Analysis of activator and repressor functions reveals the requirements for transcriptional control by LuxR, the master regulator of quorum sensing in Vibrio harveyi.
LuxR-type transcription factors are the master regulators of quorum sensing in vibrios. LuxR proteins are unique members of the TetR superfamily of transcription factors because they activate and repress large regulons of genes. Here, we used chromatin immunoprecipitation and nucleotide sequencing (ChIP-seq) to identify LuxR binding sites in the Vibrio harveyi genome. Bioinformatics analyses showed that the LuxR consensus binding site at repressed promoters is a symmetric palindrome, whereas at activated promoters it is asymmetric and contains only half of the palindrome. Using a genetic screen, we isolated LuxR mutants that separated activation and repression functions at representative promoters. These LuxR mutants exhibit sequence-specific DNA binding defects that restrict activation or repression activity to subsets of target promoters. Altering the LuxR DNA binding site sequence to one more closely resembling the ideal LuxR consensus motif can restore in vivo function to a LuxR mutant. This study provides a mechanistic understanding of how a single protein can recognize a variety of binding sites to differentially regulate gene expression. Bacteria use the cell-cell communication process called quorum sensing to regulate collective behaviors. In vibrios, LuxR-type transcription factors control the quorum-sensing gene expression cascade. LuxR-type proteins are structural homologs of TetR-type transcription factors. LuxR proteins were assumed to function analogously to TetR proteins, which typically bind to a single conserved binding site to repress transcription of one or two genes. We find here that unlike TetR proteins, LuxR acts a global regulator, directly binding upstream of and controlling more than 100 genes. Again unlike TetR, LuxR functions as both an activator and a repressor, and these two activities can be separated by mutagenesis. Finally, the consensus binding motifs driving LuxR-activated and -repressed genes are distinct. This work shows that LuxR, although structurally similar to TetR, has evolved unique features enabling it to differentially control a large regulon of genes in response to quorum-sensing cues.


A Systematic IoU-Related Method: Beyond Simplified Regression for Better Localization.
Four-variable-independent-regression localization losses, such as Smooth- l1 Loss, are used by default in modern detectors. Nevertheless, this kind of loss is oversimplified so that it is inconsistent with the final evaluation metric, intersection over union (IoU). Directly employing the standard IoU is also not infeasible, since the constant-zero plateau in the case of non-overlapping boxes and the non-zero gradient at the minimum may make it not trainable. Accordingly, we propose a systematic method to address these problems. Firstly, we propose a new metric, the extended IoU (EIoU), which is well-defined when two boxes are not overlapping and reduced to the standard IoU when overlapping. Secondly, we present the convexification technique (CT) to construct a loss on the basis of EIoU, which can guarantee the gradient at the minimum to be zero. Thirdly, we propose a steady optimization technique (SOT) to make the fractional EIoU loss approaching the minimum more steadily and smoothly. Fourthly, to fully exploit the capability of the EIoU based loss, we introduce an interrelated IoU-predicting head to further boost localization accuracy. With the proposed contributions, the new method incorporated into Faster R-CNN with ResNet50+FPN as the backbone yields 4.2 mAP gain on VOC2007 and 2.3 mAP gain on COCO2017 over the baseline Smooth- l1 Loss, at almost no training and inferencing computational cost. Specifically, the stricter the metric is, the more notable the gain is, improving 8.2 mAP on VOC2007 and 5.4 mAP on COCO2017 at metric AP90 .


Short-term results of our first 49 Scandanavian total ankle replacements (STAR).
Forty-seven consecutive patients treated for ankle arthritis with a Scandinavian total ankle replacement (STAR) by one surgeon were investigated retrospectively. A modification of the Foot Function Index (FFI), which scores pain and task difficulties, was followed prospectively. Patients were assessed clinically and radiologically. Failure was defined as revision of the prosthesis or arthrodesis for any reason. In 47 patients (16 male, 31 female) 49 total ankle replacements were carried out between May 1999 and June 2004. Indication for surgery was end stage arthritis for rheumatoid arthritis in 29 cases, post-traumatic arthritis in 12, osteoarthritis in five and arthritis secondary to degenerative flatfoot in three. Mean followup time was 28 (12 to 67) months. The modified FFI (range, 0 to 100, a high score meaning more pain and disability) improved significantly from 59 before to 35 after surgery. The mean postoperative Kofoed ankle score was 68. Sixteen procedures were complicated by fractures or temporary neurological damage. At the time of followup, 45 prostheses survived, while four replacements had failed. Radiological examination at followup showed radiolucent lines, osteolysis, and malposition of the components in 31 cases. Our results are comparable with those reported in the literature. The clinical outcome improved significantly. Due to aseptic and septic loosening, 8.2% of the prosthesis failed.


Charge-transfer complexes of 4-methylpiperidine with σ- and π-acceptors.
The solid charge-transfer (CT) molecular complexes formed in the reaction of the electron donor 4-methylpiperidine (4MP) with the σ-electron acceptor iodine and π-acceptors 7,7,8,8-tetracyanoquinodimethane (TCNQ), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCHD) have been investigated spectrophotometrically in chloroform at 25 °C. These were characterized through electronic and infrared spectra as well as elemental and thermal analysis. The obtained results showed that the formed solid CT-complexes have the formulas [(4MP) I](+)I(-)3, [(4MP)(DDQ)2] and [(4MP)(TBCHD)] and with TCNQ the adduct [TCMPQDM] is obtained through N-substitution reaction in full agreement with the known reaction stoichiometries in solution as well as the elemental measurements. The formation constant KCT, molar extinction coefficient εCT, free energy change ΔG(0), CT energy ECT and the ionization potential Ip have been calculated for the CT-complexes [(4MP) I](+)I(-)3, [(4MP)(DDQ)2] and [(4MP)(TBCHD)].


Long-term music training tunes how the brain temporally binds signals from multiple senses.
Practicing a musical instrument is a rich multisensory experience involving the integration of visual, auditory, and tactile inputs with motor responses. This combined psychophysics-fMRI study used the musician's brain to investigate how sensory-motor experience molds temporal binding of auditory and visual signals. Behaviorally, musicians exhibited a narrower temporal integration window than nonmusicians for music but not for speech. At the neural level, musicians showed increased audiovisual asynchrony responses and effective connectivity selectively for music in a superior temporal sulcus-premotor-cerebellar circuitry. Critically, the premotor asynchrony effects predicted musicians' perceptual sensitivity to audiovisual asynchrony. Our results suggest that piano practicing fine tunes an internal forward model mapping from action plans of piano playing onto visible finger movements and sounds. This internal forward model furnishes more precise estimates of the relative audiovisual timings and hence, stronger prediction error signals specifically for asynchronous music in a premotor-cerebellar circuitry. Our findings show intimate links between action production and audiovisual temporal binding in perception.


State-of-the-science assessment of non-asbestos amphibole exposure: is there a cancer risk?
The distinction between amphibole asbestos fibers and non-asbestos amphibole particles has important implications for assessing potential cancer risks associated with exposure to amphibole asbestos or amphibole-containing products. Exposure to amphibole asbestos fibers can pose a cancer risk due to its ability to reside for long periods of time in the deep lung (i.e., biopersistence). In contrast, non-asbestos amphibole particles are usually cleared rapidly from the lung and do not pose similar respiratory risks even at high doses. Most regulatory and public health agencies, as well as scientific bodies, agree that non-asbestos amphiboles possess reduced biological (e.g., carcinogenic) activity. Although non-asbestos amphibole minerals have been excluded historically from Federal regulations, non-asbestos structures may be counted as asbestos fibers on the basis of dimensional criteria specified in analytical protocols. Given the potential to mischaracterize a non-asbestos structure as a "true" asbestos fiber, our objective was to assess whether exposure to non-asbestos amphiboles that may meet the dimensional criteria for counting as a fiber pose a cancer risk similar to amphibole asbestos. We reviewed analytical methods as well as the mineralogical, epidemiological, and toxicological literature for non-asbestos amphiboles. No evidence of demonstrable cancer effects from exposure to non-asbestos amphiboles that may be counted as fibers, under certain assessment protocols, was found. Data gaps (industrial hygiene data for amphibole-exposed cohorts), inconsistencies (analytical laboratory methods/protocols used to count fibers), and sources of potential bias from misclassification of exposure were identified.


Neurocognitive predictors of treatment response to randomized treatment in adults with tic disorders.
Tourette's disorder (TS) and chronic tic disorder (CTD) are neurodevelopmental disorders characterized by involuntary vocal and motor tics. Consequently, TS/CTD have been conceptualized as disorders of cognitive and motor inhibitory control. However, most neurocognitive studies have found comparable or superior inhibitory capacity among individuals with TS/CTD relative to healthy controls. These findings have led to the hypothesis that individuals with TS/CTD develop increased inhibitory control due to the constant need to inhibit tics. However, the role of cognitive control in TS/CTD is not yet understood, particularly in adults. To examine the role of inhibitory control in TS/CTD, the present study investigated this association by assessing the relationship between inhibitory control and treatment response in a large sample of adults with TS/CTD. As part of a large randomized trial comparing behavior therapy versus supportive psychotherapy for TS/CTD, a battery of tests, including tests of inhibitory control was administered to 122 adults with TS/CTD at baseline. We assessed the association between neuropsychological test performance and change in symptom severity, as well as compared the performance of treatment responders and non-responders as defined by the Clinical Global Impression Scale. Results indicated that change in symptoms, and treatment response were not associated with neuropsychological performance on tests of inhibitory control, intellectual ability, or motor function, regardless of type of treatment. The finding that significant change in symptom severity of TS/CTD patients is not associated with impairment or change in inhibitory control regardless of treatment type suggests that inhibitory control may not be a clinically relevant facet of these disorders in adults.


Youth smoking and anti-smoking policies in North Dakota: a system dynamics simulation study.
The current study utilizes system dynamics to model the determinants of youth smoking and simulate effects of anti-smoking policies in the context of North Dakota, a state with one of the lowest cigarette tax rates in the USA. An explanatory model was built to replicate historical trends in the youth smoking rate. Three different policies were simulated: 1) an increase in cigarette excise taxes; 2) increased funding for CDC-recommended comprehensive tobacco control programs; and 3) enforcement of increased retailer compliance with age restrictions on cigarette sales. The explanatory model successfully replicated historical trends in adolescent smoking behavior in North Dakota from 1992 to 2014. The policy model showed that increasing taxes to $2.20 per pack starting in 2015 was the most effective of the three policies, producing a 32.6% reduction in youth smoking rate by 2032. Other policies reduced smoking by a much lesser degree (7.0 and 3.2% for comprehensive tobacco control program funding and retailer compliance, respectively). The effects of each policy were additive. System dynamics modeling suggests that increasing cigarette excise taxes are particularly effective at reducing adolescent smoking rates. More generally, system dynamics offers an important complement to conventional analysis of observational data.


