dense and electron-lucent areas, a characteristic seen only in a few chlamydial species. Simkania negevensis infectivity did not appreciably change during the ensuing 12 days required for host cell lysis, despite an eightfold increase in the proportion of electron-dense bacteria over this time. The emergence of electron-dense bodies, increase in infectivity and host-cell lysis were not synchronized developmental events. This is a novel finding in Chlamydiales spp. and suggests that Simkania negevensis will provide new perspectives in the mechanisms of chlamydial intracellular growth.


Implementation of the StandingTall programme to prevent falls in older people: a process evaluation protocol.
One in three people aged 65 years and over fall each year. The health, economic and personal impact of falls will grow substantially in the coming years due to population ageing. Developing and implementing cost-effective strategies to prevent falls and mobility problems among older people is therefore an urgent public health challenge. StandingTall is a low-cost, unsupervised, home-based balance exercise programme delivered through a computer or tablet. StandingTall has a simple user-interface that incorporates physical and behavioural elements designed to promote compliance. A large randomised controlled trial in 503 community-dwelling older people has shown that StandingTall is safe, has high adherence rates and is effective in improving balance and reducing falls. The current project targets a major need for older people and will address the final steps needed to scale this innovative technology for widespread use by older people across Australia and internationally. This project will endeavour to recruit 300 participants across three sites in Australia and 100 participants in the UK. The aim of the study is to evaluate the implementation of StandingTall into the community and health service settings in Australia and the UK. The nested process evaluation will use both quantitative and qualitative methods to explore uptake and acceptability of the StandingTall programme and associated resources. The primary outcome is participant adherence to the StandingTall programme over 6 months. Ethical approval has been obtained from the South East Sydney Local Health District Human Research Ethics Committee (HREC reference 18/288) in Australia and the North West- Greater Manchester South Research Ethics Committee (IRAS ID: 268954) in the UK. Dissemination will be via publications, conferences, newsletter articles, social media, talks to clinicians and consumers and meetings with health departments/managers. ACTRN12619001329156.


Multiple breath nitrogen washout: a feasible alternative to mass spectrometry.
The lung clearance index (LCI), measured by multiple breath washout (MBW), reflects global ventilation inhomogeneity and is a sensitive marker of early cystic fibrosis (CF) lung disease. Current evidence is based on a customized mass spectrometry system that uses sulfur hexafluoride (SF6) as a tracer gas, which is not widely available. Nitrogen (N2) washout may be better suited for clinical use and multi-center trials. To compare the results obtained from a N2 washout system to those generated by the SF6 based system in healthy children and children with CF. Children with CF were recruited from outpatient clinics; healthy children were recruited from the Research4Kids online portal. Participants performed MBWSF6 (Amis 2000, Innovision, Denmark) and MBWN2 (ExhalyzerD, EcoMedics, Switzerland) in triplicate, in random order on the same day. Agreement between systems was assessed by Bland-Altman plot. Sixty-two healthy and 61 children with CF completed measurements on both systems. In health there was good agreement between systems (limits of agreement -0.7 to 1.9); on average N2 produced higher values of LCI (mean difference 0.58 (95% CI 0.42 to 0.74)). In CF the difference between systems was double that in health with a clear bias towards disproportionately higher LCIN2 compared to LCISF6 at higher mean values of LCI. LCIN2 and LCISF6 have similar discriminative power and intra-session repeatability but are not interchangeable. MBWN2 offers a valid new tool to investigate early obstructive lung disease in CF, but requires independent normative values.


Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus.
Clinical trials revealed a high efficacy of mycophenolate mofetil (MMF)in inducing and maintaining remission in patients with class III-V-lupus nephritis. Also extrarenal manifestations respond to MMF treatment. However, few attempts have been undertaken to delineate its mechanism of action in systemic lupus erythematosus (SLE) a disease characterized by enhanced B cell activation. Clinical and paraclinical parameters of 107 patients with SLE were recorded consecutively and analyzed retrospectively. Patients were divided into treatment groups (MMF: n=39, azathioprine (AZA) n=30 and controls without immunosuppressive therapy n=38). To further delineate the effect of mycophenolic acid (MPA) on naive and memory B cells in vitro assays were performed. Although patients taking AZA flared more frequently than patients on MMF or controls, the analysis of clinical parameters did not reveal significant differences.However, profound differences in paraclinical parameters were found. B cell frequencies and numbers were significantly higher in patients taking MMF compared to those on AZA but lower numbers and frequencies of plasmablasts were detected compared to AZA-treated patients or controls. Notably, MMF treatment was associated with a significantly higher frequency and number of transitional B cells as well as naive B cells compared to AZA treatment. Differences in T cell subsets were not significant. MPA abrogated in vitro proliferation of purified B cells completely but had only moderate impact on B cell survival. The thorough inhibition of B cell activation and plasma cell formation by MMF might explain the favorable outcomes of previous clinical trials in patients with SLE, since enhanced B cell proliferation is a hallmark of this disease.


Use of #SaludTues Tweetchats for the Dissemination of Culturally Relevant Information on Latino Health Equity: Exploratory Case Study.
Latinx people comprise 18% of the US adult population and a large share of youth and continue to experience inequities that perpetuate health disparities. To engage Latinx people in advocacy for health equity based on this population's heavy share of smartphone, social media, and Twitter users, Salud America! launched the #SaludTues Tweetchat series. In this paper, we explore the use of #SaludTues to promote advocacy for Latinx health equity. This study aims to understand how #SaludTues Tweetchats are used to promote dissemination of culturally relevant information on social determinants of health, to determine whether tweetchats serve to drive web traffic to the Salud America! website, and to understand who participates in #SaludTues Tweetchats and what we can learn about the participants. We also aim to share our own experiences and present a step-by-step guide of how tweetchats are planned, developed, promoted, and executed. We explored tweetchat data collected between 2014 and 2018 using Symplur and Google Analytics to identify groups of stakeholders and web traffic. Network analysis and mapping tools were also used to derive insights from this series of chats. We conducted 187 chats with 24,609 reported users, 177,466 tweets, and more than 1.87 billion impressions using the hashtag #SaludTues during this span, demonstrating effective dissemination of and exposure to culturally relevant information. Traffic to the Salud America! website was higher on Tuesdays than any other day of the week, suggesting that #SaludTues Tweetchats acted effectively as a website traffic-driving tool. Most participants came from advocacy organizations (165/1000, 16.5%) and other health care-related organizations (162/1000, 16.2%), whereas others were unknown users (147/1000, 14.7%) and individual users outside of the health care sector (117/1000, 11.7%). The majority of participants were located in Texas, California, New York, and Florida, all states with high Latinx populations. Carefully planned, culturally relevant tweetchats such as #SaludTues can be a powerful tool for public health practitioners and advocates to engage audiences on Twitter around health issues, advocacy, and policy solutions for Latino health equity. Further information is needed to determine the effect that #SaludTues Tweetchats have on self- and collective efficacy for advocacy in the area of Latino health equity.


Assessment of time patterns of activity and rest in full-shift recordings of trapezius muscle activity - effects of the data processing procedure.
The purpose of this paper was to compare the effects of different data reduction procedures on the values of variables characterizing the time pattern of trapezius muscle activity during full work shifts. Surface electromyography (EMG) of the right and left upper trapezius muscles were obtained from 40 young subjects in different occupations, mainly electricians, hairdressers and students. The target EMG variables were gap frequency, muscle rest, and the number and duration of episodes with sustained muscle activity (from 0.13s to 30min as minimum duration). These variables were derived from the EMG recordings using different Root Mean Square (RMS) windows (from 0.13 to 6.38s), and discrimination levels between "activity" and "rest" (0.5%, 1% and 2% of maximal EMG). The results give basis for practical suggestions for EMG analyses of full work shifts. For most variables, a discrimination level of 0.5% EMGmax showed to be preferable. The time proportion of muscle rest and sustained muscle activity should, in general, be preferred over the corresponding frequency measures. Sustained muscle activity should be calculated using a RMS window between 1 and 3s, and preferably be stated in terms of variables describing time proportions of activity. Uninterrupted activity episodes longer than 10min proved not to be a useful variable due to limited occurrence in many work shifts.