WITHDRAWN: Opioids for the palliation of breathlessness in advanced disease and terminal illness.
Breathlessness is a common symptom in people with advanced disease. The most effective treatments are aimed at treating the underlying cause of the breathlessness but this may not be possible and symptomatic treatment is often necessary. Strategies for the symptomatic treatment of breathlessness have never been systematically evaluated. Opioids are commonly used to treat breathlessness: the mechanisms underlying their effectiveness are not completely clear and there have been few good-sized trials in this area. To determine the effectiveness of opioid drugs given by any route in relieving the symptom of breathlessness in patients who are being treated palliatively. An electronic search was carried out of Medline, Embase, CINAHL, T he Cochrane L ibrary, Dissertation Abstracts, Cancercd and SIGLE. Review articles and reference lists of retrieved articles were hand searched. Date of most recent search: May 1999. Randomised double-blind, controlled trials comparing the use of any opioid drug against placebo for the relief of breathlessness were included. Patients with any illness suffering from breathlessness were included and the intervention was any opioid, given by any route, in any dose. Studies identified by the search were imported into a reference manager database. The full texts of the relevant studies were retrieved and data were independently extracted by two review authors. Studies were quality scored according to the Oxford Quality scale. The primary outcome measure used was breathlessness and the secondary outcome measure was exercise tolerance. Studies were divided into non-nebulised and nebulised and were analysed both separately and together. A qualitative analysis was carried out of adverse effects of opioids. Where appropriate, meta-analysis was carried out. Eighteen studies were identified of which nine involved the non-nebulised route of administration and nine the nebulised route. A small but statistically significant positive effect of opioids was seen on breathlessness in the analysis of studies using non-nebulised opioids. There was no statistically significant positive effect seen for exercise tolerance in either group of studies or for breathlessness in the studies using nebulised opioids. There is evidence to support the use of oral or parenteral opioids to palliate breathlessness although numbers of patients involved in the studies were small. No evidence was found to support the use of nebulised opioids. Further research with larger numbers of patients, using standardised protocols and with quality of life measures is needed.


Cultured lymphocytes from autistic children and non-autistic siblings up-regulate heat shock protein RNA in response to thimerosal challenge.
There are reports suggesting that some autistic children are unable to mount an adequate response following exposure to environmental toxins. This potential deficit, coupled with the similarity in clinical presentations of autism and some heavy metal toxicities, has led to the suggestion that heavy metal poisoning might play a role in the etiology of autism in uniquely susceptible individuals. Thimerosal, an anti-microbial preservative previously added routinely to childhood multi-dose vaccines, is composed of 49.6% ethyl mercury. Based on the levels of this toxin that children receive through routine immunization schedules in the first years of life, it has been postulated that thimerosal may be a potential triggering mechanism contributing to autism in susceptible individuals. One potential risk factor in these individuals may be an inability to adequately up-regulate metallothionein (MT) biosynthesis in response to presentation of a heavy metal challenge. To investigate this hypothesis, cultured lymphocytes (obtained from the Autism Genetic Resource Exchange, AGRE) from autistic children and non-autistic siblings were challenged with either 10 microM ethyl mercury, 150 microM zinc, or fresh media (control). Following the challenge, total RNA was extracted and used to query "whole genome" DNA microarrays. Cultured lymphocytes challenged with zinc responded with an impressive up-regulation of MT transcripts (at least nine different MTs were over-expressed) while cells challenged with thimerosal responded by up-regulating numerous heat shock protein transcripts, but not MTs. Although there were no apparent differences between autistic and non-autistic sibling responses in this very small sampling group, the differences in expression profiles between those cells treated with zinc versus thimerosal were dramatic. Determining cellular response, at the level of gene expression, has important implications for the understanding and treatment of conditions that result from exposure to neurotoxic compounds.


Working at home and alcohol use.
Working at home has become a frequent work arrangement following the COVID-19 pandemic. However, little is known about how working at home influence alcohol use among employees. This study examines associations between working at home at least 15 h per week and alcohol consumption using data from a pre-COVID-19 sample. Self-reported questionnaire data on working at home and alcohol use from a large cross-sectional sample of Norwegian employees (N = 14,728). Data were collected between 2004 and 2019 and were analyzed by ordinal logistic regressions. Working at home for >15 h per week was significantly associated with alcohol use (OR 1.67, 95% CI: 1.30 - 2.16). The association remained significant after adjusting for age, gender, leadership position, and educational level. Working at home may facilitate alcohol use that otherwise would not happen. Organizations must ensure that policies and procedures are in place to prevent alcohol use during working hours among employees working at home.


Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII.
2B1 is a bispecific murine monoclonal antibody (BsMAb) with specificity for the c-erbB-2 and Fc gamma RIII extracellular domains. This BsMAb promotes the targeted lysis of malignant cells overexpressing the c-erbB-2 gene product of the HER2/neu proto-oncogene by human natural killer cells and mononuclear phagocytes expressing the Fc gamma RIII A isoform. In a Phase I clinical trial of 2B1, 15 patients with c-erbB-2-overexpressing tumors were treated with 1 h i.v. infusions of 2B1 on days 1, 4, 5, 6, 7, and 8 of a single course of treatment. Three patients were treated with daily doses of 1.0 mg/m2, while six patients each were treated with 2.5 mg/m2 and 5.0 mg/m2, respectively. The principal non-dose-limiting transient toxicities were fevers, rigors, nausea, vomiting, and leukopenia. Thrombocytopenia was dose limiting at the 5.0 mg/m2 dose level in two patients who had received extensive prior myelosuppressive chemotherapy. Murine antibody was detectable in serum following 2B1 administration, and its bispecific binding properties were retained. The pharmacokinetics of this murine antibody were variable and best described by nonlinear kinetics with an average t 1/2 of 20 h. Murine antibody bound extensively to all neutrophils and to a proportion of monocytes and lymphocytes. The initial 2B1 treatment induced more than 100-fold increases in circulating levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 8 and lesser rises in granulocyte-monocyte colony-stimulating factor and IFN-gamma. Brisk human anti-mouse antibody responses were induced in 14 of 15 patients. Several minor clinical responses were observed, with reductions in the thickness of chest wall disease in one patient with disseminated breast cancer. Resolution of pleural effusions and ascites, respectively, were noted in two patients with metastatic colon cancer, and one of two liver metastases resolved in a patient with metastatic colon cancer. Treatment with 2B1 BsMAb has potent immunological consequences. The maximum tolerated dose and Phase II daily dose for patients with extensive prior myelosuppressive chemotherapy was 2.5 mg/m2. Continued dose escalation is required to identify the maximally tolerated dose for patients who have been less heavily pretreated.


Synthesis and antibody-mediated detection of oligonucleotides containing multiple 2,4-dinitrophenyl reporter groups.
A series of non-nucleoside-based 2,4-dinitrophenyl (DNP) phosphoramidites have been prepared and used in the multiple labelling of oligonucleotides during solid-phase synthesis. The length of spacer arm between the DNP label and the oligonucleotide phosphate backbone, and the number of attached DNP groups have both been varied in order to determine the optimum conditions for anti-DNP antibody binding. Detection using enzyme-linked colorimetric techniques showed sensitivity equivalent to that obtainable using biotinylated oligonucleotides.


Lifelong curiosity: Frederick Novy and the rat virus.
Frederick Novy (1864-1957) was a U.S. physician, medical researcher, and influential microbiologist of the early 20th century who devised culture techniques to visualize anaerobic bacteria, parasites, and spirochetes. In 1909 he began to investigate the cause of unexplained deaths in his laboratory rats, which he hypothesized were due to an "ultramicroscopic organism" or "filterable virus." But in 1918, the test tubes he had been using for these experiments vanished from his laboratory. His dream of finding a virus as the likely cause of the mysterious deaths of his rats apparently was lost. Novy retired in 1935. Thirty-three years later, in 1951, a box containing the test tubes was discovered by chance during clean-up in preparation for a laboratory move. Novy's curiosity had not waned with time. Notified of the find, and 16 years into his retirement, he returned to his laboratory at the age of 88 to continue the experiments that he had begun more than 40 years earlier. He completed his investigations in 1953 and published his findings that a virus was indeed the unidentified organism that had swiftly killed his laboratory rats in 1909.


Visual responses of single neurons in the caudal lateral pulvinar of the macaque monkey.
Single unit recordings were made in the portion of the lateral pulvinar which forms the lateral aspect of the caudal pole of the thalamus, i.e., PL gamma (Rezak, M., and L. A. Benevento (1977) Soc. Neurosci. Abstr. 3:573; Rezak, M. (1978) Soc. Neurosci. Abstr. 4: 642), of macaque monkeys. PL gamma receives convergent inputs from the occipital cortex and has strong reciprocal interconnections with the visual association cortex, including the inferotemporal cortex (areas 20 and 21). It was found the that PL gamma has a poor or nonexistent retinotopic organization. Many of the neurons had large, unflanked, overlapping receptive fields which often included the fovea. A few neurons could be influenced by a visual stimulus placed anywhere in the visual field described by a tangent screen. The receptive fields could be bilateral or located entirely within the contralateral or ipsilateral hemifields. The majority of units were binocular and exhibited various types of binocular interaction which could be quite complex. The binocular response was not predictable from the algebraic sum of the monocular responses and could be of the opposite sign (e.g., excitatory when the monocular response was inhibitory). Neurons which were also sensitive to the direction of movement of stimuli projected upon the tangent screen formed a major group. Of the units sensitive to tangentially moving stimuli, two special subgroups were found. One group of neurons gave sustained responses to static levels of luminance, while the other group was sensitive to simuli which moved toward or away from the eyes. The nonlinear rate of change of the apparent size of approaching or receding stimuli was described by a mathematical function which also describes the response of the neurons to the same stimuli. For many of these units which were sensitive to tangentially moving stimuli and one other class of stimuli, such as luminance levels of movement in depth, the responses to one class were seemingly unrelated to the responses to the other class. The same statement may be made for monocular and binocular responses. It may be, then, that different wiring diagrams describe these different types of inputs. These physiological results are discussed in terms of the inputs to PL gamma as well as its cortical targets.


Light exposure among adolescents with delayed sleep phase disorder: a prospective cohort study.
The objective of this study was to compare light exposure and sleep parameters between adolescents with delayed sleep phase disorder (DSPD; n=16, 15.3±1.8 yrs) and unaffected controls (n=22, 13.7±2.4 yrs) using a prospective cohort design. Participants wore wrist actigraphs with photosensors for 14 days. Mean hourly lux levels from 20:00 to 05:00 h and 05:00 to 14:00 h were examined, in addition to the 9-h intervals prior to sleep onset and after sleep offset. Sleep parameters were compared separately, and were also included as covariates within models that analyzed associations with specified light intervals. Additional covariates included group and school night status. Adolescent delayed sleep phase subjects received more evening (p< .02, 22:00-02:00 h) and less morning (p .05, 08:00-09:00 h and 10:00-12:00 h) light than controls, but had less pre-sleep exposure with adjustments for the time of sleep onset (p< .03, 5-7 h prior to onset hour). No differences were identified with respect to the sleep offset interval. Increased total sleep time and later sleep offset times were associated with decreased evening (p< .001 and p= .02, respectively) and morning (p= .01 and p< .001, respectively) light exposure, and later sleep onset times were associated with increased evening exposure (p< .001). Increased total sleep time also correlated with increased exposure during the 9 h before sleep onset (p= .01), and a later sleep onset time corresponded with decreased light exposure during the same interval (p< .001). Outcomes persisted regardless of school night status. In conclusion, light exposure interpretation requires adjustments for sleep timing among adolescents with DSPD. Pre- and post-sleep light exposures do not appear to contribute directly to phase delays. Sensitivity to morning light may be reduced among adolescents with DSPD.


Functional outcomes in the Cleft Care UK study--Part 3: oral health and audiology.
To compare oral health and hearing outcomes from the Clinical Standards Advisory Group (CSAG, 1998) and the Cleft Care UK (CCUK, 2013) studies. Two UK-based cross-sectional studies of 5-year-olds born with non-syndromic unilateral cleft lip and palate undertaken 15 years apart. CSAG children were treated in a dispersed model of care with low-volume operators. CCUK children were treated in a centralized, high volume operator system. Oral health data were collected using a standardized proforma. Hearing was assessed using pure tone audiometry and middle ear status by otoscopy and tympanometry. ENT and hearing history were collected from medical notes and parental report. Oral health was assessed in 264 of 268 children (98.5%). The mean dmft was 2.3, 48% were caries free, and 44.7% had untreated caries. There was no evidence this had changed since the CSAG survey. Oral hygiene was generally good, 96% were enrolled with a dentist. Audiology was assessed in 227 of 268 children (84.7%). Forty-three per cent of children received at least one set of grommets--a 17.6% reduction compared to CSAG. Abnormal middle ear status was apparent in 50.7% of children. There was no change in hearing levels, but more children with hearing loss were managed with hearing aids. Outcomes for dental caries and hearing were no better in CCUK than in CSAG, although there was reduced use of grommets and increased use of hearing aids. The service specifications and recommendations should be scrutinized and implemented.


Resurfacing shoulder arthroplasty for the treatment of severe rheumatoid arthritis: outcome in 167 patients from the Danish Shoulder Registry.
There is no consensus on which type of shoulder prosthesis should be used in patients with rheumatoid arthritis (RA). We describe patients with RA who were treated with shoulder replacement, regarding patient-reported outcome, prosthesis survival, and causes of revision, and we compare outcome after resurfacing hemi-arthroplasty (RHA) and stemmed hemi-arthroplasty (SHA). We used data from the national Danish Shoulder Arthroplasty Registry and included patients with RA who underwent shoulder arthroplasty in Denmark between 2006 and 2010. Patient-reported outcome was obtained 1-year postoperatively using the Western Ontario Osteoarthritis of the Shoulder index (WOOS), and rates of revision were calculated by checking revisions reported until December 2011. The patient-reported outcome of RHA was compared to that of SHA using regression analysis with adjustment for age, sex, and previous surgery. During the study period, 167 patients underwent shoulder arthroplasty because of rheumatoid arthritis, 80 (48%) of whom received RHA and 34 (26%) of whom received SHA. 16 patients were treated with total stemmed shoulder arthroplasty (TSA), and 24 were treated with reverse shoulder arthroplasty (rTSA). 130 patients returned a completed questionnaire, and the total mean WOOS score was 63. The cumulative 5-year revision rate was 7%. Most revisions occurred after RHA, with a revision rate of 14%. Mean WOOS score was similar for RHA and for SHA. This study shows that shoulder arthroplasty, regardless of design, is a good option in terms of reducing pain and improving function in RA patients. The high revision rate in the RHA group suggests that other designs may offer better implant survival. However, this should be confirmed in larger studies.


The mean and the individual: integrating variable-centered and person-centered analyses of cognitive recovery in patients with substance use disorders.
Neuropsychological and cognitive deficits are observed in the majority of persons with alcohol and drug use disorders and may interfere with treatment processes and outcomes. Although, on average, the brain and cognition improve with abstinence or markedly reduced substance use, better understanding of the heterogeneity in the time-course and extent of cognitive recovery at the individual level is useful to promote bench-to-bedside translation and inform clinical decision making. This study integrated a variable-centered and a person-centered approach to characterize diversity in cognitive recovery in 197 patients in treatment for a substance use disorder. We assessed executive function, verbal ability, memory, and complex information processing speed at treatment entry, and then 6, 26, and 52 weeks later. Structural equation modeling was used to define underlying ability constructs and determine the mean level of cognitive changes in the sample while minimizing measurement error and practice effects on specific tests. Individual-level empirical growth plots of latent factor scores were used to explore prototypical trajectories of cognitive change. At the level of the mean, small to medium effect size gains in cognitive abilities were observed over 1 year. At the level of the individual, the mean trajectory of change was also the modal individual recovery trajectory shown by about half the sample. Other prototypical cognitive change trajectories observed in all four cognitive domains included Delayed Gain, Loss of Gain, and Continuous Gain. Together these trajectories encompassed between 86 and 94% of individual growth plots across the four latent abilities. Further research is needed to replicate and predict trajectory membership. Replication of the present findings would have useful implications for targeted treatment planning and the new cognitive interventions being developed to enhance treatment outcomes.


MK-0626, a dipeptidyl peptidase-4 inhibitor, improves neovascularization by increasing both the number of circulating endothelial progenitor cells and endothelial nitric oxide synthetase expression.
Current treatment modalities for critical limb ischemia (CLI) are of limited benefit; therefore, advances in therapeutic vasculogenesis may open an important new avenue for the treatment of CLI. This study examines the therapeutic potential of the DPP-4 inhibitor MK-0626 as a regulator of vasculogenesis in vivo. MK-0626 was administered daily to C57CL/B6 mice and eGFP-labeled bone marrow-transplanted ICR mice that had undergone hind limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neo-vasculogenesis and the number of circulating endothelial progenitor cells (EPCs), respectively. Cell surface markers of EPCs and the level of endothelial nitric oxide synthase (eNOS) were studied in the vessels. Mice that received MK-0626 had an elevated level of glucagon- like peptide-1 (GLP-1) and a decreased level of dipeptidyl peptidase-4 (DPP-4) in their plasma, in addition to an ischemia-induced increase in the level of stromal cell-derived factor-1 (SDF-1). In C57CL/B6 mice, blood flow in the ischemic limb was significantly improved by treatment with MK-0626. The number of circulating EPCs and both the synthesis and phosphorylation of eNOS were also increased in ischemic thigh muscle after MK-0626 treatment. In contrast, similar effects of MK-0626 were not observed in B6.129P2-Nos3(tm1Unc)/J mice (an eNOS knockout mouse). Additionally, MK-0626 treatment promoted the mobilization and homing of EPCs to ischemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mice. We conclude that both the number of circulating EPCs and neo-vasculogenesis are increased in response to DPP-4 inhibitor treatment and that this occurs via an eNOS-dependent mechanism. The results highlight the therapeutic vasculogenesis potential of the DPP-4 inhibitor MK-0626 using a hind limb ischemia mouse model.


Carriers of autosomal recessive conditions: are they really 'unaffected?'
Mendel's Law of Dominance suggests that recessive disease expression requires the inheritance of two mutated alleles as the dominant, wildtype allele suppresses disease presentation leading to the expression of physiological normal phenotypes. However, there is existing evidence that challenges this school of thought. Here, we summarise existing literature evaluating metabolic and health impacts among carriers of autosomal recessive conditions, focusing on phenylketonuria (PKU), classical homocystinuria, galactosemia and Usher syndrome as examples. Our findings suggest that carriers, often described as 'unaffected', may actually display attenuated symptoms for the recessive disease they are carrying. For instance, PKU is an inborn error of metabolism characterised by the build-up of plasma phenylalanine attributed to the deficiency of the phenylalanine hydroxylase (PAH) enzyme. While less severe, PKU carriers also exhibit this impaired enzymatic activity, leading to elevated plasma phenylalanine levels, especially after phenylalanine consumption. Related to these metabolic alterations in the PAH pathway, there is early evidence to suggest that PKU carriers may have compromised cognitive and mental health outcomes. Overall, research on the health and metabolic impacts of PKU carriers is sparse, with most studies conducted several decades ago. However, early evidence suggests that intermediate phenotypes among carriers of autosomal recessive conditions are plausible. The illustrated possible intermediate phenotypes observed among carriers necessitates future research to determine possible clinical implications among this population.


Effects of information framing on human papillomavirus vaccination.
In June 2006, the first vaccine to prevent human papillomavirus (HPV) transmission was approved for use in females in the United States. Because the vaccine was approved for females as young as 9, its success depends on parents' and individuals' willingness to accept vaccination. Little is known about how attitudes toward this vaccine will be influenced by the way the vaccine is portrayed in the media or in public debate. To assess the effects of information framing on intentions to vaccinate self or female children, if appropriate, 635 adults read one of three short descriptive paragraphs about the vaccine, each of which emphasized a different aspect of the vaccine. Participants were then asked about their intentions to vaccinate under cost or no-cost conditions. Women who read that the vaccine protects only against cervical cancer had significantly higher intentions to vaccinate themselves when the vaccine was available at little or no cost compared with women who read alternate versions of the descriptive paragraph, F(2,325) = 5.74, p = 0.004. How the HPV vaccine is framed may affect vaccination intentions under certain conditions. Women may be more receptive to the vaccine if it is framed as a cervical cancer prevention tool rather than a sexually transmitted infection (STI) prevention tool.