Release of the rat T cell alloantigen RT-6.2 from cell membranes by phosphatidylinositol-specific phospholipase C.
The mechanism by which the rat T cell alloantigen, RT-6.2, is attached to the membrane was investigated. Treatment of rat lymph node and T-hybridoma cells with phosphatidylinositol-specific phospholipase C (PI-PLC) caused a substantial reduction in the amount of RT-6.2 on the cell surface. No significant release of a rat T helper marker (visualized by the mAb W3/25) was observed in response to PI-PLC treatment. This is in sharp contrast to the effects of trypsin, which removes most of the T helper marker but had little effect on RT-6.2. SDS-PAGE analysis of the RT-6.2 released by PI-PLC indicated that the Mr was not significantly changed by this treatment. Phase separation of the released RT-6.2 in Triton X-114 showed that the PI-PLC had converted it from an amphiphilic membrane form to a water-soluble form, apparently by removing its hydrophobic membrane anchoring domain. These results strongly suggest that RT-6.2, in common with Thy-1 and several other cell surface proteins, is anchored in the membrane by the 1,2-diacylglycerol moiety of a covalently attached phosphatidylinositol molecule.


Defective antigen processing in GILT-free mice.
Processing of proteins for major histocompatibility complex (MHC) class II-restricted presentation to CD4-positive T lymphocytes occurs after they are internalized by antigen-presenting cells (APCs). Antigenic proteins frequently contain disulfide bonds, and their reduction in the endocytic pathway facilitates processing. In humans, a gamma interferon-inducible lysosomal thiol reductase (GILT) is constitutively present in late endocytic compartments of APCs. Here, we identified the mouse homolog of GILT and generated a GILT knockout mouse. GILT facilitated the processing and presentation to antigen-specific T cells of protein antigens containing disulfide bonds. The response to hen egg lysozyme, a model antigen with a compact structure containing four disulfide bonds, was examined in detail.


Isolation of an oxomanganese(V) porphyrin intermediate in the reaction of a manganese(III) porphyrin complex and H2O2 in aqueous solution.
The reaction of [Mn(TF(4)TMAP)](CF(3)SO(3))(5) (TF(4)TMAP=meso-tetrakis(2,3,5,6-tetrafluoro-N,N,N-trimethyl-4-aniliniumyl)porphinato dianion) with H(2)O(2) (2 equiv) at pH 10.5 and 0 degrees C yielded an oxomanganese(V) porphyrin complex 1 in aqueous solution, whereas an oxomanganese(IV) porphyrin complex 2 was generated in the reactions of tert-alkyl hydroperoxides such as tert-butyl hydroperoxide and 2-methyl-1-phenyl-2-propyl hydroperoxide. Complex 1 was capable of epoxidizing olefins and exchanging its oxygen with H(2) (18)O, whereas 2 did not epoxidize olefins. From the reactions of [Mn(TF(4)TMAP)](5+) with various oxidants in the pH range 3-11, the O-O bond cleavage of hydroperoxides was found to be sensitive to the hydroperoxide substituent and the pH of the reaction solution. Whereas the O-O bond of hydroperoxides containing an electron-donating tert-alkyl group is cleaved homolytically, an electron-withdrawing substituent such as an acyl group in m-chloroperoxybenzoic acid (m-CPBA) facilitates O-O bond heterolysis. The mechanism of the O-O bond cleavage of H(2)O(2) depends on the pH of the reaction solution: O-O bond homolysis prevails at low pH and O-O bond heterolysis becomes a predominant pathway at high pH. The effect of pH on (18)O incorporation from H(2) (18)O into oxygenated products was examined over a wide pH range, by carrying out the epoxidation of carbamazepine (CBZ) with [Mn(TF(4)TMAP)](5+) and KHSO(5) in buffered H(2) (18)O solutions. A high proportion of (18)O was incorporated into the CBZ-10,11-oxide product at all pH values but this proportion was not affected significantly by the pH of the reaction solution.