GABA receptors inhibited by benzodiazepines mediate fast inhibitory transmission in the central amygdala.
The amygdala is intimately involved in emotional behavior, and its role in the generation of anxiety and conditioned fear is well known. Benzodiazepines, which are commonly used for the relief of anxiety, are thought to act by enhancing the action of the inhibitory transmitter GABA. We have examined the properties of GABA-mediated inhibition in the amygdala. Whole-cell recordings were made from neurons in the lateral division of the central amygdala. Application of GABA evoked a current that reversed at the chloride equilibrium potential. Application of the GABA antagonists bicuculline or SR95531 inhibited the GABA-evoked current in a manner consistent with two binding sites. Stimulation of afferents to neurons in the central amygdala evoked an IPSC that was mediated by the release of GABA. The GABA(A) receptor antagonists bicuculline and picrotoxin failed to completely block the IPSC. The bicuculline-resistant IPSC was chloride-selective and was unaffected by GABA(B)-receptor antagonists. Furthermore, this current was insensitive to modulation by general anesthetics or barbiturates. In contrast to their actions at GABA(A) receptors, diazepam and flurazepam inhibited the bicuculline-resistant IPSC in a concentration-dependent manner. These effects were fully antagonized by the benzodiazepine site antagonist Ro15-1788. We conclude that a new type of ionotropic GABA receptor mediates fast inhibitory transmission in the central amygdala. This receptor may be a potential target for the development of new therapeutic strategies for anxiety disorders.


Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma.
Occasionally, patients with hepatocellular carcinoma (HCC) who receive radioembolization with palliative intent are downstaged for radical treatments. The aim of this study was to describe and analyze the overall survival (OS) in these patients compared with patients of the same baseline stage (UNOS T3), who were not eligible for radical treatment after radioembolization. Between September 2003 and August 2010, 118 patients with HCC received radioembolization with yttrium-90 ((90)Y) resin microspheres. Of these, 21 patients with UNOS T3 stage were retrospectively identified and included in this analysis. In total, 6 of 21 patients were downstaged and treated radically between 2 and 35 months post-radioembolization. Three patients were resected, 2 received liver transplantation and 1 was ablated and then resected. Patients treated radically were significantly younger (62 vs. 73 years, p = 0.006) and had higher tumor volume (583 mL vs. 137 mL, p = 0.001) than patients who did not achieve radical treatment. There were no differences between the groups in number of lesions, BCLC stage, previous cirrhosis, activity administered per tumor volume, or median levels of alpha-fetoprotein or total bilirubin. Across the whole series, the median OS was 27.0 months (95% CI 5.0-48.9), varying significantly between those treated radically (OS not reached after a median follow-up of 41.5 months since radical therapy) and those who received palliative treatment only (22.0 months; 95% CI 15.0-30.9). Radical therapy following tumor downstaging with radioembolization provides the possibility of long-term survival in a select subgroup (UNOS T3 stage) with otherwise limited options.


Cytosolic phosphorylation of calnexin controls intracellular Ca(2+) oscillations via an interaction with SERCA2b.
Calreticulin (CRT) and calnexin (CLNX) are lectin chaperones that participate in protein folding in the endoplasmic reticulum (ER). CRT is a soluble ER lumenal protein, whereas CLNX is a transmembrane protein with a cytosolic domain that contains two consensus motifs for protein kinase (PK) C/proline- directed kinase (PDK) phosphorylation. Using confocal Ca(2+) imaging in Xenopus oocytes, we report here that coexpression of CLNX with sarco endoplasmic reticulum calcium ATPase (SERCA) 2b results in inhibition of intracellular Ca(2+) oscillations, suggesting a functional inhibition of the pump. By site-directed mutagenesis, we demonstrate that this interaction is regulated by a COOH-terminal serine residue (S562) in CLNX. Furthermore, inositol 1,4,5-trisphosphate- mediated Ca(2+) release results in a dephosphorylation of this residue. We also demonstrate by coimmunoprecipitation that CLNX physically interacts with the COOH terminus of SERCA2b and that after dephosphorylation treatment, this interaction is significantly reduced. Together, our results suggest that CRT is uniquely regulated by ER lumenal conditions, whereas CLNX is, in addition, regulated by the phosphorylation status of its cytosolic domain. The S562 residue in CLNX acts as a molecular switch that regulates the interaction of the chaperone with SERCA2b, thereby affecting Ca(2+) signaling and controlling Ca(2+)-sensitive chaperone functions in the ER.


Environmental marine pathogen isolation using mesocosm culture of sharpsnout seabream: striking genomic and morphological features of novel Endozoicomonas sp.
Aquaculture is a burgeoning industry, requiring diversification into new farmed species, which are often at risk from infectious disease. We used a mesocosm technique to investigate the susceptibility of sharpsnout seabream (Diplodus puntazzo) larvae to potential environmental pathogens in seawater compared to control borehole water. Fish exposed to seawater succumbed to epitheliocystis from 21 days post hatching, causing mortality in a quarter of the hosts. The pathogen responsible was not chlamydial, as is often found in epitheliocystis, but a novel species of the γ-proteobacterial genus Endozoicomonas. Detailed characterisation of this pathogen within the infectious lesions using high resolution fluorescent and electron microscopy showed densely packed rod shaped bacteria. A draft genome sequence of this uncultured bacterium was obtained from preserved material. Comparison with the genome of the Endozoicomonas elysicola type strain shows that the genome of Ca. Endozoicomonas cretensis is undergoing decay through loss of functional genes and insertion sequence expansion, often indicative of adaptation to a new niche or restriction to an alternative lifestyle. These results demonstrate the advantage of mesocosm studies for investigating the effect of environmental bacteria on susceptible hosts and provide an important insight into the genome dynamics of a novel fish pathogen.


Neural Correlates of Auditory Figure-Ground Segregation Based on Temporal Coherence.
To make sense of natural acoustic environments, listeners must parse complex mixtures of sounds that vary in frequency, space, and time. Emerging work suggests that, in addition to the well-studied spectral cues for segregation, sensitivity to temporal coherence-the coincidence of sound elements in and across time-is also critical for the perceptual organization of acoustic scenes. Here, we examine pre-attentive, stimulus-driven neural processes underlying auditory figure-ground segregation using stimuli that capture the challenges of listening in complex scenes where segregation cannot be achieved based on spectral cues alone. Signals ("stochastic figure-ground": SFG) comprised a sequence of brief broadband chords containing random pure tone components that vary from 1 chord to another. Occasional tone repetitions across chords are perceived as "figures" popping out of a stochastic "ground." Magnetoencephalography (MEG) measurement in naïve, distracted, human subjects revealed robust evoked responses, commencing from about 150 ms after figure onset that reflect the emergence of the "figure" from the randomly varying "ground." Neural sources underlying this bottom-up driven figure-ground segregation were localized to planum temporale, and the intraparietal sulcus, demonstrating that this area, outside the "classic" auditory system, is also involved in the early stages of auditory scene analysis."


Apollo 11 soil mechanics investigation.
The fine-grained surface material at the Apollo 11 landing site is a brownish, medium-gray, slightly cohesive granular soil, with bulky grains in the silt-to-fine-sand range, having a specific gravity of 3.1 and exhibiting adhesive characteristics. Within the upper few centimeters, the lunar soil has an average density of about 1.6 grams per cubic centimeter and is similar in appearance and behavior to the soils studied at the Surveyor equatorial landing sites. Althouglh considerably different in composition and in range of particle shapes, it is similar in its mechanical behavior to terrestrial soils of the same grain size distribution.


Impaired cerebrovascular reactivity may predict delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.
Delayed cerebral ischemia (DCI) is a major cause of disability and death after aneurysmal subarachnoid hemorrhage. The literature suggests that impaired cerebrovascular reactivity (CVR) may be a predictor for DCI; still no CVR based prediction model has been developed. Increased knowledge about possible predictors of DCI can improve patient management in high-risk patients and allow for shorter hospital stay in low-risk patients. CVR was examined in 42 patients with aneurysmal subarachnoid hemorrhage and 37 patients treated for unruptured intracranial aneurysm, using acetazolamide test with transcranial Doppler monitoring of blood flow velocities. Patients were followed for development of DCI, separated into clinical deterioration and radiographic infarction. For all patients, regardless of aneurysm rupture status, CVR was on average 5.5 percentage points lower on the ipsilateral side of aneurysm treatment. Patients with clinical deterioration due to DCI had lower CVR than patients without DCI, and the difference was larger on the contralateral side (33.9% vs. 49.2%). Two prediction models were constructed for clinical deterioration due to DCI. The area under the receiver operating characteristic curve was 0.82 in the model using established predictors, and 0.86 in the model that also included CVR. Our findings support the hypothesis that impaired CVR may be an independent predictor of clinical deterioration due to DCI, and may assist in identifying patients at risk after aneurysmal subarachnoid hemorrhage. Ipsilateral CVR reduction occurs in all patients after aneurysm treatment, regardless of DCI development, thus highlighting the need to evaluate ipsi- and contralateral CVR separately.


Cholinergic modulation of intrinsic fibre-evoked excitatory transmission contains a nicotinic component in immature but not adult rat piriform cortex, in vitro.
The piriform cortex (PC) is highly prone to epileptogenesis, particularly in immature animals, where decreased muscarinic modulation of PC intrinsic fibre excitatory neurotransmission is implicated as a likely cause. However, whether higher levels of acetylcholine (ACh) release occur in immature vs. adult PC remains unclear. We investigated this using in vitro extracellular electrophysiological recording techniques. Intrinsic fibre-evoked extracellular field potentials (EFPs) were recorded from layers II to III in PC brain slices prepared from immature (P14-18) and adult (P>40) rats. Adult and immature PC EFPs were suppressed by eserine (1 microM) or neostigmine (1 microM) application, with a greater suppression in immature (approximately 40%) than adult (approximately 30%) slices. Subsequent application of atropine (1 microM) reversed EFP suppression, producing supranormal (approximately 12%) recovery in adult slices, suggesting that suppression was solely muscarinic ACh receptor-mediated and that some 'basal' cholinergic 'tone' was present. Conversely, atropine only partially reversed anticholinesterase effects in immature slices, suggesting the presence of additional non-muscarinic modulation. Accordingly, nicotine (50 microM) caused immature field suppression (approximately 30%) that was further enhanced by neostigmine, whereas it had no effect on adult EFPs. Unlike atropine, nicotinic antagonists, mecamylamine and methyllycaconitine, induced immature supranormal field recovery (approximately 20%) following anticholinesterase-induced suppression (with no effect on adult slices), confirming that basal cholinergic 'tone' was also present. We suggest that nicotinic inhibitory cholinergic modulation occurs in the immature rat PC intrinsic excitatory fibre system, possibly to complement the existing, weak muscarinic modulation, and could be another important developmentally regulated system governing immature PC susceptibility towards epileptogenesis.


Cord blood IGF-1 and IGFBP-3 levels in asphyxiated term newborns.
Determination and pathogenesis of perinatal asphyxia is still an important problem. During the asphyxial insult and recovery phase, alteration of the growth factors has been demonstrated and there is evidence that expression of insulin-like growth factors (IGF) and their insulin-like growth factor binding proteins (IGFBP) in injured sites in experimental studies. Aim of this study was to evaluate relationship between serum IGF-1, IGFBP-3 levels and perinatal asphyxia. 18 term-newborn who defined as perinatal asphyxia and 12 term-healthy newborn were enrolled. Umbilical cord IGF-1 and IGFBP-3 levels were detected and searched correlation with apgar scores and umbilical artery gas analysis as pH, pC02, pO2, base excess, HCO3, ctO2, SO2 and lactate levels. Cord blood IGF-1 and IGFBP-3 levels for asphyxiated newborns were lower than normal group (27.8+/-2.6 ng/ml, 55.1+/-2.8 ng/ml respectively, p<0.01 for IGF-1; 1107.7+/-320.4, 1682.5+/-364.1, p<0.001 for IGFBP-3). Cord blood IGF-1 levels were positively correlated with birth weight; first and 5th minute Apgar score, cord blood arterial pH, ABE, HCO3, SO2 levels. Cord blood IGFBP-3 levels were positively correlated with first and 5th minutes Apgar scores, cord blood arterial pH, pCO2, ABE, HCO3, sO2, and also negatively correlated with cord CO2 and cord lactate levels. Our study demonstrates that exposure to hypoxia and acidosis at birth strongly correlated with a fall in IGF-1 and IGFBP-3 levels in cord blood.


Niabella yanshanensis sp. nov., isolated from the soybean rhizosphere.
An orange-coloured bacterium, CCBAU 05354(T), was isolated from the soybean rhizosphere following growth on NA medium. The sample was taken from a field in Hebei province, People's Republic of China. The cells were aerobic, Gram-stain-negative, short rods (0.4-0.6 x 0.7-1.7 microm) and non-motile. Growth occurred at 28 degrees C (not at 10 or 37 degrees C), pH 6.0-10.0, and in the presence of 0-1 % NaCl (w/v). Flexirubin pigment was produced and the cells were resistant to some antibiotics. A phylogenetic analysis based on 16S rRNA gene sequences indicated that strain CCBAU 05354(T) was closely related to Niabella soli KACC 12604(T) (95.1 % sequence similarity). The predominant cellular fatty acids were iso-C(15 : 0), iso-C(15 : 1) G, iso-C(17 : 0) 3-OH and summed feature 3 (comprising C(16 : 1)omega7c and/or C(16 : 1)omega6c). The DNA G+C content was 42 mol%. On the basis of the phylogenetic, phenotypic and chemotaxonomic data, strain CCBAU 05354(T) represents a novel species of the genus Niabella, for which the name Niabella yanshanensis sp. nov. is proposed. The type strain is CCBAU 05354(T) (=LMG 24661(T) =HAMBI 3031(T)).


The role of cerebral cortex in the generation of voluntary saccades: a positron emission tomographic study.
The purpose of this study was to define the location and behavior of cerebral structures within the normal human brain that participate in the generation of voluntary saccadic eye movements. Changes in regional cerebral blood flow (rCBF) during task performance were assumed to reflect like changes in regional neuronal activity induced by the task. The locations of all rCBF changes were described in stereotaxic coordinates. Cerebral blood flow (CBF) was measured with positron emission tomography (PET) and bolus intravenous injection of H2(15)O. The use of H2(15)O with PET allowed six, seven-slice measurements of brain blood flow to be made in rapid sequence for each subject, without removing the subject from the tomograph between scans. Nine paid normal volunteers were studied. The paradigm included three saccadic eye-movement (SEM) conditions, one finger-movement condition and two control conditions (initial and final). The three SEM conditions allowed comparisons to be drawn between targeted versus untargeted SEMs, auditorily cued versus visually cued SEMs, and stochastic versus rhythmic SEMs. All tasks were simple and deterministic in that each movement exactly mirrored the preceding movement: finger flexion then extension, saccade-left then saccade-right. Saccadic eye movements were associated with rCBF increases within the frontal eye fields, the supplementary motor area, and the cerebellum. Finger movements were associated with rCBF changes within the sensorimotor hand areas, the supplementary motor area, and the cerebellum. The frontal eye fields were discrete cortical regions consistently active during the generation of voluntary SEMs and uninfluenced by target presence, type of cue, or task complexity, indicating a predominantly motor function. The supplementary motor area (SMA) was consistently active during all motor tasks and was uninfluenced by the degree of task complexity or stochasticity. A role for SMA in establishing "motor set" during both simple and complex motor tasks is suggested. An anterior-posterior somatotopy was found for SMA-eye (anterior) versus SMA-hand (posterior). Lateral occipital visual association cortex activation was present only during targeted saccadic conditions.(ABSTRACT TRUNCATED AT 400 WORDS)


Macromolecular synthesis in Streptomyces antibioticus: in vitro systems for aminoacylation and translation from young and old cells.
In vitro systems for the aminoacylation of transfer ribonucleic acid (tRNA) and for polypeptide synthesis have been constructed from young (12-h cultures, not producing actinomycin) and old (48-h cultures, producing actinomycin) cells of Streptomyces antibioticus. When Escherichia coli aminoacyl-tRNA synthetases were used to acylate S. antibioticus tRNA's, it was observed that, per absorbance unit of tRNA, the tRNA's from 48-h cells had a lower ability to accept the amino acids, leucine, serine, pheynlalanine, methionine, and valine than did the tRNA's from 12-h cells. Individual differences were observed between aminoacyl-tRNA synthetases from 12-h cells and those from 48-h cells with respect to the rate and extent of aminoacylation of E. coli tRNA with the five amino acids listed above. In vitro systems for the synthesis of polyphenylalanine have been constructed from 12- and 48-h cells. Ribsomes and soluble enzymes from 12-h cells are more efficient than those from 48-h cells in supporting polyphenylalanine synthesis, and, although the activity of both systems can be stimulated by the addition of E. coli tRNA, the higher level of incorporation observed in the unstimulated 12-h system (ribosomes and soluble enzymes) is maintained. Indeed, the difference in capacity for polyphenylalanine synthesis between in vitro systems from 12- and 48-h cells is greater when the systems are maximally stimulated by E. coli tRNA. Cross-mixing experiments reveal that enzymes from 48-h cells support a slightly higher level of polyphenylalanine synthesis than enzymes from 12-h cells with ribosomes from either cell type, and that the ribosomes are the primary agents responsible for the decreased efficiency of the in vito system from 48-h cells are compared with that from 12-h cells. To determine whether ribosome-associated factors were responsible for the relative inefficiency of the ribosomes from 48-h cells in translation, salt-washed ribosomes from 12- and 48-h cells were examined for their abilities to catalyze polyphenylalanine synthesis. Even after salt washing, ribosomes from 12-h cells were about five times higher in specific activity (counts per minute of polyphenylalanine synthesized per absorbance at 260 nm of ribosomes) than equivalent amounts of ribosomes from 48-h cells. Analysis of the proteins of salt-washed ribosomes of the two cell types by acrylamide gel electrophoresis suggests that the relative amounts of individual proteins present on ribosomes from 12-h cells are different from the amounts present on ribosomes from 48-h cells. These results are discussed in terms of the regulation of translation in S. antibioticus.


Stimulation of β₂-adrenergic receptors inhibits calcineurin activity in CD4(+) T cells via PKA-AKAP interaction.
The sympathetic nervous system (SNS) is able to modulate immune functions via adrenoceptor-dependent mechanisms. Activation of β₂-adrenergic receptors (AR) on CD4(+) T lymphocytes has been shown to inhibit Th1-cytokine production and cell proliferation. Here, we investigated the role of the calcium/calmodulin-dependent protein phosphatase calcineurin (CaN), a key element of the T cell receptor (TCR)-signaling pathway, in β₂-AR-mediated suppression of T cell function. Purified rat splenic CD4(+) T cells were stimulated with anti-CD3/anti-CD28 in presence or absence of the β₂-AR agonist terbutaline (TERB). Treatment with TERB induced a dose-dependent inhibition of cellular CaN activity, along with a reduction in IL-2 and IFN-γ production, and T cell proliferation. Co-administration of the β-AR antagonist nadolol abolished these effects. Blockade of the cAMP-dependent protein kinase A (PKA) with the inhibitor H-89 completely prevented TERB-induced CaN inhibition. However, a receptor-independent rise in the second messenger cAMP was not sufficient to suppress CaN activity. Disruption of the interaction between PKA and A-kinase anchoring protein (AKAP) by the inhibitor peptide St-Ht31 fully blocked TERB-induced CaN inhibition, demonstrating that PKA-AKAP interaction is essential for the β₂-AR-mediated CaN inhibition. Taken together, this study provides evidence for a link between the β₂-AR and TCR signaling pathways since expression of IL-2 and IFN-γ in activated T cells largely depends on dephosphorylation of the transcription factor NFAT by CaN, and identifies a novel intracellular mechanism that can lead to downregulation of T cell function after SNS activation.


Noninvasive red and near-infrared wavelength-induced photobiomodulation: promoting impaired cutaneous wound healing.
The innumerable intricacies associated with chronic wounds have made the development of new painless, noninvasive, biophysical therapeutic interventions as the focus of current biomedical research. Red and near-infrared light-induced photobiomodulation therapy appears to emerge as a promising drug-free approach for promoting wound healing, reduction in inflammation, pain and restoration of function owing to penetration power in conjunction with their ability to positively modulate the biochemical and molecular responses. This review will describe the physical properties of red and near-infrared light and their interaction with skin and highlight their efficacy of wound repair and regeneration. Near-infrared (800-830 nm) was found to be the most effective and widely studied wavelength range followed by red (630-680 nm) and 904 nm superpulsed light exhibiting beneficial photobiomodulatory effects on impaired dermal wound healing.


A brief self-administered psychological intervention to improve well-being in patients with cancer: results from a feasibility study.
Patients with cancer have relatively high rates of anxiety and distress, adversely affecting their well-being and quality of life. Recent studies indicate that addressing these symptoms could result in better response to cancer treatment. Researchers have found that interventions that focus on increasing mental awareness and the frequency of positive experiences may have a greater impact on reducing psychological morbidity and increasing quality of life than interventions that target relief of psychological symptoms. To develop and test a brief, easy to use intervention that could improve well-being and quality of life in cancer patients. We developed a simple well-being intervention that made few demands on patient time and required little training resource. Participants were randomly assigned to an intervention group or a deferred entry group. Measures of anxiety, depression, well-being and quality of life were administered at baseline and at follow-ups. Twenty-two women with metastatic breast cancer and 24 men with metastatic prostate cancer were recruited from oncology clinics. Thirteen women and 14 men completed the study. Both qualitative and quantitative data showed that the intervention was acceptable to users. There was statistically significant improvement in quality of life scores on WHOQOL-BREF post-intervention (p=0.046). Compliance with the intervention was good. This brief well-being intervention appears to be a promising technique for improving quality of life of cancer patients, without making undue demands on staff resources or patient time. If further studies confirm its effectiveness, it could prove to be a cost-effective intervention.


Evaluation of hyaluronidase activity in equine and bovine sera and equine synovial fluid samples by use of enzyme zymography.
To investigate the activities of hyaluronidases in equine sera and synovial fluid samples and sera from fetal and adult bovids and evaluate the extent to which the degradation of hyaluronan is influenced by chondrocytes. Commercial and noncommercial samples of equine (n = 6) and bovine (6) sera and 16 synovial fluid samples from horses. Hyaluronidase activities in sera and synovial fluid samples were assessed via enzyme zymography (performed at pH 4, 5, 6, or 7). Chondrocytes were isolated from equine cartilage and cultured with or without hyaluronan (1 mg/mL); the degradation of hyaluronan was assessed via agarose gel electrophoresis. [corrected] Hyaluronidase activity was detected in equine sera and synovial fluid samples at pH 4, but not at pH 7, and in bovine sera at both pH values. In all samples at pH 4, a major band of activity (molecular weight, approx 60 kd) and some additional higher molecular weight bands were detected; high- and low-molecular-weight activities were detected in bovine sera at pH 7 Hyaluronan in tissue culture medium with or without fetal calf serum was degraded in the presence, but not the absence, of equine chondrocytes. Hyaluronidase activity was detected in equine sera and synovial fluid at pH 4 and in bovine sera at pH 4 and 7. Primary chondrocytes in monolayer culture can degrade exogenous hyaluronan. Modulating native hyaluronidase activity may offer a new approach to improve the quantity and quality of hyaluronan in articular joints.


Relay of visual information to the lateral geniculate nucleus and the visual cortex in albino ferrets.
The abnormal organization of the central visual pathways in the albino ferret has been characterized anatomically and physiologically. Recordings in dorsal lateral geniculate nucleus of the albino ferret show that lamina A1, which receives an aberrant projection from the contralateral eye, contains an extensive representation of the ipsilateral visual hemifield with receptive fields located up to 35 degrees from the vertical meridian. This is not the case in pigmented ferrets, for which the vast majority of units, activated through either the contralateral or ipsilateral eye, have receptive fields confined to the contralateral hemifield. The few fields found in the ipsilateral hemifield are driven through the contralateral eye and none is more than 10 degrees from the midline. Cortical topography was studied by making closely spaced electrode penetrations across the area 17/18 border. In pigmented animals, the reversal of topography at the border is characterized by units with receptive fields centered a few degrees into the ipsilateral hemifield. In 22 of 25 albinos, the "Boston" aberrant topography was found: the representation of the vertical meridian is within area 17, rather than at the area 17/18 border. Instead, at the area 17/18 border, there is a reversal in the topographic progression at up to 30 degrees into the ipsilateral hemifield. This pattern was most pronounced in the upper visual field. In agreement with the "Boston" physiology, injections of retrograde tracer made in area 17 usually label neurons in either lamina A or the part of lamina A1 that is aberrantly innervated by the contralateral eye. A column of labeled cells extending through all geniculate layers is rarely seen in albinos, although this is commonly the pattern in pigmented ferrets.


The epidemiology of multidrug-resistant organisms in persons diagnosed with cancer in Norway, 2008-2018: expanding surveillance using existing laboratory and register data.
Surveillance has revealed an increase of multidrug-resistant organisms (MDROs), even in low-prevalent settings such as Norway. MDROs pose a particular threat to at-risk populations, including persons with cancer. It is necessary to include such populations in future infection surveillance. By combining existing data sources, we aimed to describe the epidemiology of MDROs in persons diagnosed with cancer in Norway from 2008 to 2018. A cohort was established using data from the Cancer Registry of Norway, which was then linked to notifications of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin- and/or linezolid-resistant enterococci (V/LRE), and carbapenemase-producing Gram-negative bacilli (CP-GNB) from the Norwegian Surveillance System for Communicable Diseases, and laboratory data on third-generation cephalosporin-resistant Enterobacterales (3GCR-E) from Oslo University Hospital (OUH). We described the incidence of MDROs and resistance proportion in Enterobacterales from 6 months prior to the person's first cancer diagnosis and up to 3 years after. The cohort included 322,005 persons, of which 0.3% (878) were diagnosed with notifiable MDROs. Peak incidence rates per 100,000 person-years were 60.9 for MRSA, 97.2 for V/LRE, and 6.8 for CP-GNB. The proportion of 3GCR-E in Enterobacterales in blood or urine cultures at OUH was 6% (746/12,534). Despite overall low MDRO incidence, there was an unfavourable trend in the incidence and resistance proportion of Gram-negative bacteria. To address this, there is a need for effective infection control and surveillance. Our study demonstrated the feasibility of expanding the surveillance of MDROs and at-risk populations through the linkage of existing laboratory and register data.


Using Hexoskin Wearable Technology to Obtain Body Metrics During Trail Hiking.
Use of wearable technology to obtain various body metrics appears to be a trending phenomenon. However there is very little literature supporting the notion that these apparatuses can be used for research purposes in the field. The purpose of this study was to utilize Hexoskin wearable technology shirts (HxS) to obtain data in a pilot study using a trail hiking situation. Ten individuals (male, n = 4, female n = 6) volunteered to participate. On the first day, volunteers completed two approximately flat trail hikes at a self-preferred pace with a 15-minute rest between trials. On the second day, participants completed a strenuous uphill hike (17.6% grade) with a 15-minute rest at the summit and then completed the downhill portion. Body metrics provided by the HxS were average heart rate (HR), maximal HR (MHR), total energy expenditure (EE), average respiratory rate (RR), maximal respiratory rate (MRR), total steps (SC), and cadence (CA). Other measurements obtained were systolic and diastolic blood pressure (SBP, DBP), and ratings of perceived exertion (RPE). Data were analyzed using both one-way repeated measures analysis of variance (ANOVA) with significance accepted at p≤0.05 and intraclass correlation coefficients (ICC) for each variable. Both were determined using Statistical Package for the Social Sciences software (SPSS). No significant differences for trail type were noted for MHR (p=0.38), RR (p=0.45) or MRR (p=0.31). The uphill trail elicited significantly elevated HR (up=154±24 bpm, easy=118±11 bpm, down=129±19 bpm; p=0.04) and EE (up=251±78 kcal, easy=124±38 kcal, down=171±52 kcal; p=0.02). Significant ICC were observed for DBP (r = 0.80, p = 0.02), RR (r = 0.98, p = 0.01), SC (r = 0.97, p = 0.01) and RPE (r = 0.94, p = 0.01). Non-significant correlation were noted for uphill RR vs CA (r=0.51, p=0.16) or RPE vs SBP (r=0.03, p=0.94), HR (r=0.60, p=0.12), and MHR (r=0.70, p=0.051). We utilized HxS to provide physiological data in an applied setting. It should be noted that HR did not register in 5 out of 10 subjects on the easy trail, and 8 of 10 participants during the uphill hike. Additionally, estimated EE appears to be linked to HR intensity. Future investigations taken in an outdoor environment should take these findings into consideration.


Merkel Cell Polyomavirus Small T Antigen Activates Noncanonical NF-κB Signaling to Promote Tumorigenesis.
Multiple human polyomaviruses (HPyV) can infect the skin, but only Merkel cell polyomavirus (MCPyV) has been implicated in the development of a cancer, Merkel cell carcinoma (MCC). While expression of HPyV6, HPyV7, and MCPyV small T antigens (sT), all induced a senescence-associated secretory phenotype (SASP), MCPyV sT uniquely activated noncanonical NF-κB (ncNF-κB), instead of canonical NF-κB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-κB signaling both by inducing H3K4 trimethylation-mediated increases of NFKB2 and RELB transcription and also by promoting NFKB2 stabilization and activation through FBXW7 inhibition. Noncanonical NF-κB signaling was required for SASP cytokine secretion, which promoted the proliferation of MCPyV sT-expressing cells through autocrine signaling. Virus-positive MCC cell lines and tumors showed ncNF-κB pathway activation and SASP gene expression, and the inhibition of ncNF-κB signaling prevented VP-MCC cell growth in vitro and in xenografts. We identify MCPyV sT-induced ncNF-κB signaling as an essential tumorigenic pathway in MCC. IMPLICATIONS: This work is the first to identify the activation of ncNF-κB signaling by any polyomavirus and its critical role in MCC tumorigenesis.


Ambient air quality and exposure assessment study of the Gulf Cooperation Council countries: A critical review.
With rapid urbanization and economic growth, many developing countries have faced a greater share of air pollutants in recent years. An increasing number of exposure studies on air pollutants have been reported lately. However, due to lack of strict regulations and monitoring stations among developing countries, such as Gulf Cooperation Council (GCC) countries, limited air pollution and exposure assessment studies have been conducted in this region. Thus, the objective of this critical review was to identify the major sources of air pollutants in the region with hot and arid/semiarid climate for the main categories contributing to specific pollutants. Finally, a summary of the limitations and knowledge gaps were discussed. Additionally, the current available regulations, emission inventories and source apportionment studies in this region were discussed. In this study, the concentration levels of carbon dioxide (CO2), carbon monoxide (CO), particulate matter (PM), metal elements, nitrogen oxides (NOx), ozone (O3), sulfur dioxide (SO2), volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs), and persistent organic pollutants (POPs) were reviewed. Due to lack of scientific studies, various databases and indexed journals from early 2000 (sometimes prior that time) were considered. The review findings clearly indicated that the sand, dust (natural and anthropogenic, such as cement, metal, stone cutting industries), chemical industries (refinery, petrochemical, etc.) and transportation activities were the major contributors to the overall air pollution in the GCC countries. Besides, the study recommended that the difference between anthropogenic pollution and natural events in dust formation should be explored extensively. Furthermore, possible suggestions for future researches in the region were proposed.


Asbestos fiber identification in liver from cholangiocarcinoma patients living in an asbestos polluted area: a preliminary study.
To assess whether asbestos fibers may be observed in liver tissue of patients with cholangiocarcinoma (CC) with environmental or working asbestos exposure. Detection of fibers was performed directly on histologic sections of liver from 7 patients with CC using optical microscope and variable pressure scanning electron microscopy equipped with energy-dispersive spectroscopy (VP-SEM/EDS). All patients were from Casale Monferrato, Italy, a highly asbestos-polluted town. Due to ethical constraints, observers were blinded to patients' clinical features. Fibers/bundles of fibers of chrysotile were detected in 5 out of 7 patients (71%). The boundary between healthy and neoplastic tissue or the fibrocollagen tissue produced by the neoplasia were identified as areas of fiber incorporation. This study is the first report about the detection of chrysotile asbestos fibers in the liver of patients with CC. Further studies on larger cohorts are needed to corroborate our preliminary findings.


Combined effects of leukocyte telomere length, p53 polymorphism and human papillomavirus infection on esophageal squamous cell carcinoma in a Han Chinese population.
Telomere shortening has been suggested to be a genetic predictor for various cancers. However, evidences about this point with respect to esophageal squamous cell carcinoma (ESCC) in Han Chinese populations remain limited. Our previous study demonstrated that p53 Arg72Pro polymorphism was associated with the risk of human papillomavirus (HPV)-related ESCC. Telomeres and p53 play important roles in maintaining genomic stability and regulating the cell cycle. HPV impacts both telomere length stabilization and p53 degradation. Given the roles of the three factors, we evaluated leukocyte telomere length, p53 variants and HPV-16 serology to examine the potential associations between them and ESCC risk in a case-control study with 308 patients and 309 cancer-free controls matched by age and sex. Compared with long telomere length, short telomere length was significantly associated with an increased risk of ESCC (adjusted OR 2.01; 95% CI 1.41-2.80). Moreover, this association was enhanced when combined with HPV-16 seropositivity and p53 Arg/Arg or Arg/Pro genotypes. Notably, individuals with short telomere length, Arg/Pro or Arg/Arg genotypes and HPV-16 seropositivity had a 12.08-fold (95% CI 5.49-26.56) increased risk of ESCC compared to those with none of the three investigated risk factors. Taken together, these results indicate that short telomere length in peripheral blood leukocytes is a biomarker for ESCC risk, and has statistically additive effects with p53 variants and HPV seropositivity with regard to the risk of ESCC in a Han Chinese population.


Pre- and postnatal development of GABA receptors in Macaca monkey visual cortex.
GABA is a putative inhibitory neurotransmitter in adult mammalian visual cortex but also has been implicated as playing a crucial role in cortical information processing during development. In order to understand better the role of GABA during primate visual cortex development, we have examined the time course of GABAA and GABAB receptor ontogenesis in 18 Macaca nemestrina monkeys ranging from fetal day 61 (F61d) to adulthood. The GABA and benzodiazepine binding sites of the GABAA receptor were detected by 3H-muscimol (3H-MS) and 3H-flunitrazepam (3H-FZ), respectively. GABAB receptors were detected by 3H-baclofen (3H-BA). All ligands were visualized by in vitro autoradiography. Quantitative analysis of film density was done to compare laminar changes during pre- and postnatal development. Saturation binding experiments were done for MS and FZ binding sites to determine receptor number (Bmax) and affinity (Kd) at selected pre- and postnatal ages. Both MS and FZ binding sites were present at F61d-72d throughout the cortical plate and marginal zone. FZ binding sites were more dense than MS binding sites over the cortical plate at young ages and were especially dense over the marginal zone. FZ binding sites also were present in lesser amounts over the subplate and intermediate zone, but not over the subventricular zone. By F119d-126d, layer 4 could be distinguished by its higher density for both ligands. The basic adult laminar pattern was established for both MS and BZ binding sites by birth (birth = F165d-170d). After birth, MS density increases dramatically in all layers, but layer 4C remains most dense to adulthood. FZ labeling is heavy in both layers 4 and 3 at birth but after 4 weeks after birth (P4 wk) it declines somewhat in the supragranular layers so that layer 4C now predominates. Labeling in layers 5/6 virtually disappears after birth. BA binding sites were present at F126d, at which time layer 4 was slightly lighter than the remainder of striate cortex; this laminar pattern remained basically the same throughout our series to adulthood. Competitive binding of agonist and antagonists for the GABAA receptor showed that MS binding characteristics were similar at F126d and P8.5 years (yr). MS binding site Bmax was about 8% of adult values at F72d, 24% by F126d, and 56% at F152d. Bmax then rose rapidly after birth to peak at P18wk at 169% of adult values, and then declined to P1yr. A second peak of 143% was found around P3.5yr, with adult values reached by P8.5yr.(ABSTRACT TRUNCATED AT 400 WORDS)


Motor unit estimations in small muscles of the hand.
A quantal method has been employed to determine the numbers of functioning motor units in small muscles of the hand. In healthy subjects below the age of 60 years the mean number of hypothenar motor units was 380 ± 79 and the mean number of thenar units innervated by the median nerve was 340 ± 87. In older subjects there was a progressive reduction in the numbers of functioning units in both muscle groups; in some of these subjects the population of motor units in the extensor digitorum brevis was also estimated for comparison. A study was also performed on patients diagnosed as having generalized denervating diseases or with lesions of peripheral nerves and cervical roots; in every instance the number of functioning motor units was markedly reduced.


Automatic treatment plan re-optimization for adaptive radiotherapy guided with the initial plan DVHs.
Adaptive radiation therapy (ART) can reduce normal tissue toxicity and/or improve tumor control through treatment adaptations based on the current patient anatomy. Developing an efficient and effective re-planning algorithm is an important step toward the clinical realization of ART. For the re-planning process, manual trial-and-error approach to fine-tune planning parameters is time-consuming and is usually considered unpractical, especially for online ART. It is desirable to automate this step to yield a plan of acceptable quality with minimal interventions. In ART, prior information in the original plan is available, such as dose-volume histogram (DVH), which can be employed to facilitate the automatic re-planning process. The goal of this work is to develop an automatic re-planning algorithm to generate a plan with similar, or possibly better, DVH curves compared with the clinically delivered original plan. Specifically, our algorithm iterates the following two loops. An inner loop is the traditional fluence map optimization, in which we optimize a quadratic objective function penalizing the deviation of the dose received by each voxel from its prescribed or threshold dose with a set of fixed voxel weighting factors. In outer loop, the voxel weighting factors in the objective function are adjusted according to the deviation of the current DVH curves from those in the original plan. The process is repeated until the DVH curves are acceptable or maximum iteration step is reached. The whole algorithm is implemented on GPU for high efficiency. The feasibility of our algorithm has been demonstrated with three head-and-neck cancer IMRT cases, each having an initial planning CT scan and another treatment CT scan acquired in the middle of treatment course. Compared with the DVH curves in the original plan, the DVH curves in the resulting plan using our algorithm with 30 iterations are better for almost all structures. The re-optimization process takes about 30 s using our in-house optimization engine.


Randomized Phase III Study of Lenalidomide Versus Placebo in RBC Transfusion-Dependent Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes and Ineligible for or Refractory to Erythropoiesis-Stimulating Agents.
This international phase III, randomized, placebo-controlled, double-blind study assessed the efficacy and safety of lenalidomide in RBC transfusion-dependent patients with International Prognostic Scoring System lower-risk non-del(5q) myelodysplastic syndromes ineligible for or refractory to erythropoiesis-stimulating agents. In total, 239 patients were randomly assigned (2:1) to treatment with lenalidomide (n = 160) or placebo (n = 79) once per day (on 28-day cycles). The primary end point was the rate of RBC transfusion independence (TI) ≥ 8 weeks. Secondary end points were RBC-TI ≥ 24 weeks, duration of RBC-TI, erythroid response, health-related quality of life (HRQoL), and safety. RBC-TI ≥ 8 weeks was achieved in 26.9% and 2.5% of patients in the lenalidomide and placebo groups, respectively (P < .001). Ninety percent of patients achieving RBC-TI responded within 16 weeks of treatment. Median duration of RBC-TI with lenalidomide was 30.9 weeks (95% CI, 20.7 to 59.1). Transfusion reduction of ≥ 4 units packed RBCs, on the basis of a 112-day assessment, was 21.8% in the lenalidomide group and 0% in the placebo group. Higher response rates were observed in patients with lower baseline endogenous erythropoietin ≤ 500 mU/mL (34.0% v 15.5% for > 500 mU/mL). At week 12, mean changes in HRQoL scores from baseline did not differ significantly between treatment groups, which suggests that lenalidomide did not adversely affect HRQoL. Achievement of RBC-TI ≥ 8 weeks was associated with significant improvements in HRQoL (P < .01). The most common treatment-emergent adverse events were neutropenia and thrombocytopenia. Lenalidomide yields sustained RBC-TI in 26.9% of RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes ineligible for or refractory to erythropoiesis-stimulating agents. Response to lenalidomide was associated with improved HRQoL. Treatment-emergent adverse event data were consistent with the known safety profile of lenalidomide.


The effect of oral antidiabetic agents on A1C levels: a systematic review and meta-analysis.
Previous reviews of the effect of oral antidiabetic (OAD) agents on A1C levels summarized studies with varying designs and methodological approaches. Using predetermined methodological criteria, we evaluated the effect of OAD agents on A1C levels. The Excerpta Medica (EMBASE), the Medical Literature Analysis and Retrieval System Online (MEDLINE), and the Cochrane Central Register of Controlled Trials databases were searched from 1980 through May 2008. Reference lists from systematic reviews, meta-analyses, and clinical practice guidelines were also reviewed. Two evaluators independently selected and reviewed eligible studies. A total of 61 trials reporting 103 comparisons met the selection criteria, which included 26,367 study participants, 15,760 randomized to an intervention drug(s), and 10,607 randomized to placebo. Most OAD agents lowered A1C levels by 0.5-1.25%, whereas thiazolidinediones and sulfonylureas lowered A1C levels by approximately 1.0-1.25%. By meta-regression, a 1% higher baseline A1C level predicted a 0.5 (95% CI 0.1-0.9) greater reduction in A1C levels after 6 months of OAD agent therapy. No clear effect of diabetes duration on the change in A1C with therapy was noted. The benefit of initiating an OAD agent is most apparent within the first 4 to 6 months, with A1C levels unlikely to fall more than 1.5% on average. Pretreated A1C levels have a modest effect on the fall of A1C levels in response to treatment.


Evidence of the adaptive evolution of immune genes in chicken.
The basis for understanding the characteristics of gene functional categories in chicken has been enhanced by the ongoing sequencing of the zebra finch genome, the second bird species to be extensively sequenced. This sequence provides an avian context for examining how variation in chicken has evolved since its divergence from its common ancestor with zebra finch as well as well as a calibrating point for studying intraspecific diversity within chicken. Immune genes have been subject to many selective processes during their evolutionary history: this gene class was investigated here in a set of orthologous chicken and zebra finch genes with functions assigned from the human ortholog. Tests demonstrated that nonsynonymous sites at immune genes were highly conserved both in chicken and on the avian lineage. McDonald-Kreitman tests provided evidence of adaptive evolution and a higher rate of selection on fixation of nonsynonymous substitutions at immune genes compared to that at non-immune genes. Further analyses showed that GC content was much higher in chicken than in zebra finch genes, and was significantly elevated in both species' immune genes. Pathogen challenges are likely to have driven the selective forces that have shaped variation at chicken immune genes, and continue to restrict diversity in this functional class.


Apple polyphenol relieves hypoxia-induced pulmonary arterial hypertension via pulmonary endothelium protection and smooth muscle relaxation: In vivo and in vitro studies.
This study aims to test the effect of apple polyphenol (APP) on hypoxia-induced pulmonary arterial hypertension (PAH) and explore its possible underlying mechanisms. Rats were treated with control, APP, hypoxia (8 h/d), hypoxia + APP. Mean pulmonary arterial pressure (mPAP) and pulmonary vessel resistance (PVR) were examined. Phenylephrine (PE)-pretreated pulmonary vessel rings were prepared for observation of APP administration. eNOS, sGC inhibitors (L-NAME, MB), Ca2+ channel blockers (NiCl2, Calhex231), K+ channel blockers (4-AP, 5-HD, TEA, BaCl2) were applied to pulmonary vessel rings and pulmonary arterial smooth muscle cell (PASMC). Flow cytometry analysis and CCK-8 assay were applied to detect apoptosis of pulmonary artery endothelium cell (PAEC). Caspase-3, NO, eNOS, iNOS were detected in PAEC. APP reversed mPAP and PVR elevation in vivo. Contraction of pulmonary vessel rings with/without endothelium induced by hypoxia were inhibited by APP. APP effect was hindered by L-NAME or MB, and could be reduced by K+channel blockers. Further, APP was found to decrease cytosolic Ca2+ in PASMC and protect PAEC from apoptosis. In PAEC, Caspase-3, iNOS were decreased and NO, eNOS were increased after APP administration. APP reverses pulmonary vasoconstriction through enzyme expression and cation channel activities, thus has effects of PASMC relaxation and PAEC protection.


Survival of liver failure pigs by transplantation of reversibly immortalized human hepatocytes with Tamoxifen-mediated self-recombination.
Hepatocyte transplantation and bioartificial liver treatment are attractive alternatives to liver transplantation. The availability of well-characterized human hepatocyte lines facilitates such cell therapies. Human hepatocytes were immortalized with a retroviral vector SSR#197 expressing catalytic subunit of human telomerase reverse transcriptase (hTERT) and enhanced green fluorescent protein (EGFP) cDNAs flanked by a pair of loxP recombination targets. Then, Tamoxifen-dependent Cre recombinase was expressed in SSR#197-immortalized hepatocytes. Cre/LoxP recombination was performed in the established cells by simple exposure to 500 nM Tamoxifen for a week. Then, the reverted population of the cells was recovered by EGFP-negative cell sorting and characterized in vitro and in vivo using a pig model of acute liver failure (ALF) induced by d-galactosamine (0.5 g/kg) injection. A human hepatocyte cell line 16T-3 was established. Reverted 16-T3 cells showed the increased expression of hepatic markers in association with enhanced levels of transcriptional factors. Compared to normal human hepatocytes, albumin production and lidocaine-metabolizing activities of reverted 16-T3 cells were 0.32 and 0.50-fold, respectively. Transplantation of reverted 16T-3 cells significantly prolonged the survival of ALF pigs. Here we demonstrate the usefulness of Cre/LoxP -mediated reversible immortalization of human hepatocytes with Tamoxifen-mediated self-recombination.


Does kV-MV dual-energy computed tomography have an advantage in determining proton stopping power ratios in patients?
Conventional kilovoltage (kV) x-ray-based dual-energy CT (DECT) imaging using two different x-ray energy spectra is sensitive to image noise and beam hardening effects. The purpose of this study was to evaluate the theoretical advantage of the DECT method for determining proton stopping power ratios (SPRs) using a combination of kV and megavoltage (MV) x-ray energies. We investigated three representative x-ray energy pairs: 100 and 140 kVp comprised the kV-kV pair, 100 kVp and 1 MV comprised the kV-MV pair, and two 1 MV x-ray beams-one with and one without external filtration-comprised the MV-MV pair. The SPRs of 34 human tissues were determined using the DECT method with these three x-ray energy pairs. Small perturbations were introduced into the CT numbers and x-ray spectra used for the DECT calculation to simulate the effects of random noise and beam hardening. An error propagation analysis was performed on the DECT calculation algorithm to investigate the propagation of CT number uncertainty to final SPR estimation and to suggest the best x-ray energy combination. We found that the DECT method using each of the three beam pairs achieved similar accuracy in determining the SPRs of human tissues in ideal conditions. However, when CT number uncertainties and artifacts such as imaging noise and beam hardening effects were considered, the kV-MV DECT improved the accuracy of SPR estimation substantially over the kV-kV or MV-MV DECT methods. Furthermore, our error propagation analysis showed that the combination of 100 kVp and 1 MV beams was close to the optimal selection when using the DECT method to determine SPRs. Overall, the kV-MV combination makes the DECT method more robust in resolving the effective atomic numbers for biological tissues than the traditional kV-kV DECT method.


Induction and abrogation of unresponsiveness in nude mouse cells.
Nude mice were injected with antigen and T cells at different times to induce unresponsiveness to SRBC. Spleen cells derived from these mice were tested in vitro for the capability to produce antibody-forming cells against sheep erythrocytes in the presence of a T-cell-replacing factor. It was found that priming with antigen alone did not result in paralysis but a later injection of thymus-derived lymphocytes together with antigen results in unresponsiveness of these cells in vitro, provided there was an interval of several days between the in vivo administration of thymus lymphocytes and the explantations of cells to in vitro cultures.


Valuation of plug-in vehicle life-cycle air emissions and oil displacement benefits.
We assess the economic value of life-cycle air emissions and oil consumption from conventional vehicles, hybrid-electric vehicles (HEVs), plug-in hybrid-electric vehicles (PHEVs), and battery electric vehicles in the US. We find that plug-in vehicles may reduce or increase externality costs relative to grid-independent HEVs, depending largely on greenhouse gas and SO(2) emissions produced during vehicle charging and battery manufacturing. However, even if future marginal damages from emissions of battery and electricity production drop dramatically, the damage reduction potential of plug-in vehicles remains small compared to ownership cost. As such, to offer a socially efficient approach to emissions and oil consumption reduction, lifetime cost of plug-in vehicles must be competitive with HEVs. Current subsidies intended to encourage sales of plug-in vehicles with large capacity battery packs exceed our externality estimates considerably, and taxes that optimally correct for externality damages would not close the gap in ownership cost. In contrast, HEVs and PHEVs with small battery packs reduce externality damages at low (or no) additional cost over their lifetime. Although large battery packs allow vehicles to travel longer distances using electricity instead of gasoline, large packs are more expensive, heavier, and more emissions intensive to produce, with lower utilization factors, greater charging infrastructure requirements, and life-cycle implications that are more sensitive to uncertain, time-sensitive, and location-specific factors. To reduce air emission and oil dependency impacts from passenger vehicles, strategies to promote adoption of HEVs and PHEVs with small battery packs offer more social benefits per dollar spent.


Participative mental health consumer research for improving physical health care: An integrative review.
People with mental illness have a significantly lower life expectancy and higher rates of chronic physical illnesses than the general population. Health care system reform to improve access and quality is greatly needed to address this inequity. The inclusion of consumers of mental health services as co-investigators in research is likely to enhance service reform. In light of this, the current paper reviews mental health consumer focussed research conducted to date, addressing the neglect of physical health in mental health care and initiatives with the aim of improving physical health care. The international literature on physical healthcare in the context of mental health services was searched for articles, including mental health consumers in research roles, via Medline, CINAHL and Google Scholar, in October 2015. Four studies where mental health consumers participated as researchers were identified. Three studies involved qualitative research on barriers and facilitators to physical health care access, and a fourth study on developing technologies for more effective communication between GPs and patients. This review found that participatory mental health consumer research in physical health care reform has only become visible in the academic literature in 2015. Heightened consideration of mental health consumer participation in research is required by health care providers and researchers. Mental health nurses can provide leadership in increasing mental health consumer research on integrated care directed towards reducing the health gap between people with and without mental illness.


Efficient computation of minimal perturbation sets in gene regulatory networks.
In the last few decades, technological and experimental advancements have enabled a more precise understanding of the mode of action of drugs with respect to human cell signaling pathways and have positively influenced the design of new drug compounds. However, as the design of compounds has become increasingly target-specific, the overall effects of a drug on adjacent cellular signaling pathways remain difficult to predict because of the complexity of the interactions involved. Off-target effects of drugs are known to influence their efficacy and safety. Similarly, drugs which are more target-specific also suffer from lack of efficacy because their scope might be too limited in the context of cellular signaling. Even in situations where the signaling pathways targeted by a drug are known, the presence of point mutations in some of the components of the pathways can render a therapy ineffective in a considerable target subpopulation. Some of these issues can be addressed by predicting Minimal Intervention Sets (MIS) of elements of the signaling pathways that when perturbed give rise to a pre-defined cellular phenotype. These minimal gene perturbation sets can then be further used to screen a library of drug compounds in order to discover effective drug therapies. This manuscript describes algorithms that can be used to discover MIS in a gene regulatory network that can lead to a defined cellular phenotype. Algorithms are implemented in our Boolean modeling toolbox, GenYsis. The software binaries of GenYsis are available for download from http://www.vital-it.ch/software/genYsis/.